As this year we are celebrating the 200th anniversary of the birth of Louis Pasteur (www.pasteur2022.com), microbiologists probably wonder what was the state of knowledge about the subject of their studies during times of Pasteur. This question also arose in my mind, namely, what was known about the fungi of the genus Cryptococcus in Louis Pasteur days? Long before the role of bacteria as the etiological agents of diseases was described [104] and before the germ theory of diseases was announced by Louis Pasteur [102, 103, 105], the pathogenicity of fungi was noticed [117]. Just during this period, before Pasteur disproved the theory of spontaneous generation [103], and long before the definition of „infection” was formulated, Robert Remak made a significant discovery in 1837 demonstrating the presence of fungal hyphae in yellow cup-shaped crusts (scutula). Indeed the description of Trichophyton schöenleinii (then known as Achorion schöenleinii) initiated the development of modern medical mycology [117] and, most importantly, gave rise to the perception of microscopic fungi, and thus other microorganisms, as potential etiological agents of infectious diseases. It wasn’t long before other etiological agents of infectious diseases were discovered. Soon after the discovery of Remak, in 1843, David Gruby, working in Paris, proved that Microsporum audouinii is the etiological agent of tinea microsporica [1]. In turn, in 1848 the Swedish microbiologist Pehr Henrik Malmsten isolated and described Trichophyton tonsurans as an etiological agent of tinea trichophytica [1], which was an extraordinary achievement in the pre-Pasteur period.
History of research on Cryptococcus and cryptococcosis
Slightly before the original descriptions of dermatophyte species appeared, the genus Cryptococcus was established and first described in 1833 by Kützing, who isolated this microorganism as saprophytic from a dirty window [74]. According to his assumption and later suggestions of Benham [6] and Vuillemin [133], this genus was to gather yeast-like fungi that did not produce hyphae, are not capable of undergoing ascospore formation and showing inability to ferment carbon sources. A year before Louis Pasteur’s death and 10 years after announcing the Koch’s postulates [1, 5], Cryptococcus neoformans was discovered as an etiological agent of cryptococcosis, a disease entity, which in many parts of the world more often leads to death in the group of HIV/AIDS patients than tuberculosis [101]. This yeast-like fungus was first isolated in 1894 by Busse [14, 15] and Buschke [13], from sarcoma-like lesion of the tibia from a 31-year-old woman and skin eruptions of the patient suspected of coccidioidomycosis, respectively. While it remains unclear whether these two scientists were aware of Koch’s postulates and Pasteur’s discoveries, it is apparent that Koch’s postulates and Pasteur’s assumptions were fully met by both researchers. Importantly, Busse and Buschke isolated the same etiological agent from the examined lesions, ultimately obtaining pure cultures of C. neoformans. It can be easily noticed that Koch's postulates and Pasteur’s assumptions were fully met by both researchers. In the same year Francesco Sanfelice isolated mentioned fungus as saprophytic microorganism from peach juice in Italy incorrectly classifying it as Saccharomyces neoformans, but species epithet „neoformans” is accepted till these days [115]. Later, in 1896 Sanfelice for the second time isolated this fungus from lymph node of a cattle indicating on its pathogenic nature [116]. All these findings did not escape the attention of Vuillemin, who transferred both Cryptococcus hominis and S. neoformans, respectively described by Busse and Sanfelice, to the genus Cryptococcus, which comprises significantly different species than members of the Saccharomyces genus – fermenting yeasts [133]. The first discoveries by Busse and Buschke and the later Sanfelice and Frothingham [41] allowed to establish that C. neoformans causes infection in both humans and animals. As it is currently known C. neoformans is not the only etiological agent of cryptococcosis. A year after descriptions of cryptococcosis by Busse and Buschke, Ferdinand Curtis postulated that Cryptococcus gattii, described then by him as Saccharomyces subcutaneous tumefaciens may also be an etiological agent of this disease entity [24]. The first cases of cryptococcal meningitis, caused respectively by C. neoformans and C. gattii, were noticed in 1914 by Verse in a dead woman [129] and in 1970 by Gatti and Eeckels in a 7-year-old leukemic child in Republic of Congo [45]. The significant progress in immunology in the 20th century and the availability of new serological techniques allowed Evans in 1949 to distinguish 3 different serotypes in the pool of pathogenic strains of Cryptococcus spp., which were isolated from humans [35]. Nearly 20 years later, Ralph Vogel added serotype D to previously described by Evans serotypes A, B and C. The new serotype introduced by Vogel was detected by using the indirect fluorescent antibody test (IFA) [132]. A growing awareness among clinicians and the availability of new diagnostic tools led to an increase of the new strains of Cryptococcus spp. isolated from sick people and animals. In the second half of the twentieth century, the name C. neoformans had 40 synonyms [112] and only in 1989 Jack W. Fell proposed conserving the genus name as Cryptococcus Vuillemin [37]. Still in 2010, in the pages of the 5th edition of the extensive monograph “The yeasts: a taxonomic study” [38], the genus Cryptococcus included 70 species of both pathogenic and nonpathogenic yeasts. In the clinical and practical context, the classification of strains isolated from humans and animals, based on determination of their serotype, was particularly important. Since the discovery of the teleomorphs Filobasidiella neoformans and F. bacillispora [64,65,66], serotypes A and D as well as B and C have been assigned to them, respectively [67, 71]. According to the newest nomenclature modifications and the recommendations established during the XVIII International Botanical Congress, (Melbourne, July 18–22, 2011) the species names of basidiomycetous yeasts have also undergone changes [55, 56]. In case of F. bacillispora, the initial change was to C. bacillisporus, then to C. neoformans var. gattii, and finally to C. gattii [68]. In turn, F. neoformans was changed to C. neoformans, for which two varieties came to be distinguished, namely C. neoformans var. neoformans (representing serotype D) and C. neoformans var. grubii (representing serotype A) [39]. Only strains representing serotype D were classified in the first varietas, and isolates of serotype A in the second [39]. The presence of four distinct serotypes (A, B, C, D) was also confirmed by Wilson in 1968 [135], who showed significant differences on the level of antigens present in polysaccharide capsule. Currently, based on advanced phylogenetic analyzes and studies at the level of genotypes and phenotypes, the Cryptococcus species complex includes seven haploid and four hybrid species [54]. Thus, there are currently two acceptable species within the Cryptococcus neoformans species complex: C. neoformans (serotype A) and C. deneoformans (serotype D). Strains that are hybrids of serotypes A and D – Cryptococcus neoformans × Cryptococcus deneoformans were also isolated from the natural environment. In turn, additional molecular characteristics of the strains currently included in the Cryptococcus gattii species complex revealed the existence of five separate species: C. gattii, C. deuterogattii, C. decagattii (all represent serotype B), C. bacillisporus and C. tetragattii (represent serotype C). The existence of three interspecific hybrids has also been demonstrated: Cryptococcus neoformans × Cryptococcus gattii (AB serotype), Cryptococcus neoformans × Cryptococcus deuterogattii (AB serotype) and Cryptococcus deneoformans × Cryptococcus gattii (DB serotype) [54]. All the mentioned species were isolated several times as aetiological agents of different disease entities in humans and animals. The nomenclature adopted in 2015 was the result of earlier efforts to systematize the naming of these pathogenic species. Earlier attempts to organize the terminology were based on the Amplified Fragment Length Polymorphism, AFLP [8]. There have also been attempts to introduce genotype nomenclature based on the Restriction Fragment Length Polymorphism, RFLP [84]. Both of these approaches provided a solid base to propose new solution by Hagen et al. [54]. Phylogenetic analyzes carried out in recent years shed new light on the proposed new systematics of the genus Cryptococcus. Based on four genes, namely LAC, URA5, mtLrRNA and ITS, it was estimated that the C. neoformans species complex split from the C. gattii species complex about 37 million years ago, and C. neoformans and C. deneoformans species evolved from a common ancestor approximately 18.5 million years ago. In turn, C. gattii and C. bacillisporus differentiated into separate species about 9.5 million years ago [138]. Recent calculations based on the analysis of the genomes suggest that the divergence between species of the C. neoformans and Cryptococcus gattii complexes could have occurred 80 to 100 million years ago [17]. Considering this finding, it is striking that the participation of individual species in causing various forms of cryptococcosis is unequal. Specifically, about 95% of cryptococcal infections are caused by strains of the species C. neoformans (serotype A), and the remaining 4% to 5% of infections are caused by C. deneoformans (serotype D) or strains of the C. gattii species complex (serotypes B and C) [81].
Cryptococcal virulence factors/determinants
Virulence/pathogenicity has been defined as the relative ability of a microorganism to enter, cause tissue damage, and proliferate in the host body. Mortality is a commonly used measure of virulence/pathogenicity in human populations [18, 106]. Most pathogenic microorganisms have several virulence factors that can damage the host’s tissues, which determines the overall net virulence phenotype [82]. Members of the Cryptococcus species complex present a particularly rich spectrum of virulence factors (recently presented during the webinar organized by Polish Mycological Society [https://tinyurl.com/bdhhurrv]). Members of the Cryptococcus species complex are well known because they produce two virulence factors that significantly interfere with the host’s immune system, namely the polysaccharide capsule and melanin. These factors not only effectively disrupt the functions of the immune system, but also protect against phagocytosis and reactive oxygen species (ROS) released by elements of the immune system [141].
The virulence factor of pathogenic Cryptococcus species that is of considerable clinical importance is the polysaccharide capsule [82]. The synthesis of the capsule material begins in the early stages of infection and is important to the development of the disease to such an extent that acapsular strains are avirulent in murine models of cryptococcosis [20]. The capsule provides resistance to stress factors such as dehydration, to which fungal cells are particularly exposed in the natural environment [143]. During infection, the capsule helps to reduce the risk of phagocytosis and increases the chance of survival of engulfed cryptococci through several mechanisms. For instance, capsule impairs the recognition of fungal cell surface antigens by macrophages, contributing to the avoidance of phagocytosis [88]. Moreover, capsular polysaccharides have antioxidant properties, protecting fungal cells against the toxic effects of ROS produced during intracellular parasitism inside the phagolysosome [143]. Capsule enlargement can also confer resistance to antimicrobial peptides and amphotericin B, but increases susceptibility to fluconazole [34, 143]. Chemically capsule consists mainly of glucuronoxylomannan (GXM, approx. 90%), galactoxylomannan (GXMGal, 5–8%), and mannoproteins (∼ 1%). Variation at the level of this structure and in the proportions of the individual components of the capsule changes its antigenic properties, which are the basis for distinguishing between serotypes[16, 135]. Fluctuations in the size of the polysaccharide capsule impact the chances of yeast cell survival inside the macrophages [98].
There are several factors which can induce capsule production in vitro, such as CO2, iron and other nutrient deficiency, and contact with mammalian serum [34]. Quantitative and qualitative changes at the capsule level result in the formation of a very heterogeneous population of Cryptococcus cells, differing in epitope composition, which reduces the effectiveness of a normal immune response [44]. Moreover, the structure and composition of the capsule can undergo microevolution even during the in vitro conditions, thanks to which the microbial population is phenotypically and antigenically variable depending on the growth conditions of the culture [83]. It is well known that the increase in capsule density makes it less permeable to elements of the immune response, such as antibodies, the complement system or antimicrobial peptides [34]. Capsule growth in thickness and increase in its density can be induced by various environmental factors. The in vitro studies showed that polysaccharides contained in the capsule are not only bound to the cell wall, but also released into the culture medium (exopolysaccharides). During infection, they can be found in tissues, cerebrospinal fluid, and blood [40]. Exopolysaccharides promote disease development through multiple mechanisms. Both GXM and GXMGal induce apoptosis of immune cells by activating membrane FasL/Fas proteins leading to the formation of complexes (trimerization) which initiates apoptosis in helper lymphocytes [130]. The secreted exopolysaccharides may also disturb the production of antibodies, induce conditions of complement deficiency [142], inhibit leukocyte migration [33], reduce the penetration of immune cells across the blood-brain barrier [26], or stimulate the production of cytokines and chemokines [128]. Thus, the polysaccharide capsule protects Cryptococcal cells in various ways, both against specific and non-specific mechanisms of host immune system defense, as well as against many environmental physico-chemical factors.
Another virulence factor of key importance for members of Cryptococcus species complex is the accumulation of dark pigment melanin in the cell wall, which may also be released extracellularly [32]. Unlike some fungi which constitutively synthesize dihydroxynaphthalene (DHN) melanin, Cryptococcus spp. produces DOPA-melanin only under induction conditions, in the presence of exogenous substrates such as 3,4-dihydroxyphenylalanine (DOPA) and other di/polyphenol compounds such as epinephrine and norepinephrine [12]. It is commonly known that the concentration of catecholamines, including adrenaline and noradrenaline, which are well known neurotransmitters, is higher in the cerebrospinal fluid than in the blood. This explains the neurotropism manifested by the cells of pathogenic Cryptococcus spp. [34]. Melanin synthesis depends on the enzyme diphenol oxidase, encoded by two genes: LAC1 and LAC2, but only LAC1 is significantly expressed under most conditions and its deletion results in a reduction in virulence [107]. Notably, the ability to synthesize melanin, and the presence of polysaccharide capsule, is not restricted to members of pathogenic Cryptococcus species complex. The presence of these virulence factors even in saprophytic species indicates the importance of these natural defense mechanisms for functioning in a changing natural environment [109]. Melanin plays an important role in changing environmental conditions, i.e. it protects against enzymatic degradation by soil microorganisms (amoebas), UV and gamma radiation [19, 62], heavy metals, and high temperature [90]. Melanin along with the capsule is described as one of the most important virulence factors for members of the Cryptococcus species complex [69]. Mutants incapable of melanization show much lower virulence [72]. Melanin has been shown to play a key role in the spread of pathogen cells from the lungs to the CNS [91], and to influence the host cytokine production [28]. This natural pigment may also directly bind and reduce efficacy of selected antifungal drugs, as has been shown for amphotericin B [27]. Laccase enzymes are mainly responsible for the synthesis of melanin which interfere with the massive release of ROS from cells, in part through iron sequestration and oxidation during the infection [139]. Moreover, it has also been shown that enzyme proteins of the laccase group are not only involved in the synthesis of melanin, but also play a role in the process of non-lytic exocytosis, allowing fungal cells to escape from macrophages, which in fact resembles the process of vomocytosis [96].
Urease is yet another important virulence factor common to fungi of the genus Cryptococcus. Urease catalyzes the decomposition of urea into carbon dioxide and ammonia, what is also manifested by an increase in pH. Urease enables yeast cells to use urea as a sole nitrogen source [141]. During infection, urease alkalizes the internal environment of the phagolysosome, limiting damage caused by the macrophage, and prolonging intracellular parasitism [42]. Relatively recently, it was shown that urease also influences non-lytic macrophage exocytosis, known as the vomocytosis phenomenon [42]. Urease has been shown to be required for CNS colonization as it promotes the sequestration of yeast cells in the microcapillary vessels of the brain. It has also been hypothesized that ammonia promotes the adhesion of C. neoformans / C. gattii cells to the surface of vascular endothelial cells, either by increasing the expression of adhesins on the endothelium, or by a direct toxic effect on the integrity of the tight connections of the blood-brain barrier, which facilitates invasion into the CNS [97]. Thus, urease contributes to virulence by allowing the pathogen to survive and spread in macrophages and invade the CNS. Interestingly, inhibition of urease activity does not block the development of infection, as mutants deficient in urease activity are still pathogenic in animal models and disseminated infections in humans caused by urease negative strains have been described [127].
One of the most important virulence determinants which enables the development of infection in the mammalian body is the ability to grow and proliferate at 37°C. It is a feature common to all pathogenic species clustered in the Cryptococcus species complex, although it is also found in some saprophytic strains of the genus Cryptococcus. This ability is believed to have allowed the members of Cryptococcus species complex to evolve into successful human and animal pathogens (reviewed in) [29]. Several proteins important for high temperature tolerance have been characterized [123]. Proteins important for high temperature growth include manganese-containing mitochondrial superoxide dismutase, which plays an important role in the response to this type of stress [50]. The importance of trechalose, a sugar specifically synthesized in fungal cells, that protects against various types of stress, including heat, was also described. Components of the trehalose biosynthetic pathway have been shown to be required for high temperature growth and thus determine the virulence of pathogen cells [134]. Various signal transduction pathways also play a role in detecting and responding to heat stress. These include the calcineurin pathway [63, 92], MAP kinase pathways, including the protein kinase C (PKC) cell integrity signaling pathway [47] and the high-osmolarity glycerol (HOG) mitogen-activated protein kinase pathway [140] and the Ras signaling pathway [3]. The pathway with the best documented influence on the ability to grow in mammal body temperature is the calcineurin A pathway. C. neoformans mutants with a deletion of the CNA1 gene (encoding calcineurin catalytic subunit) are not able to grow at temperatures above 35°C and are avirulent. Apart from the involvement of the calcineurin pathway in thermotolerance, this pathway participates in the response to other types of stress, and thus significantly influences the virulence [34].
An indispensable ability for the survival of yeast cells in the environment and in the host is the adaptation of the pathogen to the changing pH. It is commonly known that the transcription factor Rim101 is involved in the alkaline pH response and is the major protein involved in this adaptation [99]. This protein indirectly influences also virulence factors, such as polysaccharide capsule, and Titan cell formation, and impact the integrity of the cell wall [100].
Despite a general strategy to avoiding phagocytosis, Cryptococcus spp cells require macrophages to efficiently leave the lung environment and spread to other host organs, including crossing the blood-brain barrier and penetration into the CNS. This strategy, known as the Trojan horse tactic, allows the infection to spread effectively. It has been shown that fungal cells inside macrophages remain viable and replicate efficiently in the acidic environment of the phagolysosome [23]. It is therefore puzzling that, on the one hand, Cryptococcus spp cells have developed mechanisms to avoid phagocytosis, and on the other hand, proliferation inside macrophages promotes the infection into other organs. These apparently contradictory mechanisms are, in fact, two complementary strategies that account for the enormous plasticity of the pathogen’s cells depending on the prevailing conditions. In the context of antiphagocytic activity, the App1 protein, discovered by the Luberto et al. [76], plays an important role. This protein was first identified in the serum of AIDS patients and it has been shown that its release effectively inhibits the macrophage phagocytosis process [76]. In turn, proliferation inside macrophage phagolysosomes and transition to the CNS may be considered profitable for the pathogen’s cells. Supporting this view, is an evolutionary mechanism called vomocytosis that allows the fungal cells to leave the interior of macrophages without any negative effect on the pathogen and host cells. The mechanism of release from macrophages without damaging the host cells and thus without inducing inflammation, so far has been described only for members of the Cryptococcus species complex [77]. Vomocytosis, also called non-lytic exocytosis, is the fusion of the phagolysosome membrane with the macrophage plasma membrane, as a result of which the fungi are pushed out of the phagocyte. The urease catalyzes the hydrolysis of urea to form ammonia, which raises the phagosomal pH [118]. The alkalization of the phagolysosome environment causes the yeast to enter a resting state in which intracellular replication is delayed. This prolongs the intracellular parasitism of cells and increases the probability that fungal cells will have time to move from the lungs to the CNS before the yeasts will be released in the latent phase in an environment unfavorable for them [42].
An interesting and relatively recently discovered virulence factor are tubular mitochondria, the presence of which has so far been described only in members of the Cryptococcus gattii species complex [11, 131]. Tubular mitochondria form as a result of fusion, in a reversable process. The presence of this type of mitochondria in a subset of the population leads to the so-called „division of labor” [131]. The formation of cells with this phenotype is stimulated by host ROS, which are released in large quantities. As a result, some cells in the population that developed tubular mitochondria stop proliferating and are directly involved in neutralizing oxidative stress, allowing the remaining cells to proliferate intensively. It is currently known that C. deuterogattii (R265) strain that emerged recently on Vancouver Island, Canada due to its ability to form tubular mitochondria is characterized by a particularly hypervirulent phenotype [78, 89]. This is supported by the fact that mitochondria can be the source of the rapid evolution of pathogen virulence as their genomes are present in high copy numbers and show a much higher mutation rate than nuclear DNA [53].
The relatively recently described extracellular vesicles (EVs) seem to play an important role in cryptococcosis. Cells of the genus Cryptococcus produce EVs with a diameter of 80 to 500 nm, which cross the cell wall and are released into the environment. It is considered that fungal EVs participate in many biological processes related to virulence including induction of antifungal resistance and biofilm formation or transfer of virulence-associated molecules and modulation of host immune cells [111]. It has been shown that EVs are directly involved in the transport of the main component of the polysaccharide capsule – glucuronoxylomannan (GXM), but also such lipids as glucosylceramide and some sterols. These vesicles are also observed in acapsular strains, which suggests that Cryptococcus spp. may use vesicular transport to secrete very different compounds. EVs are also released during the proliferation of cryptococcal cells inside macrophages, suggesting a role in pathogenesis [75]. This is confirmed by the fact that the glucosylceramide released in this way induces the production of anticryptococcal antibodies during human infection [113]. It is currently known that glucosylceramide regulates the virulence of Cryptococcus spp. cells and is essential for fungal growth at neutral/alkaline pH in vitro and in vivo [110].
It has been shown that most of the virulence factors described herein can be regulated by both environmental factors and host environment. This means that the expression of virulence factors may be different in the natural environment compared to the environment of the host. A change in the expression level of individual virulence factors may affect the host-pathogen interaction, the host immune response, and finally the susceptibility of the pathogen’s cells to antifungal drugs [85].
Morphological transformation as a strategy to averting the host immune attack
Morphological transformation, called in some cases phenotype switching, is a reversible phenomenon that occurs both in vitro as in vivo in case of cultivable fungal species. It is defined as the spontaneous appearance of cells with altered morphology accompanied by a rate faster than that known for somatic mutations [59, 122]. Morphological transformation involves a series of changes at the cellular level, but is a reversible, controlled process, which distinguishes it from random changes caused by point mutations in the genome. For this reason, in vivo morphological transitions of the pathogen often impact the host-pathogen interaction diametrically. For instance, entirely different virulence factors are associated with blastoconidia than with other mycelial forms [59, 60]. Fungi have developed multiple regulatory pathways that recognize several environmental changes in response to which they react by switching phenotypes. The environmental signals inducing phenotype switching include the presence of blood serum, changes in temperature, pH, concentration of CO2 and specific micronutrients. Those signals can trigger a transformation of yeast cells into mycelia or vice versa, or lead to an increase in the thickness of the capsule and initiate titanization process [60, 145]. Thanks to the ability to respond to signals from the environment, pathogenic fungi can dynamically adapt to changing conditions both in the environment and in the infected host. It is well known that the ability to switch phenotypes is one of the mechanisms to avert the host immune response [52, 60]. Microorganisms must constantly adapt to changing environments. In clonal populations this can be achieved by generating diversity through phenotype switching [73].
The phenotype switching phenomenon was first described in Candida albicans almost 40 years ago [120, 121]. In many pathogenic fungi, the ability to alter cell morphology is an integral part of the infection cycle. Dimorphic fungi of the genera Histoplasma, Blastomyces, Paracoccidioides, Emergomyces, Sporothrix and Talaromyces marneffei develop in the environment mycelial form, while in the host undergo transformation into the yeast form, which allows dissemination [125]. C. albicans and Candida dubliniensis, on the other hand, under appropriate conditions, both in vitro and in vivo, can switch between yeast and mycelial form. In the case of C. albicans and C. dubliniensis, blastoconidia play an important role in the spread of the pathogen cells within body fluids, while mycelial form plays an important role at the stage of tissue and organ colonization [80]. The recently described Goliath cells represent another manifestation of the morphological transformation specific only to some Candida species. Goliath cells are formed primarily under zinc starvation conditions what is related with immune system’s strategy of limiting the development of infection [79, 136]. Phylogenetic and phenotypic analyses showed that the cell enlargement as response to zinc starvation was species-specific and developed in the common ancestor of C. albicans, C. dubliniensis and C. tropicalis and was not observed in other Candida species studied so far [2, 79]. It is well known that many other species of the genus Candida can form pseudohyphae, however these structures do not display the virulence characteristics known to true hyphae [119].
Some filamentous fungi also have an ability to induce a transformation that is not associated with changing the shape of the cell, but with a significant increase in size and in the thickness of the cell wall. [125]. One example are pathogens of the genus Emmonsia that cause adiaspiromycosis. In the lung tissue, the conidia (typically 2–4 μm in diameter) of some Emmonsia species grow in size, reaching a diameter of 40–500 μm and increasing in volume up to a million times [9] transforming into adiaspores. These structures are de facto non-endosporulating spherules. Species of the genus Emmonsia are phylogenetically closely related with Coccidioides but the last one has endosporulating spherules unique among fungal pathogens, which within the infected tissue can achieve 30–80 μm in diameter [58, 125].
Titan cells formation is unique for members of the Cryptococcus species complex
Pathogenic species of the genus Cryptococcus developed the richest spectrum of virulence factors which have contributed to their evolutionary success as pathogens [7, 29]. One of the key virulence factors is the ability to undergo morphological transformation into giant (Titan) cells. Some literature sources questioned that Titan cells are necessary for infection development as some clinical isolates of C. neoformans are presumably not capable of undergoing this morphological transition [25, 57, 124]. Such cells, due to their ten to twenty times larger volume, can effectively avoid macrophage phagocytosis. The unique phenotype of these cells consists not only of their size (diameter > 10 μm), but also significantly enlarged capsule, a thick layer of the cell wall, the presence of a large central vacuole and one polyploid nucleus [48, 94, 146]. Titan cells are not a final phenotype and are still capable of proliferation, producing both haploids, diploids and aneuploids daughter cells. In addition, Titan cells, as well as daughter cells, especially those with an aneuploid set of chromosomes, exhibit resistance to a number of physical and chemical factors [48]. The protocols for the induction of Titan cells in the presence of serum (10% or 5% fetal bovine serum, FBS), published simultaneously in 2018 [25, 124], make it possible to conduct large-scale in vitro studies on the titanization process. It has been shown that this ability to undergo such specific morphological transformation is unique for pathogenic yeasts of the Cryptococcus species complex [30]. It was confirmed then by two independent research centers that, as in the case of members of the C. neoformans species complex, species of the complex C. gattii, were able to form Titan cells, respectively according to commonly known in vitro serum protocol [31] and the newest protocol based on RPMI medium [114]. Moreover, recently it has been shown that strategies for titanization in case of members of C. gattii and C. neoformans species complexes are significantly different. While for C. neoformans typical is synchronous occurrence of cells enlargement and polyploidization, in the case of C. gattii we can observe delay in DNA endoreduplication and cell growth to around 30 μm as a haploid cell. Only after ∼ 3 days incubation under titanization conditions DNA endoreduplication can be observed, which finally leads to uninucleate polyploid cells [114]. Moreover, this process was equally effective. At the same time, it has been shown that the incubation conditions provided according to the protocol described by Hommel [57] yield typical Titan cells only for members of the C. neoformans species complex [31]. None of the tested strains belonging to C. gattii species complex was able to form Titan cells under such conditions [31]. More recent studies allowed to identify the minimum conditions sufficient to induce Titan cell formation in case of all the members of Cryptococcus species complex. Thus, it has been shown that, contrary to the assumptions made so far, serum is not a necessary and irreplaceable factor inducing the titanization process. This formed the basis for the development of a new serum-independent Titan cell induction protocols [31, 114]. In addition to determining the minimum quantitative and qualitative composition of the medium conditioning the formation of giant cells, the key role of the slightly alkaline pH (7.2–7.3) of the liquid medium used in the induction of Titan cells formation has been demonstrated [31]. Moreover, it was showed that Titan cells can be formed under lower temperature than typical for mammal body [30]. Such a new findings allow to conclude that the titanization process has been known to a limited extent only. It is commonly known, that formation of Titan cells allows averting the host immune attack [145] and it is likely a unique feature of human and animal fungal pathogens belonging to Cryptococcus neoformans/C. gattii species complex [30]. Moreover, the ability to form enlarged polyploid Titan cells seems to be important for dissemination of cryptococcosis yet it remains poorly described [145].
The qualitative changes that occur at the cell surface as a result of titanization have also been described [4, 86]. C. neoformans population present in the patient’s body is dominated by typical cells (5–7 μm in diameter) with a capsule consisting mainly of GXM and GalXM and a cell wall containing chitin, chitosan, α-glucan, melanin and β-glucan. In addition to typical blastoconidia, a significant percentage (∼ 10–20%) may constitute Titan cells with a diameter above 10 μm, which show thickened cell wall resulting from the deposition of additional chitin layers at the expense of β-1,3-glucan [4]. Additionally, in the cell walls of Titan cells there is a more exposed mannan layer [86]. It is now known that the population of C. neoformans found in body fluids is much more diverse. The so-called microcells with diameter below 1 μm and having thickened cell walls [36] and the so-called titanides (2–4 μm in diameter) with an oval shape and thinner cell walls have been identified. Titanides are associated with the induction of Titan cells in vitro, but surprisingly have not yet been observed in vivo [25]. Undoubtedly, the differentiation of cell sizes in the population present in the infected organism significantly influences the host-pathogen interactions. Some studies suggest that cell size varies depending on where the infection is located. Cells taken from the lungs of mice had thicker capsules and were larger, while cells isolated from the brain were smaller with thinner capsules [21]. This organ-dependent variation in cell size of Cryptococcus spp. has been also reported in human infections [137]. Different cell sizes may be advantageous at various stages of infection. For example, smaller cells may aid in proliferation and survival in macrophages, while larger cells may facilitate pathogen survival in lung tissue under conditions of increased oxidative stress. It has been shown, inter alia, that during the infection, a significant proportion of the yeast in the lungs has a volume of up to 900 times greater than that of cells grown under standard laboratory conditions [144]. This hypothesis seems to be the most correct since the highest percentage of Titan cells and also those with the largest size have been found so far in lungs (up to 100 μm including the capsule) [94]. It has also been shown that these cells promote pathogenesis by reducing the rate of phagocytosis and increasing stress tolerance [48, 93]. In the context of pathogenesis, the faster rate of budding (∼ 60 min/per bud) and a higher degree of melanization, demonstrated for Titan cells, also seem to be important [48]. It has also been shown that Titan cells grow from senescent cells and that the daughter cells they produce are of typical size [57].
It is currently known that the induction of titanization is mediated by Gpr5 and Ste3 G-protein coupled receptors which induce the protein kinase A cycle (cAMP/PKA) via the α subunit of Gpa1 [95]. Cyclic AMP also regulates the formation of polysaccharide capsule, in particular by acting on the ubiquitin-proteasome pathway [46]. It has been shown that adequate intracellular concentration of cAMP is required for titanization thus cells deficient in adenylate cyclase do not form Titan cells [25]. Carbon dioxide is also required to induce the titanization process. The carbonic anhydrase enzyme converts CO2 into HCO3−, which activates adenylate cyclase [49], so a higher concentration of CO2 (optimally 5%) induces cell growth via the cAMP pathway [124]. In the context of the information provided here, it is also worth noting that the appropriate concentration of HCO3− in the blood is extremely important for maintaining the proper pH [51]. The role of Titan cells in cryptococcosis has not been fully elucidated, but they have been shown to be involved in several processes that allow to evade the immune system and persist in the host organism for a long time. The number of Titan cells is especially high during asymptomatic infections, which led to the conclusion that this type of cells can survive in the host organism for a long time as a latent form without causing disease [144]. Titan cells cannot be phagocytosed due to their size. Interestingly, they are also able to confer resistance to phagocytosis to smaller, neighboring yeast cells, what may be caused by extracellular vesicles produced by the pathogen [34, 93]. Given how large their capsule is, it is also likely that the exopolysaccharide secreted may have a strong influence on the surrounding environment and phagocytic cells. The number of formed Titan cells is highly dependent on the host environment, and therefore the percentage of these cells observed in vivo can vary considerably, as shown in experimentally infected mice. In mice that develop a Th1-type immune response (interferon-γ and TNF-α dependent), the percentage of Titan cells is low (approximately 15%). In contrast, mice that induce a Th2-type response (related with interleukines 4, 5, 10, and 13) have a very high percentage of Titan cells, even above 50% of the total population of Cryptococcus spp. cells [43]. Currently, it is impossible to clearly explain this relationship, however, Th2-type immune response which is de facto anti-inflammatory response is associated with a less aggressive environment, which, unlike the environment generated by Th1 lymphocytes and the associated with them proinflammatory response, significantly favors the formation of Titan cells [34].
Conclusions
At the end of the 19th century, exactly 128 years ago, Busse and Buschke almost simultaneously described the first two cases of cryptococcosis [13,14,15]. Certainly no one assumed that at the end of the next century, this disease entity in many places around the world would collect a greater death toll than tuberculosis [101], which was one of the most significant health problems in the nineteenth century. Observations performed during the last two to three decades demonstrate that members of the Cryptococcus species complex cause infection in approximately 1 million people per year, with more than 600 thousand mortalities, contributing to death toll in one-third AIDS patients [101, 108]. In recent years, thanks to the antiretroviral therapy (ART) implemented in many countries, the number of deaths caused by cryptococcosis in the group of AIDS patients has started to decline [10, 87]. For comparison, only in 2014 and 2020 on a global scale 223,100 and 152,000 people suffered from cryptococcosis of the central nervous system (CNS), of which 181,100 and 112,000 died, respectively [61, 108]. Currently, thanks to the increasingly better knowledge of the virulence factors of pathogenic fungi of the Cryptococcus species complex and thanks to the sequenced genomes of these fungi, there is a hope for more effective and less toxic anticryptococcal therapy. Furthermore, promising is also an ongoing intensive work on the anticryptococcal vaccine [22, 126] and the cyclical International Conferences on Cryptococcus and Cryptococcosis (ICCC) every three years [70]. Future work to delineate a set of unsolved problems in the cryptococcal virulence factors field will provide fertile ground for future improvements of therapies against cryptococcosis. It is impossible not to notice that the real need for research on pathogenic fungi of the genus Cryptococcus and the disease entities caused by them means that from the day of discovering this life-threatening etiological agent we have to deal with a never ending story.
Ainsworth G.C.: Introduction to the History of Mycology; Cambridge University Press, 1–246, (1976)AinsworthG.C.Introduction to the History of MycologyCambridge University Press12461976Search in Google Scholar
Alspaugh J.A., Cavallo L.M., Perfect J.R., Heitman J.: RAS1 Regulates filamentation, mating and growth at high temperature of Cryptococcus neoformans. Mol. Microbiol.36, 352–365 (2000)AlspaughJ.A.CavalloL.M.PerfectJ.R.HeitmanJ.RAS1 Regulates filamentation, mating and growth at high temperature of Cryptococcus neoformansMol. Microbiol.36352365200010.1046/j.1365-2958.2000.01852.x10792722Search in Google Scholar
Altamirano S., Li Z., Fu M.S., Ding M., Fulton S.R., Yoder J.M., Tran V., Nielsen K. The Cyclin Cln1 Controls Polyploid Titan Cell Formation Following a Stress-Induced G2 Arrest in Cryptococcus. mBio12, e02509–21 (2021)AltamiranoS.LiZ.FuM.S.DingM.FultonS.R.YoderJ.M.TranV.NielsenK.The Cyclin Cln1 Controls Polyploid Titan Cell Formation Following a Stress-Induced G2 Arrest in CryptococcusmBio12e0250921202110.1101/2021.08.24.457603Search in Google Scholar
Antonelli G., Cutler S.: Evolution of the Koch postulates: towards a 21st-century understanding of microbial infection. Clin Microbiol Infect.22, 583–584 (2016)AntonelliG.CutlerS.Evolution of the Koch postulates: towards a 21st-century understanding of microbial infectionClin Microbiol Infect.22583584201610.1016/j.cmi.2016.03.03027064135Search in Google Scholar
Benham R.W.: Cryptococci-Their Identification by Morphology and by Serology. J. Infect. Dis.57, 255–274 (1935)BenhamR.W.Cryptococci-Their Identification by Morphology and by SerologyJ. Infect. Dis.57255274193510.1093/infdis/57.3.255Search in Google Scholar
Bielska E., May R.C.: What Makes Cryptococcus gattii a Pathogen? FEMS Yeast Res.16, fov106 (2016)BielskaE.MayR.C.What Makes Cryptococcus gattii a Pathogen?FEMS Yeast Res.16fov106201610.1093/femsyr/fov10626614308Search in Google Scholar
Boekhout T., Theelen B., Diaz M., Fell J.W., Hop W.C.J., Abeln E.C.A., Dromer F., Meyer W.: Hybrid Genotypes in the Pathogenic Yeast Cryptococcus neoformans. Microbiology147, 891–907 (2001)BoekhoutT.TheelenB.DiazM.FellJ.W.HopW.C.J.AbelnE.C.A.DromerF.MeyerW.Hybrid Genotypes in the Pathogenic Yeast Cryptococcus neoformansMicrobiology147891907200110.1099/00221287-147-4-89111283285Search in Google Scholar
Borman A.M., Simpson V.R., Palmer M.D., Linton C.J., Johnson E.M.: Adiaspiromycosis Due to Emmonsia crescens Is Widespread in Native British Mammals. Mycopathologia168, 153–163 (2009)BormanA.M.SimpsonV.R.PalmerM.D.LintonC.J.JohnsonE.M.Adiaspiromycosis Due to Emmonsia crescens Is Widespread in Native British MammalsMycopathologia168153163200910.1007/s11046-009-9216-619533414Search in Google Scholar
Boulware D.R., Meya D.B., Muzoora C., Rolfes M.A., Huppler Hullsiek K., Musubire A., Taseera K., Nabeta H.W., Schutz C., Williams D.A., Rajasingham R., Rhein J., Thienemann F., Lo M.W., Nielsen K., Bergemann T.L., Kambugu A., Manabe Y.C., Janoff E.N., Bohjanen P.R., Meintjes G.: Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis. N. Engl. J. Med.370, 2487–2498 (2014)BoulwareD.R.MeyaD.B.MuzooraC.RolfesM.A.Huppler HullsiekK.MusubireA.TaseeraK.NabetaH.W.SchutzC.WilliamsD.A.RajasinghamR.RheinJ.ThienemannF.LoM.W.NielsenK.BergemannT.L.KambuguA.ManabeY.C.JanoffE.N.BohjanenP.R.MeintjesG.Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal MeningitisN. Engl. J. Med.37024872498201410.1056/NEJMoa1312884412787924963568Search in Google Scholar
Bovers M., Hagen F., Kuramae E.E., Boekhout T.: Promiscuous Mitochondria in Cryptococcus gattii. FEMS Yeast Res.9, 489–503 (2009)BoversM.HagenF.KuramaeE.E.BoekhoutT.Promiscuous Mitochondria in Cryptococcus gattiiFEMS Yeast Res.9489503200910.1111/j.1567-1364.2009.00494.x19281475Search in Google Scholar
Brilhante R.S.N., Rocha M.G., Oliveira J.S., Pereira-Neto W.A., Guedes G.M., Cordeiro R., Sidrim J.J.C., Rocha M.F.G., Castelo-Branco D.: Cryptococcus neoformans/Cryptococcus gattii Species Complex Melanized by Epinephrine: Increased Yeast Survival after Amphotericin B Exposure. Microb. Pathog.143, 104123 (2020)BrilhanteR.S.N.RochaM.G.OliveiraJ.S.Pereira-NetoW.A.GuedesG.M.CordeiroR.SidrimJ.J.C.RochaM.F.G.Castelo-BrancoD.Cryptococcus neoformans/Cryptococcus gattii Species Complex Melanized by Epinephrine: Increased Yeast Survival after Amphotericin B ExposureMicrob. Pathog.143104123202010.1016/j.micpath.2020.10412332169493Search in Google Scholar
Buschke A.: Uber Eine Durch Coccidien Hervergerufene Krankheit Des Menschen. Dtsch. Med Wochenschr21, 14 (1895)BuschkeA.Uber Eine Durch Coccidien Hervergerufene Krankheit Des MenschenDtsch. Med Wochenschr21141895Search in Google Scholar
Busse O.: Über Parasitare Zelleinschlusse Und Ihre Zuchtung. Zentralbl Bakteriol16, 175–180 (1894)BusseO.Über Parasitare Zelleinschlusse Und Ihre ZuchtungZentralbl Bakteriol161751801894Search in Google Scholar
Busse O.: Über Saccharomycosis Hominis. Virchows Arch. Path. Anat.140, 23–46 (1895)BusseO.Über Saccharomycosis HominisVirchows Arch. Path. Anat.1402346189510.1007/BF02116125Search in Google Scholar
Casadevall A., Coelho C., Cordero R.J.B., Dragotakes Q., Jung E., Vij R., Wear M.P.: The Capsule of Cryptococcus neoformans. Virulence10, 822–831 (2019)CasadevallA.CoelhoC.CorderoR.J.B.DragotakesQ.JungE.VijR.WearM.P.The Capsule of Cryptococcus neoformansVirulence10822831201910.1080/21505594.2018.1431087677939029436899Search in Google Scholar
Casadevall A., Freij J.B., Hann-Soden C., Taylor J.: Continental Drift and Speciation of the Cryptococcus neoformans and Cryptococcus gattii Species Complexes. mSphere2, e00103–17 (2017)CasadevallA.FreijJ.B.Hann-SodenC.TaylorJ.Continental Drift and Speciation of the Cryptococcus neoformans and Cryptococcus gattii Species ComplexesmSphere2e0010317201710.1128/mSphere.00103-17539756528435888Search in Google Scholar
Casadevall A., Pirofski L.A.: Host-Pathogen Interactions: Redefining the Basic Concepts of Virulence and Pathogenicity. Infect. Immun.67, 3703–3713 (1999)CasadevallA.PirofskiL.A.Host-Pathogen Interactions: Redefining the Basic Concepts of Virulence and PathogenicityInfect. Immun.6737033713199910.1128/IAI.67.8.3703-3713.19999664310417127Search in Google Scholar
Casadevall A., Rosas A.L., Nosanchuk J.D.: Melanin and Virulence in Cryptococcus Neoformans. Curr. Opin. Microbiol.3, 354–358 (2000)CasadevallA.RosasA.L.NosanchukJ.D.Melanin and Virulence in Cryptococcus NeoformansCurr. Opin. Microbiol.3354358200010.1016/S1369-5274(00)00103-X10972493Search in Google Scholar
Chang Y.C., Kwon-Chung K.J.: Complementation of a Capsule-Deficient Mutation of Cryptococcus neoformans Restores Its Virulence. Mol. Cell. Biol.14, 4912–4919 (1994)ChangY.C.Kwon-ChungK.J.Complementation of a Capsule-Deficient Mutation of Cryptococcus neoformans Restores Its VirulenceMol. Cell. Biol.14491249191994Search in Google Scholar
Charlier C., Chrétien F., Baudrimont M., Mordelet E., Lortholary O., Dromer F.: Capsule Structure Changes Associated with Cryptococcus neoformans Crossing of the Blood-Brain Barrier. Am. J. Pathol.166, 421–432 (2005)CharlierC.ChrétienF.BaudrimontM.MordeletE.LortholaryO.DromerF.Capsule Structure Changes Associated with Cryptococcus neoformans Crossing of the Blood-Brain BarrierAm. J. Pathol.166421432200510.1016/S0002-9440(10)62265-1160233615681826Search in Google Scholar
Chaturvedi A.K., Wormley F.L.: Methodology for Anti-Cryptococcal Vaccine Development BT – Vaccines for Invasive Fungal Infections: Methods and Protocols, Kalkum M., Semis M., (eds), Springer, New York 129–140 (2017)ChaturvediA.K.WormleyF.L.Methodology for Anti-Cryptococcal Vaccine Development BT – Vaccines for Invasive Fungal Infections: Methods and ProtocolsKalkumM.SemisM.(eds),SpringerNew York129140201710.1007/978-1-4939-7104-6_1028584988Search in Google Scholar
Coelho C., Bocca A.L., Casadevall A.: The Intracellular Life of Cryptococcus neoformans. Annu. Rev. Pathol. Mech. Dis.9, 219–238 (2014)CoelhoC.BoccaA.L.CasadevallA.The Intracellular Life of Cryptococcus neoformansAnnu. Rev. Pathol. Mech. Dis.9219238201410.1146/annurev-pathol-012513-104653512771624050625Search in Google Scholar
Curtis F.: Contribution à l’étude de La Saccharomycose Humaine. Ann. Inst. Pasteur10, 20 (1896)CurtisF.Contribution à l’étude de La Saccharomycose HumaineAnn. Inst. Pasteur10201896Search in Google Scholar
Dambuza I.M., Drake T., Chapuis A., Zhou X., Correia J., Taylor-Smith L., LeGrave N., Rasmussen T., Fisher M.C., Bicanic T., Harrison T.S., Jaspars M., May R.C., Brown G.D., Yuecel R., MacCallum D.M., Ballou E.R.: The Cryptococcus neoformans Titan Cell Is an Inducible and Regulated Morphotype Underlying Pathogenesis. PLOS Pathog.14, e1006978 (2018)DambuzaI.M.DrakeT.ChapuisA.ZhouX.CorreiaJ.Taylor-SmithL.LeGraveN.RasmussenT.FisherM.C.BicanicT.HarrisonT.S.JasparsM.MayR.C.BrownG.D.YuecelR.MacCallumD.M.BallouE.R.The Cryptococcus neoformans Titan Cell Is an Inducible and Regulated Morphotype Underlying PathogenesisPLOS Pathog.14e1006978201810.1371/journal.ppat.1006978595907029775474Search in Google Scholar
Denham S.T., Verma S., Reynolds R.C., Worne C.L., Daugherty J.M., Lane T.E., Brown J.C.S.: Regulated Release of Cryptococcal Polysaccharide Drives Virulence and Suppresses Immune Cell Infiltration into the Central Nervous System. Infect. Immun.86, e00662–17 (2018)DenhamS.T.VermaS.ReynoldsR.C.WorneC.L.DaughertyJ.M.LaneT.E.BrownJ.C.S.Regulated Release of Cryptococcal Polysaccharide Drives Virulence and Suppresses Immune Cell Infiltration into the Central Nervous SystemInfect. Immun.86e0066217201810.1128/IAI.00662-17582095329203547Search in Google Scholar
Duin D., Casadevall A., Nosanchuk J.D.: Melanization of Cryptococcus Neoformans and Histoplasma Capsulatum Reduces Their Susceptibilities to Amphotericin B and Caspofungin. Antimicrob. Agents Chemother.46, 3394–3400 (2002)DuinD.CasadevallA.NosanchukJ.D.Melanization of Cryptococcus Neoformans and Histoplasma Capsulatum Reduces Their Susceptibilities to Amphotericin B and CaspofunginAntimicrob. Agents Chemother.4633943400200210.1128/AAC.46.11.3394-3400.200212874812384341Search in Google Scholar
Duin D., Casadevall A., Nosanchuk J.D.: Melanization of Cryptococcus neoformans Affects Lung Inflammatory Responses during Cryptococcal Infection. Infect. Immun.73, 2012–2019 (2005)DuinD.CasadevallA.NosanchukJ.D.Melanization of Cryptococcus neoformans Affects Lung Inflammatory Responses during Cryptococcal InfectionInfect. Immun.7320122019200510.1128/IAI.73.4.2012-2019.2005108747015784542Search in Google Scholar
Dyląg M.: Etiological factors of cryptococcosis – what makes them pathogens ? Med. Dosw. Mikrobiol.67, 221–231 (2015)DylągM.Etiological factors of cryptococcosis – what makes them pathogens ?Med. Dosw. Mikrobiol.672212312015Search in Google Scholar
Dyląg M., Colon-Reyes R.J., Kozubowski L.: Titan cell formation is unique to Cryptococcus species complex. Virulence11, 719–729 (2020)DylągM.Colon-ReyesR.J.KozubowskiL.Titan cell formation is unique to Cryptococcus species complexVirulence11719729202010.1080/21505594.2020.1772657754998932498590Search in Google Scholar
Dyląg M., Colón-Reyes R.J., Loperena-Álvarez Y., Kozubowski L.: Establishing minimal conditions sufficient for the development of Titan-like cells in Cryptococcus neoformans/gattii species complex. Pathogens11, 768 (2022)DylągM.Colón-ReyesR.J.Loperena-ÁlvarezY.KozubowskiL.Establishing minimal conditions sufficient for the development of Titan-like cells in Cryptococcus neoformans/gattii species complexPathogens11768202210.3390/pathogens11070768932218535890013Search in Google Scholar
Eisenman H.C., Nosanchuk J.D., Webber J.B.W., Emerson R.J., Camesano T.A., Casadevall A.: Microstructure of Cell Wall-Associated Melanin in the Human Pathogenic Fungus Cryptococcus neoformans. Biochemistry44, 3683–3693 (2005)EisenmanH.C.NosanchukJ.D.WebberJ.B.W.EmersonR.J.CamesanoT.A.CasadevallA.Microstructure of Cell Wall-Associated Melanin in the Human Pathogenic Fungus Cryptococcus neoformansBiochemistry4436833693200510.1021/bi047731m15751945Search in Google Scholar
Ellerbroek P.M., Hoepelman A.I., Wolbers F., Zwaginga J.J, Coenjaerts F.E.: Cryptococcal Glucuronoxylomannan Inhibits Adhesion of Neutrophils to Stimulated Endothelium In Vitro by Affecting Both Neutrophils and Endothelial Cells. Infect. Immun.70, 4762–4771 (2002)EllerbroekP.M.HoepelmanA.I.WolbersF.ZwagingaJ.JCoenjaertsF.E.Cryptococcal Glucuronoxylomannan Inhibits Adhesion of Neutrophils to Stimulated Endothelium In Vitro by Affecting Both Neutrophils and Endothelial CellsInfect. Immun.7047624771200210.1128/IAI.70.9.4762-4771.200212823512183517Search in Google Scholar
Esher S.K., Zaragoza Ó., Alspaugh J.A.: Cryptococcal Pathogenic Mechanisms: A Dangerous Trip from the Environment to the Brain. Mem. Inst. Oswaldo Cruz113, e180057 (2018)EsherS.K.ZaragozaÓ.AlspaughJ.A.Cryptococcal Pathogenic Mechanisms: A Dangerous Trip from the Environment to the BrainMem. Inst. Oswaldo Cruz113e180057201810.1590/0074-02760180057590908929668825Search in Google Scholar
Evans E.E.: An Immunologic Comparison of Twelve Strains of Cryptococcus neoformans (Torula histolytica). Proc. Soc. Exp. Biol. Med.71, 644–646 (1949)EvansE.E.An Immunologic Comparison of Twelve Strains of Cryptococcus neoformans (Torula histolytica)Proc. Soc. Exp. Biol. Med.71644646194910.3181/00379727-71-1728318148185Search in Google Scholar
Feldmesser M., Kress Y., Casadevall A.: Dynamic Changes in the Morphology of Cryptococcus neoformans during Murine Pulmonary Infection. Microbiology147, 2355–2365 (2001)FeldmesserM.KressY.CasadevallA.Dynamic Changes in the Morphology of Cryptococcus neoformans during Murine Pulmonary InfectionMicrobiology14723552365200110.1099/00221287-147-8-235511496012Search in Google Scholar
Fell J.W., Kurtzman C.P., Kwon-Chung K.J.: Proposal to Conserve Cryptococcus (Fungi). Taxon38, 151–152 (1989)FellJ.W.KurtzmanC.P.Kwon-ChungK.J.Proposal to Conserve Cryptococcus (Fungi)Taxon38151152198910.2307/1220923Search in Google Scholar
Fonseca Á., Fell J.W., Boekhout T.: Cryptococcus Vuillemin. In The yeasts, a taxonomic study; Kurtzman C.P., Fell J.W., Boekhout T., (eds), Elsevier: Amsterdam 1665–1740 (2010)FonsecaÁ.FellJ.W.BoekhoutT.Cryptococcus Vuillemin. In The yeasts, a taxonomic studyKurtzmanC.P.FellJ.W.BoekhoutT.(eds),ElsevierAmsterdam16651740201010.1016/B978-0-444-52149-1.00138-5Search in Google Scholar
Franzot S.P., Salkin I.F., Casadevall A.: Cryptococcus neoformans var. grubii: Separate Varietal Status for Cryptococcus neoformans Serotype A Isolates. J. Clin. Microbiol.37, 838–840 (1999)FranzotS.P.SalkinI.F.CasadevallA.Cryptococcus neoformans var. grubii: Separate Varietal Status for Cryptococcus neoformans Serotype A IsolatesJ. Clin. Microbiol.37838840199910.1128/JCM.37.3.838-840.1999845789986871Search in Google Scholar
Frases S., Nimrichter L., Viana N.B., Nakouzi A., Casadevall A.: Cryptococcus neoformans Capsular Polysaccharide and Exopolysaccharide Fractions Manifest Physical, Chemical, and Antigenic Differences. Eukaryot. Cell7, 319–327 (2008)FrasesS.NimrichterL.VianaN.B.NakouziA.CasadevallA.Cryptococcus neoformans Capsular Polysaccharide and Exopolysaccharide Fractions Manifest Physical, Chemical, and Antigenic DifferencesEukaryot. Cell7319327200810.1128/EC.00378-07223816518156290Search in Google Scholar
Frothingham L.: A Tumor-like Lesion in the Lung of a Horse Caused by a Blastomyces (Torula). J. Med. Res.8, 31–43 (1902)FrothinghamL.A Tumor-like Lesion in the Lung of a Horse Caused by a Blastomyces (Torula)J. Med. Res.831431902Search in Google Scholar
Fu M.S., Coelho C., De Leon-Rodriguez C.M., Rossi D.C.P., Camacho E., Jung E.H., Kulkarni M., Casadevall A.: Cryptococcus neoformans Urease Affects the Outcome of Intracellular Pathogenesis by Modulating Phagolysosomal PH. PLOS Pathog.14, e1007144 (2018)FuM.S.CoelhoC.De Leon-RodriguezC.M.RossiD.C.P.CamachoE.JungE.H.KulkarniM.CasadevallA.Cryptococcus neoformans Urease Affects the Outcome of Intracellular Pathogenesis by Modulating Phagolysosomal PHPLOS Pathog.14e1007144201810.1371/journal.ppat.1007144602111029906292Search in Google Scholar
García-Barbazán I., Trevijano-Contador N., Rueda C., de Andrés B., Pérez-Tavárez R., Herrero-Fernández I., Gaspar M.L., Zaragoza O.: The Formation of Titan Cells in Cryptococcus neoformans Depends on the Mouse Strain and Correlates with Induction of Th2-Type Responses. Cell. Microbiol.18, 111–124 (2016)García-BarbazánI.Trevijano-ContadorN.RuedaC.de AndrésB.Pérez-TavárezR.Herrero-FernándezI.GasparM.L.ZaragozaO.The Formation of Titan Cells in Cryptococcus neoformans Depends on the Mouse Strain and Correlates with Induction of Th2-Type ResponsesCell. Microbiol.18111124201610.1111/cmi.1248826243235Search in Google Scholar
Garcia-Hermoso D., Dromer F., Janbon G.: Cryptococcus neoformans Capsule Structure Evolution In Vitro and during Murine Infection. Infect. Immun.72, 3359–3365 (2004)Garcia-HermosoD.DromerF.JanbonG.Cryptococcus neoformans Capsule Structure Evolution In Vitro and during Murine InfectionInfect. Immun.7233593365200410.1128/IAI.72.6.3359-3365.200441570615155641Search in Google Scholar
Gatti F., Eeckels R.: An Atypical Strain. Ann. Soc. belge Méd. trop50, 689–694 (1970)GattiF.EeckelsR.An Atypical StrainAnn. Soc. belge Méd. trop506896941970Search in Google Scholar
Geddes J.M.H., Caza D., Croll N., Stoynov L.J., Foster J.W., Kronstad J.: Analysis of the Protein Kinase A-Regulated Proteome of Cryptococcus neoformans Identifies a Role for the Ubiquitin-Proteasome Pathway in Capsule Formation. mBio7, e01862–15 (2016)GeddesJ.M.H.CazaD.CrollN.StoynovL.J.FosterJ.W.KronstadJ.Analysis of the Protein Kinase A-Regulated Proteome of Cryptococcus neoformans Identifies a Role for the Ubiquitin-Proteasome Pathway in Capsule FormationmBio7e0186215201610.1128/mBio.01862-15472500626758180Search in Google Scholar
Gerik K.J., Bhimireddy S.R., Ryerse J.S., Specht C.A., Lodge J.K.: PKC1 Is Essential for Protection against Both Oxidative and Nitrosative Stresses, Cell Integrity, and Normal Manifestation of Virulence Factors in the Pathogenic Fungus Cryptococcus neoformans. Eukaryot. Cell7, 1685–1698 (2008)GerikK.J.BhimireddyS.R.RyerseJ.S.SpechtC.A.LodgeJ.K.PKC1 Is Essential for Protection against Both Oxidative and Nitrosative Stresses, Cell Integrity, and Normal Manifestation of Virulence Factors in the Pathogenic Fungus Cryptococcus neoformansEukaryot. Cell716851698200810.1128/EC.00146-08256805718689526Search in Google Scholar
Gerstein A.C., Fu M.S., Mukaremera L., Li Z., Ormerod K.L., Fraser J.A., Berman J., Nielsen K.: Polyploid Titan Cells Produce Haploid and Aneuploid Progeny to Promote Stress Adaptation. mBio6, e01340–15 (2015)GersteinA.C.FuM.S.MukaremeraL.LiZ.OrmerodK.L.FraserJ.A.BermanJ.NielsenK.Polyploid Titan Cells Produce Haploid and Aneuploid Progeny to Promote Stress AdaptationmBio6e0134015201510.1128/mBio.01340-15462046326463162Search in Google Scholar
Gewiss M.E., Guilhem J., James C., Clemens S., Shun F.M., Frédérique M., Torsten K., Jochen B.: Cryptococcus neoformans Senses CO2 through the Carbonic Anhydrase Can2 and the Adenylyl Cyclase Cac1. Eukaryot. Cell5, 103–111 (2006)GewissM.E.GuilhemJ.JamesC.ClemensS.ShunF.M.FrédériqueM.TorstenK.JochenB.Cryptococcus neoformans Senses CO2 through the Carbonic Anhydrase Can2 and the Adenylyl Cyclase Cac1Eukaryot. Cell5103111200610.1128/EC.5.1.103-111.2006136026816400172Search in Google Scholar
Giles S.S., Batinic-Haberle I., Perfect J.R., Cox G.M.: Cryptococcus neoformans Mitochondrial Superoxide Dismutase: An Essential Link between Antioxidant Function and High-Temperature Growth. Eukaryot. Cell4, 46–54 (2005)GilesS.S.Batinic-HaberleI.PerfectJ.R.CoxG.M.Cryptococcus neoformans Mitochondrial Superoxide Dismutase: An Essential Link between Antioxidant Function and High-Temperature GrowthEukaryot. Cell44654200510.1128/EC.4.1.46-54.200554416215643059Search in Google Scholar
Gomez H., Kellum J.A.: Understanding Acid Base Disorders. Crit. Care Clin.31, 849–860 (2015)GomezH.KellumJ.A.Understanding Acid Base DisordersCrit. Care Clin.31849860201510.1016/j.ccc.2015.06.01626410149Search in Google Scholar
Guerrero A., Jain N., Goldman D.L., Fries B.C.: Phenotypic Switching in Cryptococcus neoformans. Microbiology152, 3–9 (2006)GuerreroA.JainN.GoldmanD.L.FriesB.C.Phenotypic Switching in Cryptococcus neoformansMicrobiology15239200610.1099/mic.0.28451-0272179716385110Search in Google Scholar
Haag-Liautard C., Coffey N., Houle D., Lynch M., Charlesworth B., Keightley P.D.: Direct Estimation of the Mitochondrial DNA Mutation Rate in Drosophila Melanogaster. PLOS Biol.6, e204 (2008)Haag-LiautardC.CoffeyN.HouleD.LynchM.CharlesworthB.KeightleyP.D.Direct Estimation of the Mitochondrial DNA Mutation Rate in Drosophila MelanogasterPLOS Biol.6e204200810.1371/journal.pbio.0060204251761918715119Search in Google Scholar
Hagen F., Khayhan K., Theelen B., Kolecka A., Polacheck I., Sionov E., Falk R., Parnmen S., Lumbsch H.T., Boekhout T.: Recognition of Seven Species in the Cryptococcus gattii/Cryptococcus neoformans Species Complex. Fungal Genet. Biol.78, 16–48 (2015)HagenF.KhayhanK.TheelenB.KoleckaA.PolacheckI.SionovE.FalkR.ParnmenS.LumbschH.T.BoekhoutT.Recognition of Seven Species in the Cryptococcus gattii/Cryptococcus neoformans Species ComplexFungal Genet. Biol.781648201510.1016/j.fgb.2015.02.00925721988Search in Google Scholar
Hawksworth D.L.: A New Dawn for the Naming of Fungi: Impacts of Decisions Made in Melbourne in July 2011 on the Future Publication and Regulation of Fungal Names. IMA Fungus2, 155–162 (2011)HawksworthD.L.A New Dawn for the Naming of Fungi: Impacts of Decisions Made in Melbourne in July 2011 on the Future Publication and Regulation of Fungal NamesIMA Fungus2155162201110.5598/imafungus.2011.02.02.06335981322679600Search in Google Scholar
Hibbett D.S., Taylor J.W.: Fungal Systematics: Is a New Age of Enlightenment at Hand? Nat. Rev. Microbiol.11, 129–133 (2013)HibbettD.S.TaylorJ.W.Fungal Systematics: Is a New Age of Enlightenment at Hand?Nat. Rev. Microbiol.11129133201310.1038/nrmicro296323288349Search in Google Scholar
Hommel B., Mukaremera L., Cordero R.J.B., Coelho C., Desjardins C.A., Sturny-Leclère A., Janbon G., Perfect J.R., Fraser J.A., Casadevall A., Cuomo C.A., Dromer F., Nielsen K., Alanio A.: Titan Cells Formation in Cryptococcus Neoformans Is Finely Tuned by Environmental Conditions and Modulated by Positive and Negative Genetic Regulators. PLOS Pathog.14, e1006982 (2018)HommelB.MukaremeraL.CorderoR.J.B.CoelhoC.DesjardinsC.A.Sturny-LeclèreA.JanbonG.PerfectJ.R.FraserJ.A.CasadevallA.CuomoC.A.DromerF.NielsenK.AlanioA.Titan Cells Formation in Cryptococcus Neoformans Is Finely Tuned by Environmental Conditions and Modulated by Positive and Negative Genetic RegulatorsPLOS Pathog.14e1006982201810.1371/journal.ppat.1006982595906229775480Search in Google Scholar
Hung C.Y., Xue J., Cole G.T.: Virulence Mechanisms of Coccidioides. Ann. N. Y. Acad. Sci.1111, 225–235 (2007)HungC.Y.XueJ.ColeG.T.Virulence Mechanisms of CoccidioidesAnn. N. Y. Acad. Sci.1111225235200710.1196/annals.1406.02017513466Search in Google Scholar
Jain N., Guerrero A., Fries B.C.: Phenotypic Switching and Its Implications for the Pathogenesis of Cryptococcus neoformans. FEMS Yeast Res.6, 480–488 (2006)JainN.GuerreroA.FriesB.C.Phenotypic Switching and Its Implications for the Pathogenesis of Cryptococcus neoformansFEMS Yeast Res.6480488200610.1111/j.1567-1364.2006.00039.x274563016696644Search in Google Scholar
Jain N., Hasan F., Fries B.C.: Phenotypic Switching in Fungi. Curr. Fungal Infect. Rep.2, 180–188 (2008)JainN.HasanF.FriesB.C.Phenotypic Switching in FungiCurr. Fungal Infect. Rep.2180188200810.1007/s12281-008-0026-y274669719768140Search in Google Scholar
Kabir Z., Cunningham C.: The global burden of cryptococcosis-a neglected tropical disease? Lancet Infect. Dis. S1473-3099(22)00516-3 (2022)KabirZ.CunninghamC.The global burden of cryptococcosis-a neglected tropical disease?Lancet Infect. Dis.S1473-3099(22)00516-3202210.1016/S1473-3099(22)00516-336049487Search in Google Scholar
Khajo A., Bryan R.A., Friedman M., Burger R.M., Levitsky Y., Casadevall A., Magliozzo R.S., Dadachova E.: Protection of Melanized Cryptococcus Neoformans from Lethal Dose Gamma Irradiation Involves Changes in Melanin’s Chemical Structure and Paramagnetism. PLoS One6, e25092 (2011)KhajoA.BryanR.A.FriedmanM.BurgerR.M.LevitskyY.CasadevallA.MagliozzoR.S.DadachovaE.Protection of Melanized Cryptococcus Neoformans from Lethal Dose Gamma Irradiation Involves Changes in Melanin’s Chemical Structure and ParamagnetismPLoS One6e25092201110.1371/journal.pone.0025092317860121966422Search in Google Scholar
Kraus P.R., Heitman J.: Coping with Stress: Calmodulin and Calcineurin in Model and Pathogenic Fungi. Biochem. Biophys. Res. Commun.311, 1151–1157 (2003)KrausP.R.HeitmanJ.Coping with Stress: Calmodulin and Calcineurin in Model and Pathogenic FungiBiochem. Biophys. Res. Commun.31111511157200310.1016/S0006-291X(03)01528-6Search in Google Scholar
Kwon-Chung K.J.: A New Genus, Filobasidiella, the Perfect State of Cryptococcus neoformans. Mycologia67, 1197–1200 (1975)Kwon-ChungK.J.A New Genus, Filobasidiella, the Perfect State of Cryptococcus neoformansMycologia6711971200197510.1080/00275514.1975.12019866Search in Google Scholar
Kwon-Chung K.J.: A New Species of Filobasidiella, the Sexual State of Cryptococcus neoformans B and C Serotypes. Mycologia68, 942–946 (1976)Kwon-ChungK.J.A New Species of Filobasidiella, the Sexual State of Cryptococcus neoformans B and C SerotypesMycologia68942946197610.1080/00275514.1976.12019972Search in Google Scholar
Kwon-Chung K.J.: Filobasidiella Kwon-Chung. In The yeast, a taxonomic Study; Kurtzman C.P., Fell J.W., Boekhout T. (eds) Elsevier: Amsterdam, 1443–1455 (2010)Kwon-ChungK.J.Filobasidiella Kwon-ChungInThe yeast, a taxonomic StudyKurtzmanC.P.FellJ.W.BoekhoutT.(eds)ElsevierAmsterdam14431455201010.1016/B978-044481312-1/50087-3Search in Google Scholar
Kwon-Chung K.J., Bennett J.E., Theodore T.S.: Cryptococcus bacillisporus sp. nov.: Serotype BC of Cryptococcus neoformans. Int. J. Syst. Evol. Microbiol.28, 616–620 (1978)Kwon-ChungK.J.BennettJ.E.TheodoreT.S.Cryptococcus bacillisporus sp. nov.: Serotype BC of Cryptococcus neoformansInt. J. Syst. Evol. Microbiol.28616620197810.1099/00207713-28-4-616Search in Google Scholar
Kwon-Chung K.J., Boekhout T., Fell J.W., Diaz M.: Proposal to Conserve the Name Cryptococcus gattii against C. hondurianus and C. bacillisporus (Basidiomycota, Hymenomycetes, Tremellomycetidae). Taxon51, 804–806 (2002)Kwon-ChungK.J.BoekhoutT.FellJ.W.DiazM.Proposal to Conserve the Name Cryptococcus gattii against C. hondurianus and C. bacillisporus (Basidiomycota, Hymenomycetes, Tremellomycetidae)Taxon51804806200210.2307/1555045Search in Google Scholar
Kwon-Chung K.J., Fraser J.A., Doering T.L., Wang Z., Janbon G., Idnurm A., Bahn Y.S.: Cryptococcus neoformans and Cryptococcus gattii, the Etiologic Agents of Cryptococcosis. Cold Spring Harb. Perspect. Med.4, e019760 (2014)Kwon-ChungK.J.FraserJ.A.DoeringT.L.WangZ.JanbonG.IdnurmA.BahnY.S.Cryptococcus neoformans and Cryptococcus gattii, the Etiologic Agents of CryptococcosisCold Spring Harb. Perspect. Med.4e019760201410.1101/cshperspect.a019760406663924985132Search in Google Scholar
Kwon-Chung K.J., Perfect J.R., Levitz S.M.: A Chronological History of the International Conference on Cryptococcus and Cryptococcosis (ICCC), an Invaluable Forum for Growth of the Cryptococcal Research Field and Clinical Practice. Mycopathologia173, 287–293 (2012)Kwon-ChungK.J.PerfectJ.R.LevitzS.M.A Chronological History of the International Conference on Cryptococcus and Cryptococcosis (ICCC), an Invaluable Forum for Growth of the Cryptococcal Research Field and Clinical PracticeMycopathologia173287293201210.1007/s11046-011-9481-z22038679Search in Google Scholar
Kwon-Chung K.J., Polacheck I., Bennett J.E. Improved Diagnostic Medium for Separation of Cryptococcus neoformans var. neoformans (Serotypes A and D) and Cryptococcus Neoformans Var. Gattii (Serotypes B and C). J. Clin. Microbiol.15, 535–537 (1982)Kwon-ChungK.J.PolacheckI.BennettJ.E.Improved Diagnostic Medium for Separation of Cryptococcus neoformans var. neoformans (Serotypes A and D) and Cryptococcus Neoformans Var. Gattii (Serotypes B and C)J. Clin. Microbiol.15535537198210.1128/jcm.15.3.535-537.19822721347042750Search in Google Scholar
Kwon-Chung K.J., Polacheck I., Popkin T.J.: Melanin-Lacking Mutants of Cryptococcus Neoformans and Their Virulence for Mice. J. Bacteriol.150, 1414–1421 (1982)Kwon-ChungK.J.PolacheckI.PopkinT.J.Melanin-Lacking Mutants of Cryptococcus Neoformans and Their Virulence for MiceJ. Bacteriol.15014141421198210.1128/jb.150.3.1414-1421.19822163686804444Search in Google Scholar
Kussell E., Leibler S.: Phenotypic Diversity, Population Growth, and Information in Fluctuating Environments. Science309, 2075–2078 (2005)KussellE.LeiblerS.Phenotypic Diversity, Population Growth, and Information in Fluctuating EnvironmentsScience30920752078200510.1126/science.111438316123265Search in Google Scholar
Kützing F.: Systematische Zusammenstellung Der Niedern Algen-Gattungen Und Arten. Linnaea8, 365 (1833)KützingF.Systematische Zusammenstellung Der Niedern Algen-Gattungen Und ArtenLinnaea83651833Search in Google Scholar
Lei Z., Keming Z., Hang L., Carolina C., Diego S.G., Shun F.M., Xinhua L., Young-Mo K., Wanqing L., Weihua P., Casadevall A.: Cryptococcus Neoformans-Infected Macrophages Release Proinflammatory Extracellular Vesicles: Insight into Their Components by Multi-Omics. MBio12, e00279–21 (2021)LeiZ.KemingZ.HangL.CarolinaC.DiegoS.G.ShunF.M.XinhuaL.Young-MoK.WanqingL.WeihuaP.CasadevallA.Cryptococcus Neoformans-Infected Macrophages Release Proinflammatory Extracellular Vesicles: Insight into Their Components by Multi-OmicsMBio12e00279212021Search in Google Scholar
Luberto C., Martinez-Mariño B., Taraskiewicz D., Bolaños B., Chitano P., Toffaletti D.L., Cox G.M., Perfect J.R., Hannun Y.A., Balish E., del Poeta M.: Identification of App1 as a Regulator of Phagocytosis and Virulence of Cryptococcus neoformans. J. Clin. Invest.112, 1080–1094 (2003)LubertoC.Martinez-MariñoB.TaraskiewiczD.BolañosB.ChitanoP.ToffalettiD.L.CoxG.M.PerfectJ.R.HannunY.A.BalishE.del PoetaM.Identification of App1 as a Regulator of Phagocytosis and Virulence of Cryptococcus neoformansJ. Clin. Invest.11210801094200310.1172/JCI1830919852814523045Search in Google Scholar
Ma, H., Croudace J.E., Lammas D.A., May R.C.: Expulsion of Live Pathogenic Yeast by Macrophages. Curr. Biol.16, 2156–2160 (2006)MaH.CroudaceJ.E.LammasD.A.MayR.C.Expulsion of Live Pathogenic Yeast by MacrophagesCurr. Biol.1621562160200610.1016/j.cub.2006.09.03217084701Search in Google Scholar
Ma H., Hagen F., Stekel D.J., Johnston S.A., Sionov E., Falk R., Polacheck I., Boekhout T., May R.C.: The Fatal Fungal Outbreak on Vancouver Island Is Characterized by Enhanced Intracellular Parasitism Driven by Mitochondrial Regulation. Proc. Natl. Acad. Sci.106, 12980–12985 (2009)MaH.HagenF.StekelD.J.JohnstonS.A.SionovE.FalkR.PolacheckI.BoekhoutT.MayR.C.The Fatal Fungal Outbreak on Vancouver Island Is Characterized by Enhanced Intracellular Parasitism Driven by Mitochondrial RegulationProc. Natl. Acad. Sci.1061298012985200910.1073/pnas.0902963106272235919651610Search in Google Scholar
Malavia D., Lehtovirta-Morley L.E., Alamir O., Weiß E., Gow N.A.R., Hube B., Wilson D.: Zinc Limitation Induces a Hyper-Adherent Goliath Phenotype in Candida albicans. Front Microbiol8, e2238 (2017)MalaviaD.Lehtovirta-MorleyL.E.AlamirO.WeißE.GowN.A.R.HubeB.WilsonD.Zinc Limitation Induces a Hyper-Adherent Goliath Phenotype in Candida albicansFront Microbiol8e2238201710.3389/fmicb.2017.02238569448429184547Search in Google Scholar
Mavor L.A., Thewes S., Hube B.: Systemic Fungal Infections Caused by Candida Species: Epidemiology, Infection Process and Virulence Attributes. Current Drug Targets.6, 863–874 (2005)MavorL.A.ThewesS.HubeB.Systemic Fungal Infections Caused by Candida Species: Epidemiology, Infection Process and Virulence AttributesCurrent Drug Targets.6863874200510.2174/13894500577491273516375670Search in Google Scholar
Maziarz E.K., Perfect J.R.: Cryptococcosis. Infect. Dis. Clin. North Am.30, 179–206 (2016)MaziarzE.K.PerfectJ.R.CryptococcosisInfect. Dis. Clin. North Am.30179206201610.1007/978-3-319-13090-3_15Search in Google Scholar
McClelland EE, Bernhardt P, Casadevall A.: Estimating the Relative Contributions of Virulence Factors for Pathogenic Microbes. Infect. Immun.74, 1500–1504 (2006)McClellandEEBernhardtPCasadevallA.Estimating the Relative Contributions of Virulence Factors for Pathogenic MicrobesInfect. Immun.7415001504200610.1128/IAI.74.3.1500-1504.2006141867816495520Search in Google Scholar
McFadden D., Zaragoza O., Casadevall A.: The Capsular Dynamics of Cryptococcus neoformans. Trends Microbiol.14, 497–505 (2006)McFaddenD.ZaragozaO.CasadevallA.The Capsular Dynamics of Cryptococcus neoformansTrends Microbiol.14497505200610.1016/j.tim.2006.09.00316996739Search in Google Scholar
Meyer W., Castañeda A., Jackson S., Huynh M., Castañeda E.: Molecular Typing of IberoAmerican Cryptococcus neoformans Isolates. Emerg. Infect. Dis. J.9, 189–195 (2003)MeyerW.CastañedaA.JacksonS.HuynhM.CastañedaE.Molecular Typing of IberoAmerican Cryptococcus neoformans IsolatesEmerg. Infect. Dis. J.9189195200310.3201/eid0902.020246290194712603989Search in Google Scholar
Momin M., Webb G.: The Environmental Effects on Virulence Factors and the Antifungal Susceptibility of Cryptococcus neoformans. Int. J. Mol. Sci.22, e6302 (2021)MominM.WebbG.The Environmental Effects on Virulence Factors and the Antifungal Susceptibility of Cryptococcus neoformansInt. J. Mol. Sci.22e6302202110.3390/ijms22126302823080934208294Search in Google Scholar
Mukaremera L., Lee K.K., Wagener J., Wiesner D.L., Gow N.A.R., Nielsen K.: Titan Cell Production in Cryptococcus neoformans Reshapes the Cell Wall and Capsule Composition during Infection. Cell Surf.1, 15–24 (2018)MukaremeraL.LeeK.K.WagenerJ.WiesnerD.L.GowN.A.R.NielsenK.Titan Cell Production in Cryptococcus neoformans Reshapes the Cell Wall and Capsule Composition during InfectionCell Surf.11524201810.1016/j.tcsw.2017.12.001609566230123851Search in Google Scholar
Muzazu S.G.Y., Assefa D.G., Phiri C., Getinet T., Solomon S., Yismaw G., Manyazewal T.: Prevalence of Cryptococcal Meningitis among People Living with Human Immuno-Deficiency Virus and Predictors of Mortality in Adults on Induction Therapy in Africa: A Systematic Review and Meta-Analysis. Frontiers in Medicine.9, e989265 (2022)MuzazuS.G.Y.AssefaD.G.PhiriC.GetinetT.SolomonS.YismawG.ManyazewalT.Prevalence of Cryptococcal Meningitis among People Living with Human Immuno-Deficiency Virus and Predictors of Mortality in Adults on Induction Therapy in Africa: A Systematic Review and Meta-AnalysisFrontiers in Medicine.9e989265202210.3389/fmed.2022.989265949429736160163Search in Google Scholar
Netski D., Kozel T.R.: Fc-Dependent and Fc-Independent Opsonization of Cryptococcus neoformans by Anticapsular Monoclonal Antibodies: Importance of Epitope Specificity. Infect. Immun.70, 2812–2819 (2002)NetskiD.KozelT.R.Fc-Dependent and Fc-Independent Opsonization of Cryptococcus neoformans by Anticapsular Monoclonal Antibodies: Importance of Epitope SpecificityInfect. Immun.7028122819200210.1128/IAI.70.6.2812-2819.200212799412010967Search in Google Scholar
Ngamskulrungroj P., Price J., Sorrell T., Perfect J.R., Meyer W.: Cryptococcus gattii Virulence Composite: Candidate Genes Revealed by Microarray Analysis of High and Less Virulent Vancouver Island Outbreak Strains. PLoS One6, e16076 (2011)NgamskulrungrojP.PriceJ.SorrellT.PerfectJ.R.MeyerW.Cryptococcus gattii Virulence Composite: Candidate Genes Revealed by Microarray Analysis of High and Less Virulent Vancouver Island Outbreak StrainsPLoS One6e16076201110.1371/journal.pone.0016076302096021249145Search in Google Scholar
Nosanchuk J.D., Casadevall A.: Impact of Melanin on Microbial Virulence and Clinical Resistance to Antimicrobial Compounds. Antimicrob. Agents Chemother.50, 3519–3528 (2006)NosanchukJ.D.CasadevallA.Impact of Melanin on Microbial Virulence and Clinical Resistance to Antimicrobial CompoundsAntimicrob. Agents Chemother.5035193528200610.1128/AAC.00545-06163521317065617Search in Google Scholar
Noverr M.C., Williamson P.R., Fajardo R.S., Huffnagle G.B.: CNLAC1 Is Required for Extrapulmonary Dissemination of Cryptococcus neoformans but Not Pulmonary Persistence. Infect. Immun.72, 1693–1699 (2004)NoverrM.C.WilliamsonP.R.FajardoR.S.HuffnagleG.B.CNLAC1 Is Required for Extrapulmonary Dissemination of Cryptococcus neoformans but Not Pulmonary PersistenceInfect. Immun.7216931699200410.1128/IAI.72.3.1693-1699.200435601114977977Search in Google Scholar
Odom A., Muir S., Lim E., Toffaletti D.L., Perfect J., Heitman J.: Calcineurin Is Required for Virulence of Cryptococcus neoformans. EMBO J.16, 2576–2589 (1997)OdomA.MuirS.LimE.ToffalettiD.L.PerfectJ.HeitmanJ.Calcineurin Is Required for Virulence of Cryptococcus neoformansEMBO J.1625762589199710.1093/emboj/16.10.257611698699184205Search in Google Scholar
Okagaki L.H., Nielsen K.: Titan Cells Confer Protection from Phagocytosis in Cryptococcus neoformans Infections. Eukaryot. Cell11, 820–826 (2012)OkagakiL.H.NielsenK.Titan Cells Confer Protection from Phagocytosis in Cryptococcus neoformans InfectionsEukaryot. Cell11820826201210.1128/EC.00121-12337046122544904Search in Google Scholar
Okagaki L.H., Wang Y., Ballou E.R., O’Meara T.R., Bahn Y., Alspaugh J.A., Xue C., Nielsen K.: Cryptococcal Titan Cell Formation Is Regulated by G-Protein Signaling in Response to Multiple Stimuli. Eukaryot. Cell10, 1306–1316 (2011)OkagakiL.H.WangY.BallouE.R.O’MearaT.R.BahnY.AlspaughJ.A.XueC.NielsenK.Cryptococcal Titan Cell Formation Is Regulated by G-Protein Signaling in Response to Multiple StimuliEukaryot. Cell1013061316201110.1128/EC.05179-11318707121821718Search in Google Scholar
Oliveira F.S., de Sousa H.R., da Silva l.G., dos Santos J., Gorgonha K.C., de Oliveira G.P., Soares M.S., Silva-Pereira F.I., Casadevall A., Moraes N., Albuquerquea P.: Laccase Affects the Rate of Cryptococcus neoformans Nonlytic Exocytosis from Macrophages. MBio11, e02085–20 (2020)OliveiraF.S.de SousaH.R.da Silval.G.dos SantosJ.GorgonhaK.C.de OliveiraG.P.SoaresM.S.Silva-PereiraF.I.CasadevallA.MoraesN.AlbuquerqueaP.Laccase Affects the Rate of Cryptococcus neoformans Nonlytic Exocytosis from MacrophagesMBio11e02085202020Search in Google Scholar
Olszewski M.A., Noverr M.C., Chen G.H., Toews G.B., Cox G.M., Perfect J.R., Huffnagle G.B.: Urease Expression by Cryptococcus neoformans Promotes Microvascular Sequestration, Thereby Enhancing Central Nervous System Invasion. Am. J. Pathol.164, 1761–1771 (2004)OlszewskiM.A.NoverrM.C.ChenG.H.ToewsG.B.CoxG.M.PerfectJ.R.HuffnagleG.B.Urease Expression by Cryptococcus neoformans Promotes Microvascular Sequestration, Thereby Enhancing Central Nervous System InvasionAm. J. Pathol.16417611771200410.1016/S0002-9440(10)63734-0161567515111322Search in Google Scholar
O’Meara T.R., Alspaugh J.A.: The Cryptococcus neoformans Capsule: A Sword and a Shield. Clin. Microbiol. Rev.25, 387–408 (2012)O’MearaT.R.AlspaughJ.A.The Cryptococcus neoformans Capsule: A Sword and a ShieldClin. Microbiol. Rev.25387408201210.1128/CMR.00001-12341649122763631Search in Google Scholar
O’Meara T.R., Norton D., Price M.S., Hay C., Clements M.F., Nichols C.B., Alspaugh J.A.: Interaction of Cryptococcus neoformans Rim101 and Protein Kinase A Regulates Capsule. PLOS Pathog.6, e1000776 (2010)O’MearaT.R.NortonD.PriceM.S.HayC.ClementsM.F.NicholsC.B.AlspaughJ.A.Interaction of Cryptococcus neoformans Rim101 and Protein Kinase A Regulates CapsulePLOS Pathog.6e1000776201010.1371/journal.ppat.1000776282475520174553Search in Google Scholar
Ost K.S., O’Meara T.R., Huda N., Esher S.K., Alspaugh J.A.: The Cryptococcus neoformans Alkaline Response Pathway: Identification of a Novel Rim Pathway Activator. PLOS Genet.11, e1005159 (2015)OstK.S.O’MearaT.R.HudaN.EsherS.K.AlspaughJ.A.The Cryptococcus neoformans Alkaline Response Pathway: Identification of a Novel Rim Pathway ActivatorPLOS Genet.11e1005159201510.1371/journal.pgen.1005159439310225859664Search in Google Scholar
Park B.J., Wannemuehler K.A., Marston B.J., Govender N., Pappas P.G., Chiller T.M.: Estimation of the Current Global Burden of Cryptococcal Meningitis among Persons Living with HIV/AIDS. AIDS23, 525–530 (2009)ParkB.J.WannemuehlerK.A.MarstonB.J.GovenderN.PappasP.G.ChillerT.M.Estimation of the Current Global Burden of Cryptococcal Meningitis among Persons Living with HIV/AIDSAIDS23525530200910.1097/QAD.0b013e328322ffac19182676Search in Google Scholar
Pasteur L.: Memoire sur la fermentation alcoolique. Ann. Chim. Phys.58, 323–426 (1860)PasteurL.Memoire sur la fermentation alcooliqueAnn. Chim. Phys.583234261860Search in Google Scholar
Pasteur L.: Memoirs sur les corpuscles organises qui existent dans l’atmosphere. Examen de la doctrine des generations spontanees. Ann. Sci. Nat.16, 5–98 (1861)PasteurL.Memoirs sur les corpuscles organises qui existent dans l’atmosphere. Examen de la doctrine des generations spontaneesAnn. Sci. Nat.165981861Search in Google Scholar
Pasteur L.: Sur les maladies virulentes, et en particulier sur la maladie appelee vulgairement cholera des poules. C.R. Acad. Sci.90, 248–249 (1880)PasteurL.Sur les maladies virulentes, et en particulier sur la maladie appelee vulgairement cholera des poulesC.R. Acad. Sci.902482491880Search in Google Scholar
Pasteur L.: Mémoire Sur La Fermentation Appelée Lactique (Extrait Par l’auteur). Molecular Medicine1, 599–601 (1995)PasteurL.Mémoire Sur La Fermentation Appelée Lactique (Extrait Par l’auteur)Molecular Medicine1599601199510.1007/BF03401599Search in Google Scholar
Poulin R., Combes C.: The Concept of Virulence: Interpretations and Implications. Parasitol. Today15, 474–475 (1999)PoulinR.CombesC.The Concept of Virulence: Interpretations and ImplicationsParasitol. Today15474475199910.1016/S0169-4758(99)01554-910557145Search in Google Scholar
Pukkila-Worley R., Gerrald Q.D., Kraus P.R., Boily M.J., Davis M.J., Giles S.S., Cox G.M., Heitman J., Alspaugh J.A.: Transcriptional Network of Multiple Capsule and Melanin Genes Governed by the Cryptococcus neoformans Cyclic AMP Cascade. Eukaryot. Cell4, 190–201 (2005)Pukkila-WorleyR.GerraldQ.D.KrausP.R.BoilyM.J.DavisM.J.GilesS.S.CoxG.M.HeitmanJ.AlspaughJ.A.Transcriptional Network of Multiple Capsule and Melanin Genes Governed by the Cryptococcus neoformans Cyclic AMP CascadeEukaryot. Cell4190201200510.1128/EC.4.1.190-201.200554416615643074Search in Google Scholar
Rajasingham R., Smith R.M., Park B.J., Jarvis J.N., Govender N.P., Chiller T.M., Denning D.W., Loyse A., Boulware D.R.: Global Burden of Disease of HIV-Associated Cryptococcal Meningitis: An Updated Analysis. Lancet. Infect. Dis.17, 873–881 (2017)RajasinghamR.SmithR.M.ParkB.J.JarvisJ.N.GovenderN.P.ChillerT.M.DenningD.W.LoyseA.BoulwareD.R.Global Burden of Disease of HIV-Associated Cryptococcal Meningitis: An Updated AnalysisLancet. Infect. Dis.17873881201710.1016/S1473-3099(17)30243-8581815628483415Search in Google Scholar
Reiko I., Takashi S.S., Takako S.: Laccase and Melanizationin Clinically Important Cryptococcus Species Other than Cryptococcus neoformans. J. Clin. Microbiol.40, 1214–1218 (2002)ReikoI.TakashiS.S.TakakoS.Laccase and Melanizationin Clinically Important Cryptococcus Species Other than Cryptococcus neoformansJ. Clin. Microbiol.4012141218200210.1128/JCM.40.4.1214-1218.200214032811923334Search in Google Scholar
Rittershaus P.C., Kechichian T.B., Allegood J.C., Merrill A.H., Hennig M., Luberto C., Del Poeta M.: Glucosylceramide Synthase Is an Essential Regulator of Pathogenicity of Cryptococcus neoformans. J. Clin. Invest.116, 1651–1659 (2006)RittershausP.C.KechichianT.B.AllegoodJ.C.MerrillA.H.HennigM.LubertoC.Del PoetaM.Glucosylceramide Synthase Is an Essential Regulator of Pathogenicity of Cryptococcus neoformansJ. Clin. Invest.11616511659200610.1172/JCI27890146654816741577Search in Google Scholar
Rizzo J., Wong S.S., Gazi A.D., Moyrand F., Chaze T., Commere P.H., Novault S., Matondo M., Péhau-Arnaudet G., Reis F.C.G., Vos M., Alves L.R., May R.C., Nimrichter L., Rodrigues M.L., Aimanianda V., Janbon G.: Cryptococcus Extracellular Vesicles Properties and Their Use as Vaccine Platforms. J. Extracell. Vesicles10, e12129 (2021)RizzoJ.WongS.S.GaziA.D.MoyrandF.ChazeT.CommereP.H.NovaultS.MatondoM.Péhau-ArnaudetG.ReisF.C.G.VosM.AlvesL.R.MayR.C.NimrichterL.RodriguesM.L.AimaniandaV.JanbonG.Cryptococcus Extracellular Vesicles Properties and Their Use as Vaccine PlatformsJ. Extracell. Vesicles10e12129202110.1002/jev2.12129832999234377375Search in Google Scholar
Rodrigues M.L.: Genus 5. Cryptococcus Kutzing emend. Phaff et Spencer In: Kreger-van Rij NJW (ed) The yeasts: a taxonomic study, 3rd edn. Elsevier, Amsterdam, 845–872 (1984)RodriguesM.L.Genus 5. Cryptococcus Kutzing emend. Phaff et SpencerIn:Kreger-van RijNJW(ed)The yeasts: a taxonomic study3rd edn.ElsevierAmsterdam8458721984Search in Google Scholar
Rodrigues M.L., Travassos L.R., Miranda K.R., Franzen A.J., Rozental S., de Souza W., Alviano C.S., Barreto-Bergter E.: Human Antibodies against a Purified Glucosylceramide from Cryptococcus neoformans Inhibit Cell Budding and Fungal Growth. Infect. Immun.68, 7049–7060 (2000)RodriguesM.L.TravassosL.R.MirandaK.R.FranzenA.J.RozentalS.de SouzaW.AlvianoC.S.Barreto-BergterE.Human Antibodies against a Purified Glucosylceramide from Cryptococcus neoformans Inhibit Cell Budding and Fungal GrowthInfect. Immun.6870497060200010.1128/IAI.68.12.7049-7060.20009781511083830Search in Google Scholar
Saidykhan L., Correia J., Romanyuk A., Peacock A.F.A., Desanti G.E., Taylor-Smith L., Makarova M., Ballou E.R., May R.C.: An in Vitro Method for Inducing Titan Cells Reveals Novel Features of Yeast-to-Titan Switching in the Human Fungal Pathogen Cryptococcus gattii. PLOS Pathog.18, e1010321 (2022)SaidykhanL.CorreiaJ.RomanyukA.PeacockA.F.A.DesantiG.E.Taylor-SmithL.MakarovaM.BallouE.R.MayR.C.An in Vitro Method for Inducing Titan Cells Reveals Novel Features of Yeast-to-Titan Switching in the Human Fungal Pathogen Cryptococcus gattiiPLOS Pathog.18e1010321202210.1371/journal.ppat.1010321942692035969643Search in Google Scholar
Sanfelice F.: Contributo Alla Morfologia e Biologia Dei Blastomiceti Che Si Sviluppano Nei Succhi Di Alcuni Frutti. Ann Ig.4, 463–495 (1894)SanfeliceF.Contributo Alla Morfologia e Biologia Dei Blastomiceti Che Si Sviluppano Nei Succhi Di Alcuni FruttiAnn Ig.44634951894Search in Google Scholar
Sanfelice F.: Ueber Die Pathogene Wirkung Der Blastomyceten. Zeitschrift für Hyg. und Infekt.22, 171–200 (1896)SanfeliceF.Ueber Die Pathogene Wirkung Der BlastomycetenZeitschrift für Hyg. und Infekt.22171200189610.1007/BF02288375Search in Google Scholar
Seeliger H.P.R.: The Discovery of Achorion Schoenleinii: Facts and “Stories”: Die Entdeckung Des Achorion Schoenleinii Tatsachen Und „Geschichten”. Mycoses28, 161–182 (1985)SeeligerH.P.R.The Discovery of Achorion Schoenleinii: Facts and “Stories”: Die Entdeckung Des Achorion Schoenleinii Tatsachen Und „Geschichten”Mycoses28161182198510.1111/j.1439-0507.1985.tb02110.xSearch in Google Scholar
Seoane P.I., May R.C.: Vomocytosis: What We Know so Far. Cell. Microbiol.22, e13145 (2020)SeoaneP.I.MayR.C.Vomocytosis: What We Know so FarCell. Microbiol.22e13145202010.1111/cmi.1314531730731Search in Google Scholar
Silva S., Negri M., Henriques M., Oliveira R., Williams D.W., Azeredo J.: Candida glabrata, Candida parapsilosis and Candida tropicalis: Biology, Epidemiology, Pathogenicity and Antifungal Resistance. FEMS Microbiol. Rev.36, 288–305 (2012)SilvaS.NegriM.HenriquesM.OliveiraR.WilliamsD.W.AzeredoJ.Candida glabrata, Candida parapsilosis and Candida tropicalis: Biology, Epidemiology, Pathogenicity and Antifungal ResistanceFEMS Microbiol. Rev.36288305201210.1111/j.1574-6976.2011.00278.x21569057Search in Google Scholar
Slutsky B., Buffo J., Soll D.R.: High-Frequency Switching of Colony Morphology in Candida albicans. Science230, 666–669 (1985)SlutskyB.BuffoJ.SollD.R.High-Frequency Switching of Colony Morphology in Candida albicansScience230666669198510.1126/science.39012583901258Search in Google Scholar
Slutsky B., Staebell M., Anderson J., Risen L., Pfaller M., Soll D.R.: ‘White-Opaque Transition’: A Second High-Frequency Switching System in Candida albicans. J. Bacteriol.169, 189–197 (1987)SlutskyB.StaebellM.AndersonJ.RisenL.PfallerM.SollD.R.‘White-Opaque Transition’: A Second High-Frequency Switching System in Candida albicansJ. Bacteriol.169189197198710.1128/jb.169.1.189-197.19872117523539914Search in Google Scholar
Soll D.R.: High-Frequency Switching in Candida albicans. Clin. Microbiol. Rev.5, 183–203 (1992)SollD.R.High-Frequency Switching in Candida albicansClin. Microbiol. Rev.5183203199210.1128/CMR.5.2.1833582341576587Search in Google Scholar
Stempinski P.R., Zielinski J.M., Dbouk N.H., Huey E.S., McCormack E.C., Rubin A.M., Chandrasekaran S., Kozubowski L.: Genetic Contribution to High Temperature Tolerance in Cryptococcus neoformans. Genetics217, 1–15 (2021)StempinskiP.R.ZielinskiJ.M.DboukN.H.HueyE.S.McCormackE.C.RubinA.M.ChandrasekaranS.KozubowskiL.Genetic Contribution to High Temperature Tolerance in Cryptococcus neoformansGenetics217115202110.1093/genetics/iyaa009804569533683363Search in Google Scholar
Trevijano-Contador N., de Oliveira H.C., García-Rodas R., Rossi S.A., Llorente I., Zaballos Á., Janbon G., Ariño J., Zaragoza Ó.: Cryptococcus neoformans Can Form Titan-like Cells in Vitro in Response to Multiple Signals. PLOS Pathog.14, e1007007 (2018)Trevijano-ContadorN.de OliveiraH.C.García-RodasR.RossiS.A.LlorenteI.ZaballosÁ.JanbonG.AriñoJ.ZaragozaÓ.Cryptococcus neoformans Can Form Titan-like Cells in Vitro in Response to Multiple SignalsPLOS Pathog.14e1007007201810.1371/journal.ppat.1007007595907329775477Search in Google Scholar
Van Dyke M.C.C., Teixeira M.M., Barker B.M.: Fantastic Yeasts and Where to Find Them: The Hidden Diversity of Dimorphic Fungal Pathogens. Curr. Opin. Microbiol.52, 55–63 (2019)Van DykeM.C.C.TeixeiraM.M.BarkerB.M.Fantastic Yeasts and Where to Find Them: The Hidden Diversity of Dimorphic Fungal PathogensCurr. Opin. Microbiol.525563201910.1016/j.mib.2019.05.00231181385Search in Google Scholar
Van Dyke M.C., Wormley J.F.L.: A Call to Arms: Quest for a Cryptococcal Vaccine. Trends Microbiol.26, 436–446 (2018)Van DykeM.C.WormleyJ.F.L.A Call to Arms: Quest for a Cryptococcal VaccineTrends Microbiol.26436446201810.1016/j.tim.2017.10.002591024629103990Search in Google Scholar
Varma A., Wu S., Guo N., Liao W., Lu G., Li A., Hu Y., Bulmer G., Kwon-Chung K.J.: Identification of a Novel Gene, URE2, That Functionally Complements a Urease-Negative Clinical Strain of Cryptococcus neoformans. Microbiology152, 3723–3731 (2006)VarmaA.WuS.GuoN.LiaoW.LuG.LiA.HuY.BulmerG.Kwon-ChungK.J.Identification of a Novel Gene, URE2, That Functionally Complements a Urease-Negative Clinical Strain of Cryptococcus neoformansMicrobiology15237233731200610.1099/mic.0.2006/000133-017159224Search in Google Scholar
Vecchiarelli A., Pericolini E., Gabrielli E., Chow S.K., Bistoni F., Cenci E., Casadevall A.: Cryptococcus neoformans Galactoxylomannan Is a Potent Negative Immunomodulator, Inspiring New Approaches in Anti-Inflammatory Immunotherapy. Immunotherapy3, 997–1005 (2011)VecchiarelliA.PericoliniE.GabrielliE.ChowS.K.BistoniF.CenciE.CasadevallA.Cryptococcus neoformans Galactoxylomannan Is a Potent Negative Immunomodulator, Inspiring New Approaches in Anti-Inflammatory ImmunotherapyImmunotherapy39971005201110.2217/imt.11.8621843086Search in Google Scholar
Verse M.: Über Einen Full von General Isofierter Blastomycose Beim Menschen. Dtsch. Pathol. Ges.17, 275–278 (1914)VerseM.Über Einen Full von General Isofierter Blastomycose Beim MenschenDtsch. Pathol. Ges.172752781914Search in Google Scholar
Villena S.N., Pinheiro R.O., Pinheiro C.S., Nunes M.P., Takiya C.M., DosReis G.A., Previato J.O., Mendonça-Previato L., Freire-de-Lima C.G.: Capsular Polysaccharides Galactoxylomannan and Glucuronoxylomannan from Cryptococcus neoformans Induce Macrophage Apoptosis Mediated by Fas Ligand. Cell. Microbiol.10, 1274–1285 (2008)VillenaS.N.PinheiroR.O.PinheiroC.S.NunesM.P.TakiyaC.M.DosReisG.A.PreviatoJ.O.Mendonça-PreviatoL.Freire-de-LimaC.G.Capsular Polysaccharides Galactoxylomannan and Glucuronoxylomannan from Cryptococcus neoformans Induce Macrophage Apoptosis Mediated by Fas LigandCell. Microbiol.1012741285200810.1111/j.1462-5822.2008.01125.x18284419Search in Google Scholar
Voelz K., Johnston S.A., Smith L.M., Hall R.A., Idnurm A., May R.C.: ‘Division of Labour’ in Response to Host Oxidative Burst Drives a Fatal Cryptococcus gattii Outbreak. Nat. Commun.5, 5194 (2014)VoelzK.JohnstonS.A.SmithL.M.HallR.A.IdnurmA.MayR.C.‘Division of Labour’ in Response to Host Oxidative Burst Drives a Fatal Cryptococcus gattii OutbreakNat. Commun.55194201410.1038/ncomms6194420809525323068Search in Google Scholar
Vogel R.A. The Indirect Fluorescent Antibody Test for the Detection of Antibody in Human Cryptococcal Disease. J. Infect. Dis.116, 573–580 (1966)VogelR.A.The Indirect Fluorescent Antibody Test for the Detection of Antibody in Human Cryptococcal DiseaseJ. Infect. Dis.116573580196610.1093/infdis/116.5.5735334249Search in Google Scholar
Vuillemin P.: Les Blastomycètes Pathogènes. Rev. Gen. Sci. Pures. Appl.12, 732–751, (1901)VuilleminP.Les Blastomycètes PathogènesRev. Gen. Sci. Pures. Appl.127327511901Search in Google Scholar
Wills E.P., Himmelreich U., Mylonakis E., Rude T., Toffaletti D., Cox G.M., Miller J.L., Perfect J.R.: Characterization and Regulation of the Trehalose Synthesis Pathway and Its Importance in the Pathogenicity of Cryptococcus neoformans. Infect. Immun.74, 5877–5887 (2006)WillsE.P.HimmelreichU.MylonakisE.RudeT.ToffalettiD.CoxG.M.MillerJ.L.PerfectJ.R.Characterization and Regulation of the Trehalose Synthesis Pathway and Its Importance in the Pathogenicity of Cryptococcus neoformansInfect. Immun.7458775887200610.1128/IAI.00624-06159492416988267Search in Google Scholar
Wilson D.E., Bennett J.E., Bailey J.W.: Serologic Grouping of Cryptococcus neoformans. Proc. Soc. Exp. Biol. Med.127, 820–823 (1968)WilsonD.E.BennettJ.E.BaileyJ.W.Serologic Grouping of Cryptococcus neoformansProc. Soc. Exp. Biol. Med.127820823196810.3181/00379727-127-328125651140Search in Google Scholar
Wilson D.: The Role of Zinc in the Pathogenicity of Human Fungal Pathogens, chapter two. Academic Press, 117, 35–61 (2021)WilsonD.The Role of Zinc in the Pathogenicity of Human Fungal Pathogens, chapter twoAcademic Press11735612021Search in Google Scholar
Xie S., Sao R., Braun A., Bottone E.J.: Difference in Cryptococcus neoformans Cellular and Capsule Size in Sequential Pulmonary and Meningeal Infection: A Postmortem Study. Diagn. Microbiol. Infect. Dis.73, 49–52 (2012)XieS.SaoR.BraunA.BottoneE.J.Difference in Cryptococcus neoformans Cellular and Capsule Size in Sequential Pulmonary and Meningeal Infection: A Postmortem StudyDiagn. Microbiol. Infect. Dis.734952201210.1016/j.diagmicrobio.2012.01.00822424901Search in Google Scholar
Xu J., Vilgalys R., Mitchell T.G.: Multiple Gene Genealogies Reveal Recent Dispersion and Hybridization in the Human Pathogenic Fungus Cryptococcus neoformans. Mol. Ecol.9, 1471–1481 (2000)XuJ.VilgalysR.MitchellT.G.Multiple Gene Genealogies Reveal Recent Dispersion and Hybridization in the Human Pathogenic Fungus Cryptococcus neoformansMol. Ecol.914711481200010.1046/j.1365-294x.2000.01021.x11050543Search in Google Scholar
Xudong Z., Gibbons J., Garcia-Rivera J., Casadevall A., Williamson PR.: Laccase of Cryptococcus neoformans Is a Cell Wall-Associated Virulence Factor. Infect. Immun.69, 5589–5596 (2001)XudongZ.GibbonsJ.Garcia-RiveraJ.CasadevallA.WilliamsonPR.Laccase of Cryptococcus neoformans Is a Cell Wall-Associated Virulence FactorInfect. Immun.6955895596200110.1128/IAI.69.9.5589-5596.20019867311500433Search in Google Scholar
Yong-Sun B., Scarlett G.B., Joseph H.: Ssk2 Mitogen-Activated Protein Kinase Kinase Kinase Governs Divergent Patterns of the Stress-Activated Hog1 Signaling Pathway in Cryptococcus neoformans. Eukaryot. Cell6, 2278–2289 (2007)Yong-SunB.ScarlettG.B.JosephH.Ssk2 Mitogen-Activated Protein Kinase Kinase Kinase Governs Divergent Patterns of the Stress-Activated Hog1 Signaling Pathway in Cryptococcus neoformansEukaryot. Cell622782289200710.1128/EC.00349-07216824317951522Search in Google Scholar
Zaragoza O.: Basic Principles of the Virulence of Cryptococcus. Virulence10, 490–501 (2019)ZaragozaO.Basic Principles of the Virulence of CryptococcusVirulence10490501201910.1080/21505594.2019.1614383655055231119976Search in Google Scholar
Zaragoza O., Casadevall A.: Monoclonal Antibodies Can Affect Complement Deposition on the Capsule of the Pathogenic Fungus Cryptococcus Neoformans by Both Classical Pathway Activation and Steric Hindrance. Cell. Microbiol.8, 1862–1876 (2006)ZaragozaO.CasadevallA.Monoclonal Antibodies Can Affect Complement Deposition on the Capsule of the Pathogenic Fungus Cryptococcus Neoformans by Both Classical Pathway Activation and Steric HindranceCell. Microbiol.818621876200610.1111/j.1462-5822.2006.00753.x16824038Search in Google Scholar
Zaragoza O., Chrisman C.J., Castelli M.V., Frases S., Cuenca-Estrella M., Rodríguez-Tudela J.L., Casadevall A.: Capsule Enlargement in Cryptococcus Neoformans Confers Resistance to Oxidative Stress Suggesting a Mechanism for Intracellular Survival. Cell. Microbiol.10, 2043–2057 (2008)ZaragozaO.ChrismanC.J.CastelliM.V.FrasesS.Cuenca-EstrellaM.Rodríguez-TudelaJ.L.CasadevallA.Capsule Enlargement in Cryptococcus Neoformans Confers Resistance to Oxidative Stress Suggesting a Mechanism for Intracellular SurvivalCell. Microbiol.1020432057200810.1111/j.1462-5822.2008.01186.x440538118554313Search in Google Scholar
Zaragoza O., García-Rodas R., Nosanchuk J.D., Cuenca-Estrella M., Rodríguez-Tudela J.L., Casadevall A.: Fungal Cell Gigantism during Mammalian Infection. PLoS Pathog.6, e1000945 (2010)ZaragozaO.García-RodasR.NosanchukJ.D.Cuenca-EstrellaM.Rodríguez-TudelaJ.L.CasadevallA.Fungal Cell Gigantism during Mammalian InfectionPLoS Pathog.6e1000945201010.1371/journal.ppat.1000945288747420585557Search in Google Scholar
Zaragoza O., Nielsen K.: Titan Cells in Cryptococcus Neoformans: Cells with a Giant Impact. Curr. Opin. Microbiol.16, 409–413 (2013)ZaragozaO.NielsenK.Titan Cells in Cryptococcus Neoformans: Cells with a Giant ImpactCurr. Opin. Microbiol.16409413201310.1016/j.mib.2013.03.006372369523588027Search in Google Scholar
Zhou X., Ballou E. R.: The Cryptococcus Neoformans Titan Cell: From In Vivo Phenomenon to In Vitro Model. Curr. Clin. Microbiol. Reports5, 252–260 (2018)ZhouX.BallouE. R.The Cryptococcus Neoformans Titan Cell: From In Vivo Phenomenon to In Vitro ModelCurr. Clin. Microbiol. Reports5252260201810.1007/s40588-018-0107-9Search in Google Scholar
