Skip to main content
  • Loading metrics

The Cryptococcus gattii species complex: Unique pathogenic yeasts with understudied virulence mechanisms

  • Lamin Saidykhan,

    Affiliations Institute of Microbiology & Infection and School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom, Division of Physical and Natural Science, University of The Gambia, Brikama Campus, West Coast Region, The Gambia

  • Chinaemerem U. Onyishi,

    Affiliation Institute of Microbiology & Infection and School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom

  • Robin C. May

    Affiliation Institute of Microbiology & Infection and School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom


Members of Cryptococcus gattii/neoformans species complex are the etiological agents of the potentially fatal human fungal infection cryptococcosis. C. gattii and its sister species cause disease in both immunocompetent and immunocompromised hosts, while the closely related species C. neoformans and C. deneoformans predominantly infect immunocompromised hosts. To date, most studies have focused on similarities in pathogenesis between these two groups, but over recent years, important differences have become apparent. In this review paper, we highlight some of the major phenotypic differences between the C. gattii and neoformans species complexes and justify the need to study the virulence and pathogenicity of the C. gattii species complex as a distinct cryptococcal group.


Cryptococcus gattii (sensu stricto) was first recognized and described as a distinct cryptococcal strain from Cryptococcus neoformans in 1970 [1]. Initially recognized as a variety of Cryptococcus, the Cryptococcus neoformans var. gattii lineage was subsequently elevated to species status as C. gattii [2]. Further genetic, biochemical, morphological, ecological, and serological characterization of C. gattii environmental and clinical isolates provided more evidence for the classification of C. gattii as a unique cryptococcal species [210].

The C. gattii divergence from C. neoformans is estimated to have occurred 37 to 49 million years ago [11,12]. Since then, C. gattii has maintained diversity by continuous recombination and evolution into novel lineages with significant genetic diversity that warranted their classification into monophyletic genotypes [1214]. Recently, the five recognized C. gattii genotypes, VGI, VGII, VGIII, VGIV, and VGVI were elevated to five individual species: C. gattii, C. deuterogattii, C. bacillisporus, C. tetragattii, and C. decagattii, respectively, while the two main lineages of C. neoformans were raised to species level, becoming C. neoformans and C. deneoformans [15]. Different phylogenetic analysis based on concatenated genetic loci unanimously identified C. deuterogattii/VGII to be the basal lineage of the C. gattii species complex [11,12,14]. VGI, VGIV, and VGIII diverged from VGII approximately 12.4 million years ago [12,16]. Thereafter, C. tetragattii/VGIV diverged from C. bacillisporus/VGIII and C. gattii/VGI sister clades 11.7 million years ago, finally followed by the split between C. bacillisporus/VGIII and C. gattii/VGI 8.5 million years ago.

All seven species of Cryptococcus are capable of causing the life-threatening disease cryptococcosis in humans [17]. C. neoformans (sensu stricto), which accounts for 99% of cases worldwide [1820], typically presents as fungal meningitis in immunocompromised patients. In contrast, infections by the C. gattii species complex occurs more commonly in otherwise healthy individuals and can often present as fungal pneumonia. During the 20th century, most research considered C. gattii and C. neoformans to be interchangeable in their biology. However, the emergence of C. deuterogattii as the cause of the most devastating and unprecedented fungal outbreak in a healthy human population [21,22] refocused attention on this species, and, as a result, recent research has highlighted key differences between the C. gattii species complex (CGSC) and C. neoformans species complex (CNSC). In particular, the apparently low propensity for CGSC species to disseminate from the lung to the central nervous system, and their ability to act as primary pathogens in healthy individuals, remain key unanswered questions [5,23,24].

Phylogeny and speciation

To date, the majority of C. gattii studies have focused on C. deuterogattii/VGII, because of its exceedingly high pathogenicity [21,25] and its role as the predominant etiological agent of the devastating Pacific Northwest Outbreak (PNW) [21,22,26,27]. VGII is not only the cause of the outbreak [27,28] but also possesses a high recombination frequency (via sexual macroevolution and asexual microevolution) producing the highly clonal lineages VGIIa, VGIIb, VGIIc, and VGIIx, which were responsible for the dissemination of the outbreak [21,2931]. The high clonality of the VGII subtypes has been found to emanate from VGII exhibition of nonclassical same-sex mating, in which sexual reproduction occurs between two alpha mating-type (MATα-MATα) parents [28], which has only been previously described in C. neoformans [32]. Hence, the PNW outbreak owes its origin and dissemination to this VGII-specific reproductive phenotype.

Morphological differences between C. gattii and C. neoformans species complexes

Most of the virulence-related phenotypic differences between C. gattii and C. neoformans are morphological. Within the Cryptococcus species complex as a whole, variation in morphological traits such as cell body/capsule size, shape, budding, surface morphology, and cell wall structure and composition are key factors employed not only for the identification of the different cryptococcal lineages [2,3336], but also to support their elevation to distinct species [15]. In an in vitro study of 70 cryptococcal clinical isolates (53 C. neoformans and 17 C. gattii), Fernandes and colleagues documented that cellular and capsular enlargement in response to a host-relevant environment is more common in C. gattii while capsule shedding and production of micro cells were primarily C. neoformans traits (Table 1) [37]. In the same study, “giant cells” (also known as titan cells; [38]) measuring >15 μm were predominantly found in CGSC rather than in CNSC (50.0% versus 10.75%, respectively), an observation that was recapitulated in a Drosophila model of infection [39].

Table 1. Comparison of morphological attributes between 70 clinical isolates of cryptococci from HIV/AIDS patients in Botswana-Africa (adapted from [37] and summarized).

Using an in vitro titan induction system, we recently showed that the capacity to produce titan cells, an atypical morphotype that is formed when cryptococcal yeast cells transform into extremely enlarged polyploid cells, is more abundant in CGSC than in CNSC [40]. Interestingly, this correlates with a “staggered” cell cycle in C. deuterogattii, in which cell size increase precedes DNA replication—something that is not seen in C. neoformans [40]. Whereas C. neoformans titan cells undergo cell division to produce daughter cells [4043], CGSC titan cells exhibit a growth arrest to form large unbudded cells [40] (Fig 1). It is possible that this difference may partially explain C. deuterogattii’s lower ability to disseminate outside the lungs, since C. neoformans titan cells likely rely on their small-sized daughter cells for dissemination [41,42].

Fig 1. Micrograph showing the budding nature of C. deuterogattii yeast (left panel) vs. titan (right panel) cells [44].

Scale bar = 5 μm.

These morphological differences also lead to differences in the host response. For example, the presence of enlarged CGSC cells was associated with high CD4+ T cell count, while the formation of small phenotype “micro” cells by CNSC correlates with meningeal irritation and an aggressive inflammatory response [37].

Compositional differences in capsule are also likely to play a major role in varying virulence profiles. While exploring the interaction of C. gattii with the phagocytic amoebae Acanthamoeba castellanii, Malliaris and colleagues [45] discovered a significantly lower phagocytosis profile and reduced virulence of an acapsular cryptococcal mutant strain, cap67, when the mutant strain was coated with capsular extract from C. gattii (serotype B), versus extract from C. neoformans (serotype A). Although the underlying mechanism is not known, the result suggests the presence of structural difference(s) in C. gattii capsular polysaccharide, which have a direct impact on virulence. Chemical and biophysical differences in the structure of the major capsular polysaccharides in CGSC versus CNSC have been well documented [46]; consequently, it will be interesting in the future to assess how these biochemical differences relate to the differing host response.

After the polysaccharide capsule, the most important virulence determinant of cryptococci [46,47] is cell wall melanisation [33,4853]. Melanin is a negatively charged hydrophobic pigment formed by the oxidative polymerization of phenolic compounds [51] and its synthesis is catalysed by laccase. The production of melanin is not only essential for maintaining cell wall integrity but also protects the fungi from environmental stressors, such as UV light and high temperature, and the host immune system [54]. Interestingly, its pattern of distribution varies between strains; for instance, being homogenous in the C. deuterogattii/VGII hypervirulent outbreak strain CDCR265 [33] but heterogeneously distributed in C. neoformans H99. Interestingly, in a Galleria mellonella infection model, melanization profiles (as determined by laccase activity) of the four C. gattii molecular types have been directly associated with virulence, such that C. gattii species complex strains with higher melanin production showed higher lethality towards Galleria larvae.

Immunomodulatory attributes of C. gattii species complex

The morphological and molecular traits of CGSC discussed above influence how the host immune system responds to infection. The C. deuterogattii outbreak in the Pacific Northwest (outside its regions of endemicity) that started in 1999 [55] had a mortality rate ranging from 8.7% to 50% even when treated with antifungal drugs [5661], highlighting significant differences in the host response to this infection.

Innate immune response to C. gattii species complex

Cryptococcal infection begins with the inhalation of the fungi into the lungs. Lung-resident macrophages are among the first host immune cells that inhaled fungi interact with; however, there are relatively few studies that investigate the precise mechanisms by which phagocytes respond to the presence of CGSC, as opposed to CNSC, in the host. As with C. neoformans, the capsule of CGSC cells, which is composed of a majority glucuronoxylomannan (GXM) and a minority galactoxylomannan (GalXM) polysaccharide, functions as a fungal virulence factor and has antiphagocytic properties [62]. The phagocytosis of foreign particles is initiated by the recognition of pathogen-associated molecular patterns (PAMPs) by host pattern recognition receptors (PRRs), such as members of the Toll-like receptor (TLR) family and the C-type lectin receptor (CLR) family [63]. GXM from C. deuterogattii was found to be recognised by Dectin-3, a CLR, ultimately leading to NF-κB and ERK-dependent inflammatory responses (Fig 2A) [64]. In the same study, wild-type and Dectin3−/− mice were infected with C. deuterogattii intratracheally, and it was observed that Dectin3−/− mice had decreased survival, greater lung and brain fungal burden, and decreased TNF-α and IL-6 production (Fig 2B). Thus, engagement of Dectin-3 with C. deuterogattii GXM may activate a broader anticryptococcal immune response. In another study, HEK293A cells transfected with TLR2/1 and TLR2/6 were able to induce NF-κB activation after stimulation with GXM isolated from five different Cryptococcus strains among which were C. gattii serotype B strain CN23/10.993 (C. deuterogattii/VGII) and serotype C strain HEC40143 (VGIII/C. bacillisporus) and C. neoformans serotype A strains T1444 and HEC3393 (VNI) and serotype D strain ATCC 28938 (VNIV) [65,66]. Interestingly, GXM from the C. deuterogattii strain resulted in the greatest activation of NF-κB, suggesting the existence of structural and immunomodulatory differences between the strains [65] in a way that is reminiscent of the study by Malliaris and colleagues [45] discussed above. The five GXM samples were also used to stimulate nitric oxide (NO) production by RAW264.7 macrophages, and it was found that GXM samples from both CGSC strains were able to induce NO production, while those from the three CNSC strains did not [65].

Fig 2. The role of Dectin-3 in host response to C. deuterogattii infection in vitro and in vivo.

(A) The C-type lectin receptor, Dectin-3, recognises C. deuterogattii (Cd) capsular glucuronoxylomannan (GXM) [64]. The recognition of GXM leads to the activation of NF-κB and ERK signalling pathways to drive proinflammatory cytokine production. (B) Dectin-3 deficient mice showed increased susceptibility to C. deuterogattii infection [64]. Figure created with

In a study that sought to define the cytokine profile produced by cryptococcal infection, human peripheral blood mononuclear cells (PBMCs) from healthy individuals were infected with heat-killed CGSC and CNSC clinical isolates. It was found that CGSC isolates induced a greater expression of IL-1β, TNF-α, IL-6, IL-17, and IL-22, compared to CNSC isolates [67]. Meanwhile, there was no difference in IL1Ra levels between the strains. Lastly, it was observed that the modulation of CGSC-induced cytokine production required TLR4 and TLR9, but not TLR2.

Adaptive immune response to C. gattii species complex

The uptake of fungi into phagosomes and subsequent phagosome maturation results in the degradation of the fungus and the presentation of fungal peptides on major histocompatibility complex (MHC) molecules [68]. These peptides are then recognised by CD4+ T cells, thereby activating the adaptive immune response [69]. Additionally, the cytokine profile produced by the activation of PRRs results in the differentiation of naïve T cells into Th1, Th2, or Th17 cells [70]. The Th1 and Th17 responses are known to be protective against C. neoformans, Candida albicans, and Aspergillus fumigatus [7173]. Meanwhile, the Th2 response is anti-inflammatory and promotes fungal survival and dissemination in C. neoformans [23,68]. It has been shown that mice infected with C. deuterogattii and C. gattii had reduced Th1 and Th17 cells in their lungs compared to those infected with C. neoformans H99 [24]. This suggests that CGSC is able to successfully infect immunocompetent hosts by dampening the activation of the protective Th1/Th17 response and enhancing the nonprotective Th2 response [24]. The diminished Th1/Th17 response was likely driven by a decrease in the expression of MHC-II on the surface of dendritic cells from C. deuterogattii- and C. gattii-infected mice. Huston and colleagues [74] have also shown that dendritic cells infected with C. deuterogattii fail to exhibit increased expression of MHC-II molecules, CD86, CD83, CD80, and CCR7, which are needed for T cell activation. Therefore, at least two CGSC strains are able to subvert dendritic cell–mediated activation of the adaptive immune response.

Another mechanism by which CGSC is thought to subvert immune recognition is through its capsule polysaccharide. Urai and colleagues [66] found that mice infected with C. deuterogattii/VGII strain JP02 showed poorer survival and decreased inflammatory cell infiltration when compared to mice infected with C. neoformans H99. This difference in virulence was attributed to the C. deuterogattii capsule structure because exposing dendritic cells to purified GXM from JP02 did not induce IL6, IL12p40, and TNF-α production but stimulation with H99 GXM did. This finding is reinforced by a 2021 study by Ueno and colleagues [75] that found that an acapsular cap60Δ C. gattii (VGI) mutant was easily phagocytosed and killed by dendritic cells; however, when capsular polysaccharide from C. gattii was deposited onto the acapsular mutant, phagocytosis was hindered and IL6 and IL23 proinflammatory cytokine expression was dampened [75]. Therefore, capsular polysaccharide aids immune evasion by shielding C. gattii sensu stricto from recognition by dendritic cells, thereby preventing the expression of proinflammatory cytokines and hindering clearance of the fungi [75]. This ability to evade immune detection also provides an explanation for why strains within the C. gattii species complex are able to infect both immunocompetent and immunocompromised individuals while C. neoformans strains predominantly infect immunocompromised people.

It is important to mention that the result by Urai and colleagues [66] and Ueno and colleagues [75] is in contrast with earlier findings by Fonseca and colleagues [65], which showed that GXM from C. deuterogattii were the most potent in inducing TLR-mediated NF-κB expression and NO production in macrophages. It also contrasts with results from Schoffelen and colleagues [67], which found that PBMC exposed to CGSC strains produced more proinflammatory cytokines than those exposed to CNSC strains. This may be explained as differences in macrophage versus dendritic cell response. Alternatively, it may represent variation within the CGSC, highlighting the need to be precise about the “C. gattii” species used. Aside from the within CGSC variation, all these studies point to the existence of significant variation in immune response to CGSC and CNSC infection. As more is understood about host interaction with cryptococcal species, novel therapeutic agents can be developed to decrease the case–fatality rate of infection with cryptococci.

What are the drivers of the C. deuterogattii outbreak?

In 1999, an outbreak of C. gattii (now recognised as C. deuterogattii) was identified in British Columbia, which went on to become the largest life-threatening primary fungal outbreak in a healthy population. This unprecedented outbreak has driven an intense research effort to discover the underlying determining factors [25,26,76,77]. Over the last decade, studies focused on outbreak strains revealed a hypervirulent C. gattii molecular type C. deuterogattii/VGII, to be the primary agent driving the pathogenesis [21,78,79] and spread [28,80] of the outbreak.

C. deuterogattii/VGII outbreak isolates harbour several unique cellular and genetic attributes that contribute to their hypervirulence and pathogenicity. Compared to other CGSC lineages, VGII outbreak strains display higher resistance to host immune defence mechanisms [78,79] and an overall increased survival profile within the host [79,81]. Upon phagocytosis by macrophages, C. deuterogattii/VGII responds to the host oxidative burst by triggering rapid intracellular proliferation [78]. A follow-up study revealed that there is in fact a “division of labour” mechanism where a subpopulation of fungal cells undergo growth arrest, thereby facilitating the rapid proliferation of neighbouring fungal cells [79], in a process that is mediated through the exchange of extracellular vehicles (EVs) [81]. Interestingly, the pattern of titan cell formation also differs in this outbreak lineage (discussed above), and it will be interesting to explore and potentially establish the correlation between this unique VGII-titan feature, division of labour responses, and their combined influence on virulence.

In addition to cellular phenotypes, novel genomic traits found in PNW outbreak isolates are thought to contribute to their hypervirulence [16,31]. Genomic analysis among the four VG lineages reveals that, unlike other VG lineages, VGII outbreak isolates have acquired genes encoding proteins involved with membrane trafficking such as Friend of Prmt1 (Fop), and genes involved in heat tolerance such as heat shock protein 70 (HSP70), genes that are known to be required for virulence in C. neoformans [82]. Perhaps the most striking genomic trait of VGII is the lack of RNA interference (RNAi) machinery due to the absence of genes encoding the Argonaute proteins Ago1 and Ago2 [16], PAZ, Piwi, and DUF1785 genes, which are key regulator of the RNAi machinery in C. neoformans [31,83]. In fact, analysis from whole genome studies discovered a total of 146 genes (including the RNAi-associated ones) missing in VGII outbreak isolates, which is three times more than those lost in VGI-III/VGIV combined [31]. Although the true significance of the absence of these genes/pathways as a whole is not yet elucidated, it is likely that they contribute to the unique host–pathogen interaction seen in this lineage [28,84].

Understudied virulence-associated phenotypes of C. gattii

Studies elucidating the virulence of CGSC phenotypes and their impact on pathogenesis and disease outcomes are somewhat overshadowed by that of C. neoformans [76]. Often, the biology, virulence factors, and pathogenicity of Cryptococcus are highlighted using C. neoformans as a model or the primary theme of study [46,52,85,86]. Below are some examples of understudied CGSC virulence phenotypes.


The cryptococcal polysaccharide capsule is essential for both cellular function and pathogenesis of Cryptococcus, protecting the fungus against desiccation in the environment and playing the synergistic role of a shield and virulence mechanism in animal host [46,47]. Thus, the capsule is considered the most important virulence determinant of cryptococci. Evidence has shown that capsular size and its impact on host immune response in the C. gattii lineage differs from that of C. neoformans [37,84]. Despite these differences in capsule properties, the biosynthesis properties [18], biophysical properties [46,47,87,88], and immunogenic properties [89] of cryptococcal capsule have primarily been characterized in C. neoformans. Although the physical impact of capsule on fungal biology is likely to be similar for both species, the impact of varying capsule composition on CGSC virulence remains less well understood [90].


The most dramatic host adaption phenotype exhibited by Cryptococcus is the formation of titan cells [43,91,92], a phenomenon that has thus far been largely studied in C. neoformans [9296]. We and others have recently investigated titan cell formation across the broader Cryptococcus species complex, which has revealed some subtle differences between lineages [44]. The impact of these differences on the CGSC–host interaction remains largely unknown [9799]. Similarly, while several signalling pathways, receptors, and genes have been identified as driving titan cell formation in C. neoformans (including the cyclic AMP (cAMP)/protein kinase A (PKA) pathway (putatively associated with C. neoformans pathogenesis), G protein-coupled receptors (Gpr4 and Gpr5), St3a [38], and the CLN1 genes [93]), such investigations are yet to be performed with C. gattii and its sister species.

Extracellular vesicles

Extracellular vesicles (EVs) are rounded bilayered particles produced by prokaryotic and eukaryotic cells to mediate intercellular communication by transferring information between cells [100]. EVs have significant roles in the cellular and pathogenic lifestyle of cells including stress response, intercellular competition, lateral gene transfer (via RNA or DNA), pathogenicity, and detoxification [101]. The first fungal EV was described in C. neoformans, and, therefore, the biology of EVs and its role in C. neoformans virulence is well studied and documented [102105]. Cryptococcal EVs are carriers of several virulence molecules such as capsular GXM, laccase, urease, and a repertoire of immunogenic proteins and thus have been termed “virulence bags” [104,105].

The biological and functional features of EVs including biosynthesis, secretory pathways, composition, structure, virulence properties and mechanism, influence in pathogen–host interaction, and immunogenic-related attributes have been well characterized in C. neoformans [102,104107]. However, our knowledge and concepts of C. neoformans-derived EVs cannot be directly applied to CGSC strains, since evidence has shown distinctive features of EVs in the two species complexes [102]. For instance, the size of C. deuterogattii EVs is significantly smaller than C. neoformans and C. deneoformans [102]. Although homologous EV-protein families, such as the putative glyoxal oxidase (Gox proteins) and Ricin-type beta-trefoil lectin domain-containing protein (Ril), were characterized in all three species, the Sur7/Pal1 family of tetraspanin membrane proteins was exclusive to C. deuterogattii [102]. Moreover, two of the ferroxidase Cfo proteins investigated were found to be expressed only by C. deuterogattii EVs but not in the two other species [108].

In terms of function, the novel discovery of C. deuterogattii EV-based long-distance pathogen-to-pathogen communication (which has not been reported for non-gattii strains) [81], its role in exploiting host immune cells, and ultimate impact on virulence [79,81] provide strong evidence that the functional mechanism of EVs differs in the two lineages. This discovery and other findings on CGSC-specific EV traits highlight the need for probing the already-studied concepts of C. neoformans-derived EV and novel EV-associated phenotypes in these other species. Research focused on CGSC EVs will not only diversify our understanding of cryptococcal EVs but also holds potential for revealing new paradigms around the biological and pathogenic functions of fungal EVs more broadly.

We conclude this section with a list of C. neoformans phenotypic virulence traits that are somewhat neglected and could potentially be studied in C. gattii (Table 2).

Table 2. List of virulence-related phenotypic traits whose underlying molecular, genetic, and metabolic mechanism has been studied in C. neoformans but not C. gattii.

Concluding remarks

Despite their similar appearance, it is now clear that many features of the CGSC are remarkably different from those in the CNSC (Fig 3). However, studies elucidating the virulence of C. gattii phenotypes and their impact on pathogenesis and disease outcomes have been overshadowed by those focusing on CNSC. While the prevalence of cryptococcosis due to CNSC makes this a logical choice, several unique features of C. gattii and its sister species warrant further investigation, including their ability to infect otherwise healthy individuals, their role in an unprecedented fungal outbreak and several distinct phenotypic traits that differ from those in C. neoformans. Such features are likely to underlie important differences in clinical presentation between the two pathogens, most notably in their varying patterns of dissemination from the lungs to the brain. In the future, it will be important to revisit many paradigms of cryptococcal pathogenesis in CGSC strains and, indeed, other Cryptococcus species and, in doing so, reveal the full range of diversity within this genus.

Fig 3. Schematic diagram illustrating CGSC distinct phenotypic virulence traits as compared to C. neoformans.

Upon inhalation from the environment, CGSC yeast cells/spores responds to the lung extracellular niche by exhibiting phenotypic traits including larger capsule (with less immunogenic properties), larger cell body (with higher degree of homogeneity), and thinner but more compacted cell wall with higher chitosan content than C. neoformans. The manner in which CGSC strains exhibit these host-adaptive traits is perhaps responsible for its low affinity to dissemination from the lungs to the brain. Within the host macrophage, the intracellular phenotypes (mitochondrial fusion and “division of labour” proliferation mechanism mediated by extracellular vesicles) exhibited by C. deuterogattii (which drives the fatal Pacific Northwest outbreak) are absent in C. neoformans.

Key Learning Points

  • Although morphologically similar, members of the Cryptococcus gattii species complex and Cryptococcus neoformans species complex exhibit important differences in biology and pathogenesis.
  • Their interaction with the human immune system is one such key difference, with evidence for more profound immune-dampening mechanisms within the C. gattii species complex, contributing towards its enhanced ability to infect healthy hosts.
  • Both species complexes form titan cells, but the triggers and mechanisms by which they do so are subtly different.
  • Extracellular vesicle release occurs in both species, but only C. deuterogattii has thus far been shown to use these vesicles to coordinate a virulence strategy.
  • The recent recognition that lineages within both species are sufficiently different to warrant elevation to species level should serve as a prompt for a more detailed examination and appreciation of the varying biology within this genus.

Top Five Papers

  1. Byrnes EJ, 3rd, Li W, Lewit Y, Ma H, Voelz K, Ren P, et al. Emergence and pathogenicity of highly virulent Cryptococcus gattii genotypes in the northwest United States. PLoS Pathog. 2010;6(4):e1000850. Epub 2010/04/28. doi: 10.1371/journal.ppat.1000850. PubMed PMID: 20421942; PubMed Central PMCID: PMC2858702.
  2. Hagen F, Khayhan K, Theelen B, Kolecka A, Polacheck I, Sionov E, et al. Recognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex. Fungal Genet Biol. 2015;78:16–48. Epub 2015/02/28. doi: 10.1016/j.fgb.2015.02.009. PubMed PMID: 25721988.
  3. Kidd SE, Hagen F, Tscharke R, Huynh M, Bartlett KH, Fyfe M, et al. A rare genotype of Cryptococcus gattii caused the cryptococcosis outbreak on Vancouver Island (British Columbia, Canada). Proceedings of the national academy of sciences. 2004;101(49):17258–63.
  4. Voelz K, Johnston SA, Smith LM, Hall RA, Idnurm A, May RC. ‘Division of labour’in response to host oxidative burst drives a fatal Cryptococcus gattii outbreak. Nat Commun. 2014;5(1):1–12.
  5. Cheng PY, Sham A, Kronstad JW. Cryptococcus gattii isolates from the British Columbia cryptococcosis outbreak induce less protective inflammation in a murine model of infection than Cryptococcus neoformans. Infect Immun. 2009;77(10):4284–94. Epub 2009/07/29. doi: 10.1128/iai.00628-09. PubMed PMID: 19635827; PubMed Central PMCID: PMC2747943.


  1. 1. Gatti F, Eeckels R. An atypical strain of Cryptococcus neoformans (San Felice) Vuillemin 1894. I. Description of the disease and of the strain. Ann Soc Belges Med Trop Parasitol Mycol. 1970;50(6):689–93. Epub 1970/01/01. pmid:5519205.
  2. 2. Kwon-Chung KJ, Fraser JA, Doering TL, Wang Z, Janbon G, Idnurm A, et al. Cryptococcus neoformans and Cryptococcus gattii, the etiologic agents of cryptococcosis. Cold Spring Harb Perspect Med. 2014;4(7):a019760. Epub 2014/07/06. pmid:24985132; PubMed Central PMCID: PMC4066639.
  3. 3. Kwon-Chung KJ, Boekhout T, Fell JW, Diaz M. 1557) Proposal to Conserve the Name Cryptococcus gattii against C. hondurianus and C. bacillisporus (Basidiomycota, Hymenomycetes, Tremellomycetidae. Taxon. 2002;51(4):804–806.
  4. 4. Kwon-Chung KJ. Filobasidiella Kwon-Chung (1975). The Yeasts 2011. p. 1443–55.
  5. 5. Kwon-Chung KJ, Polacheck I, Bennett JE. 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. 1982;15(3):535–7. Epub 1982/03/01. pmid:7042750; PubMed Central PMCID: PMC272134.
  6. 6. Ellis DH. Cryptococcus neoformans var. gattii in Australia. J Clin Microbiol. 1987;25(2):430–1. Epub 1987/02/01. pmid:3546370; PubMed Central PMCID: PMC265916.
  7. 7. Aulakh HS, Straus SE, Kwon-Chung KJ. Genetic Relatedness of Filobasidiella neoformans (Cryptococcus neoformans) and Filobasidiella bacillispora (Cryptococcus bacillisporus) as Determined by Deoxyribonucleic Acid Base Composition and Sequence Homology Studies. Int J Syst Evol Microbiol. 1981;31:97–103.
  8. 8. Ellis DH, Pfeiffer TJ. Natural habitat of Cryptococcus neoformans var. gattii. J Clin Microbiol. 1990;28:1642–1644. pmid:2199524
  9. 9. Speed BR, Dunt DR. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin Infect Dis. 1995;21(1):28–34. discussion 35–6. pmid:7578756
  10. 10. Chen SCA, Sorrell TC, Nimmo GR, Speed BR, Currie BJ, Ellis DH, et al. Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group. Clin Infect Dis. 2000;31(2):499–508. pmid:10987712
  11. 11. Xu J, Vilgalys R, Mitchell TG. Multiple gene genealogies reveal recent dispersion and hybridization in the human pathogenic fungus Cryptococcus neoformans. Mol Ecol. 2000;9(10):1471–1481. pmid:11050543
  12. 12. Ngamskulrungroj P, Gilgado F, Faganello J, Litvintseva AP, Leal AL, Tsui KM, et al. Genetic diversity of the Cryptococcus species complex suggests that Cryptococcus gattii deserves to have varieties. PLoS ONE. 2009;4(6):e5862. pmid:19517012
  13. 13. Firacative C, Trilles L, Meyer W. MALDI-TOF MS enables the rapid identification of the major molecular types within the Cryptococcus neoformans/C. gattii species complex. PLoS ONE. 2012;7(5):e37566. Epub 2012/06/06. pmid:22666368; PubMed Central PMCID: PMC3362595.
  14. 14. Bovers M, Hagen F, Kuramae E, Boekhout T. Six monophyletic lineages identified within Cryptococcus neoformans and Cryptococcus gattii by multi-locus sequence typing. Fungal Genet Biol. 2008;45(4):400–421. pmid:18261945
  15. 15. Hagen F, Khayhan K, Theelen B, Kolecka A, Polacheck I, Sionov E, et al. Recognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex. Fungal Genet Biol. 2015;78:16–48. Epub 2015/02/28. pmid:25721988.
  16. 16. D’Souza CA, Kronstad JW, Taylor G, Warren R, Yuen M, Hu G, et al. Genome variation in Cryptococcus gattii, an emerging pathogen of immunocompetent hosts. MBio. 2011;2(1):e00342–10. Epub 2011/02/10. pmid:21304167; PubMed Central PMCID: PMC3037005.
  17. 17. Perfect JR. Cryptococcosis: a model for the understanding of infectious diseases. J Clin Invest. 2014;124(5):1893–5. Epub 2014/04/20. pmid:24743152; PubMed Central PMCID: PMC4001560.
  18. 18. Botts MR, Giles SS, Gates MA, Kozel TR, Hull CM. Isolation and characterization of Cryptococcus neoformans spores reveal a critical role for capsule biosynthesis genes in spore biogenesis. Eukaryot Cell. 2009;8(4):595–605. Epub 2009/02/03. pmid:19181873; PubMed Central PMCID: PMC2669189.
  19. 19. Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis. 2017;17(8):873–81. Epub 2017/05/10. pmid:28483415; PubMed Central PMCID: PMC5818156.
  20. 20. Brandt ME, Hutwagner LC, Klug LA, Baughman WS, Rimland D, Graviss EA, et al. Molecular subtype distribution of Cryptococcus neoformans in four areas of the United States. Cryptococcal Disease Active Surveillance Group. J Clin Microbiol. 1996;34(4):912–7. Epub 1996/04/01. pmid:8815107; PubMed Central PMCID: PMC228916.
  21. 21. Byrnes EJ 3rd, Li W, Lewit Y, Ma H, Voelz K, Ren P, et al. Emergence and pathogenicity of highly virulent Cryptococcus gattii genotypes in the northwest United States. PLoS Pathog. 2010;6(4):e1000850. Epub 2010/04/28. pmid:20421942; PubMed Central PMCID: PMC2858702.
  22. 22. Bartlett KH, Kidd SE, Kronstad JW. The emergence of Cryptococcus gattii in British Columbia and the Pacific Northwest. Curr Infect Dis Rep. 2008;10(1):58–65. pmid:18377817
  23. 23. Müller U, Stenzel W, Köhler G, Werner C, Polte T, Hansen G, et al. IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans. J Immunol. 2007;179(8):5367–77. Epub 2007/10/04. pmid:17911623.
  24. 24. Angkasekwinai P, Sringkarin N, Supasorn O, Fungkrajai M, Wang Y-H, Chayakulkeeree M, et al. Cryptococcus gattii infection dampens Th1 and Th17 responses by attenuating dendritic cell function and pulmonary chemokine expression in the immunocompetent hosts. Infect Immun. 2014;82(9):3880–90. Epub 2014/06/30. pmid:24980974.
  25. 25. Chen SCA, Meyer W, Sorrell TC. Cryptococcus gattii infections. Clin Microbiol Rev. 2014;27(4):980–1024. pmid:25278580.
  26. 26. Byrnes EJ III, Bartlett KH, Perfect JR, Heitman J. Cryptococcus gattii: an emerging fungal pathogen infecting humans and animals. Microbes Infect. 2011;13(11):895–907. pmid:21684347
  27. 27. Kidd SE, Hagen F, Tscharke RL, Huynh M, Bartlett KH, Fyfe M, et al. A rare genotype of Cryptococcus gattii caused the cryptococcosis outbreak on Vancouver Island (British Columbia, Canada). Proc Natl Acad Sci U S A. 2004;101(49):17258–63. Epub 2004/12/02. pmid:15572442; PubMed Central PMCID: PMC535360.
  28. 28. Fraser JA, Giles SS, Wenink EC, Geunes-Boyer SG, Wright JR, Diezmann S, et al. Same-sex mating and the origin of the Vancouver Island Cryptococcus gattii outbreak. Nature. 2005;437(7063):1360–4. Epub 2005/10/14. pmid:16222245.
  29. 29. May RC, Stone NR, Wiesner DL, Bicanic T, Nielsen K. Cryptococcus: from environmental saprophyte to global pathogen. Nat Rev Microbiol. 2016;14(2):106–17. Epub 2015/12/22. pmid:26685750; PubMed Central PMCID: PMC5019959.
  30. 30. Billmyre RB, Croll D, Li W, Mieczkowski P, Carter DA, Cuomo CA, et al. Highly recombinant VGII Cryptococcus gattii population develops clonal outbreak clusters through both sexual macroevolution and asexual microevolution. MBio. 2014;5(4):e01494–e01414. pmid:25073643
  31. 31. Farrer RA, Desjardins CA, Sakthikumar S, Gujja S, Saif S, Zeng Q, et al. Genome evolution and innovation across the four major lineages of Cryptococcus gattii. MBio. 2015;6(5):e00868–e00815. pmid:26330512
  32. 32. Lin X, Hull CM, Heitman J. Sexual reproduction between partners of the same mating type in Cryptococcus neoformans. Nature. 2005;434(7036):1017–1021. pmid:15846346
  33. 33. Firacative C, Duan S, Meyer W. Galleria mellonella model identifies highly virulent strains among all major molecular types of Cryptococcus gattii. PLoS ONE. 2014;9(8):e105076–e. pmid:25133687.
  34. 34. Franzot SP, Salkin IF, Casadevall A. Cryptococcus neoformans var. grubii: separate varietal status for Cryptococcus neoformans serotype A isolates. J Clin Microbiol. 1999;37(3):838–40. Epub 1999/02/13. pmid:9986871; PubMed Central PMCID: PMC84578.
  35. 35. Xie S, Sao R, Braun A, Bottone EJ. Difference in Cryptococcus neoformans cellular and capsule size in sequential pulmonary and meningeal infection: a postmortem study. Diagn Microbiol Infect Dis. 2012;73(1):49–52. Epub 2012/03/20. pmid:22424901.
  36. 36. Fernandes KE, Dwyer C, Campbell LT, Carter DA. Species in the Cryptococcus gattii complex differ in capsule and cell size following growth under capsule-inducing conditions. mSphere. 2016;1(6):e00350–e00316. pmid:28066814
  37. 37. Fernandes KE, Brockway A, Haverkamp M, Cuomo CA, van Ogtrop F, Perfect JR, et al. Phenotypic variability correlates with clinical outcome in Cryptococcus isolates obtained from Botswanan HIV/AIDS patients. MBio. 2018;9(5):e02016–e02018. pmid:30352938
  38. 38. Zaragoza O, Nielsen K. Titan cells in Cryptococcus neoformans: cells with a giant impact. Curr Opin Microbiol. 2013;16(4):409–13. Epub 2013/04/17. pmid:23588027; PubMed Central PMCID: PMC3723695.
  39. 39. Thompson GR III, Albert N, Hodge G, Wilson MD, Sykes JE, Bays DJ, et al. Phenotypic differences of Cryptococcus molecular types and their implications for virulence in a Drosophila model of infection. Infect Immun. 2014;82(7):3058–3065. pmid:24799631
  40. 40. Odom A, Muir S, Lim E, Toffaletti DL, Perfect J, Heitman J. Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J. 1997;16(10):2576–2589. pmid:9184205
  41. 41. Dambuza IM, Drake T, Chapuis A, Zhou X, Correia J, Taylor-Smith L, et al. The Cryptococcus neoformans Titan cell is an inducible and regulated morphotype underlying pathogenesis. PLoS Pathog. 2018;14(5):e1006978–e. pmid:29775474.
  42. 42. Gerstein AC, Fu MS, Mukaremera L, Li Z, Ormerod KL, Fraser JA, et al. Polyploid titan cells produce haploid and aneuploid progeny to promote stress adaptation. mBio. 2015;6(5):e01340–15. Epub 2015/10/16. pmid:26463162; PubMed Central PMCID: PMC4620463.
  43. 43. Zaragoza O, Garcia-Rodas R, Nosanchuk JD, Cuenca-Estrella M, Rodriguez-Tudela JL, Casadevall A. Fungal cell gigantism during mammalian infection. PLoS Pathog. 2010;6(6):e1000945. Epub 2010/06/30. pmid:20585557; PubMed Central PMCID: PMC2887474.
  44. 44. Saidykhan L, Correia J, Romanyuk A, Peacock AFA, Desanti GE, Taylor-Smith L, et al. 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. 2022;18(8):e1010321. Epub 20220815. pmid:35969643; PubMed Central PMCID: PMC9426920.
  45. 45. Malliaris SD, Steenbergen JN, Casadevall A. Cryptococcus neoformans var. gattii can exploit Acanthamoeba castellanii for growth. Med Mycol. 2004;42(2):149–158. pmid:15124868
  46. 46. O’Meara TR, Alspaugh JA. The Cryptococcus neoformans capsule: a sword and a shield. Clin Microbiol Rev. 2012;25(3):387–408. pmid:22763631
  47. 47. Zaragoza O, Rodrigues ML, De Jesus M, Frases S, Dadachova E, Casadevall A. The capsule of the fungal pathogen Cryptococcus neoformans. Adv Appl Microbiol. 2009;68:133–216. pmid:19426855
  48. 48. Nosanchuk JD, Valadon P, Feldmesser M, Casadevall A. Melanization of Cryptococcus neoformans in murine infection. Mol Cell Biol. 1999;19(1):745–750. pmid:9858597
  49. 49. de Sousa HR, de Oliveira GP, de Oliveira FS, de Melo Gorgonha KC, Rosa CP, Garcez EM, et al. Faster Cryptococcus melanization increases virulence in experimental and human cryptococcosis. bioRxiv. 2020.
  50. 50. Garcia-Rivera J, Casadevall A. Melanization of Cryptococcus neoformans reduces its susceptibility to the antimicrobial effects of silver nitrate. Sabouraudia. 2001;39(4):353–357.
  51. 51. Casadevall A, Rosas AL, Nosanchuk JD. Melanin and virulence in Cryptococcus neoformans. Curr Opin Microbiol. 2000;3(4):354–358. pmid:10972493
  52. 52. Ma H, May RC. Virulence in Cryptococcus species. Adv Appl Microbiol. 2009;67:131–190. pmid:19245939
  53. 53. Oliveira LSS, Pinto LM, Medeiros MAP, Toffaletti DL, Tenor JL, Barros TF, et al. Comparison of Cryptococcus gattii/neoformans species complex to related genera (Papiliotrema and Naganishia) reveal variances in virulence associated factors and antifungal susceptibility. Front Cell Infect Mi. 2021;11:573. pmid:34277464
  54. 54. Gilbert AS, Wheeler RT, May RC. Fungal pathogens: survival and replication within macrophages. Cold Spring Harb Perspect Med. 2015;5(7):a019661.
  55. 55. Byrnes EJ 3rd, Marr KA. The Outbreak of Cryptococcus gattii in Western North America: Epidemiology and Clinical Issues. Curr Infect Dis Rep. 2011;13(3):256–261. pmid:21461678.
  56. 56. Galanis E, Macdougall L, Kidd S, Morshed M, British Columbia Cryptococcus gattii Working G. Epidemiology of Cryptococcus gattii, British Columbia, Canada, 1999–2007. Emerg Infect Dis. 2010;16(2):251–7. pmid:20113555.
  57. 57. Chen SC-A, Slavin MA, Heath CH, Playford EG, Byth K, Marriott D, et al. Clinical Manifestations of Cryptococcus gattii Infection: Determinants of Neurological Sequelae and Death. Clin Infect Dis. 2012;55(6):789–798. pmid:22670042
  58. 58. Gerstein AC, Nielsen K. It’s not all about us: evolution and maintenance of Cryptococcus virulence requires selection outside the human host. Yeast. 2017;34(4):143–54. Epub 2016/11/20. pmid:27862271.
  59. 59. Lalloo D, Fisher D, Naraqi S, Laurenson I, Temu P, Sinha A, et al. Cryptococcal meningitis (C. neoformans var. gattii) leading to blindness in previously healthy Melanesian adults in Papua New Guinea. Q J Med. 1994;87(6):343–9. Epub 1994/06/01. pmid:8041866.
  60. 60. Harris JR, Lockhart SR, Debess E, Marsden-Haug N, Goldoft M, Wohrle R, et al. Cryptococcus gattii in the United States: clinical aspects of infection with an emerging pathogen. Clin Infect Dis. 2011;53(12):1188–95. Epub 2011/10/22. pmid:22016503.
  61. 61. Martins LMS, Wanke B, Lazéra MS, Trilles L, Barbosa GG, Macedo RCL, et al. Genotypes of Cryptococcus neoformans and Cryptococcus gattii as agents of endemic cryptococcosis in Teresina, Piauí (northeastern Brazil). Mem I Oswaldo Cruz. 2011;106:725–730.
  62. 62. Bielska E, May RC. What makes Cryptococcus gattii a pathogen? FEMS Yeast Res. 2016;16(1):fov106. Epub 2015/11/29. pmid:26614308.
  63. 63. Freeman SA, Grinstein S. Phagocytosis: receptors, signal integration, and the cytoskeleton. Immunol Rev. 2014;262(1):193–215. Epub 2014/10/17. pmid:25319336.
  64. 64. Huang H-R, Li F, Han H, Xu X, Li N, Wang S, et al. Dectin-3 Recognizes Glucuronoxylomannan of Cryptococcus neoformans Serotype AD and Cryptococcus gattii Serotype B to Initiate Host Defense Against Cryptococcosis. Front Immunol. 2018;9:1781. pmid:30131805.
  65. 65. Fonseca FL, Nohara LL, Cordero RJB, Frases S, Casadevall A, Almeida IC, et al. Immunomodulatory effects of serotype B glucuronoxylomannan from Cryptococcus gattii correlate with polysaccharide diameter. Infect Immun. 2010;78(9):3861–70. Epub 2010/06/14. pmid:20547742.
  66. 66. Urai M, Kaneko Y, Ueno K, Okubo Y, Aizawa T, Fukazawa H, et al. Evasion of innate immune responses by the highly virulent Cryptococcus gattii by altering capsule glucuronoxylomannan structure. Front Cell Infect Mi. 2016;5:101. pmid:26779451
  67. 67. Illnait-Zaragozi M-T, Joosten LA, Netea MG, Boekhout T, Meis JF, Sprong T. Cryptococcus gattii induces a cytokine pattern that is distinct from other cryptococcal species. PLoS ONE. 2013;8(1):e55579. pmid:23383232
  68. 68. Campuzano A, Wormley FL. Innate Immunity against Cryptococcus, from Recognition to Elimination. J Fungi (Basel). 2018;4(1):33. pmid:29518906.
  69. 69. Rohatgi S, Pirofski L-A. Host immunity to Cryptococcus neoformans. Future Microbiol. 2015;10(4):565–581. pmid:25865194.
  70. 70. Kaiko GE, Horvat JC, Beagley KW, Hansbro PM. Immunological decision-making: how does the immune system decide to mount a helper T-cell response? Immunology. 2008;123(3):326–38. Epub 2007/11/05. pmid:17983439.
  71. 71. Jolink H, de Boer R, Hombrink P, Jonkers RE, van Dissel JT, Falkenburg JF, et al. Pulmonary immune responses against Aspergillus fumigatus are characterized by high frequencies of IL-17 producing T-cells. J Inf Secur. 2017;74(1):81–88. pmid:27838522
  72. 72. Zhang Y, Wang F, Tompkins KC, McNamara A, Jain AV, Moore BB, et al. Robust Th1 and Th17 immunity supports pulmonary clearance but cannot prevent systemic dissemination of highly virulent Cryptococcus neoformans H99. Am J Pathol. 2009;175(6):2489–2500. pmid:19893050
  73. 73. Conti HR, Gaffen SL. IL-17-Mediated Immunity to the Opportunistic Fungal Pathogen Candida albicans. J Immunol. 2015;195(3):780–8. Epub 2015/07/19. pmid:26188072; PubMed Central PMCID: PMC4507294.
  74. 74. Huston SM, Li SS, Stack D, Timm-McCann M, Jones GJ, Islam A, et al. Cryptococcus gattii is killed by dendritic cells, but evades adaptive immunity by failing to induce dendritic cell maturation. J Immunol. 2013;191(1):249–261. pmid:23740956
  75. 75. Ueno K, Otani Y, Yanagihara N, Urai M, Nagamori A, Sato-Fukushima M, et al. Cryptococcus gattii evades CD11b-mediated fungal recognition by coating itself with capsular polysaccharides. Eur J Immunol. 2021;51(9):2281–95. Epub 2021/03/18. pmid:33728652.
  76. 76. Chaturvedi V, Chaturvedi S. Cryptococcus gattii: a resurgent fungal pathogen. Trends Microbiol. 2011;19(11):564–71. Epub 2011/09/02. pmid:21880492; PubMed Central PMCID: PMC3205261.
  77. 77. Marr KA. Cryptococcus gattii as an important fungal pathogen of western North America. Expert Rev Anti-Infe. 2012;10(6):637–643. pmid:22734955
  78. 78. Ma H, Hagen F, Stekel DJ, Johnston SA, Sionov E, Falk R, et al. The fatal fungal outbreak on Vancouver Island is characterized by enhanced intracellular parasitism driven by mitochondrial regulation. Proc Natl Acad Sci. 2009;106(31):12980. pmid:19651610
  79. 79. Voelz K, Johnston SA, Smith LM, Hall RA, Idnurm A, May RC. ‘Division of labour’in response to host oxidative burst drives a fatal Cryptococcus gattii outbreak. Nat Commun. 2014;5(1):1–12. pmid:25323068
  80. 80. Byrnes EJ III, Bildfell RJ, Frank SA, Mitchell TG, Marr KA, Heitman J. Molecular evidence that the range of the Vancouver Island outbreak of Cryptococcus gattii infection has expanded into the Pacific Northwest in the United States. J Infect Dis. 2009;199(7):1081–1086. pmid:19220140
  81. 81. Bielska E, Sisquella MA, Aldeieg M, Birch C, O’Donoghue EJ, May RC. Pathogen-derived extracellular vesicles mediate virulence in the fatal human pathogen Cryptococcus gattii. Nat Commun. 2018;9(1):1–9.
  82. 82. Zhang S, Hacham M, Panepinto J, Hu G, Shin S, Zhu X, et al. The Hsp70 member, Ssa1, acts as a DNA-binding transcriptional co-activator of laccase in Cryptococcus neoformans. Mol Microbiol. 2006;62(4):1090–1101. pmid:17040492
  83. 83. Janbon G, Maeng S, Yang D-H, Ko Y-J, Jung K-W, Moyrand F, et al. Characterizing the role of RNA silencing components in Cryptococcus neoformans. Fungal Genet Biol. 2010;47(12):1070–1080. pmid:21067947
  84. 84. Cheng PY, Sham A, Kronstad JW. Cryptococcus gattii isolates from the British Columbia cryptococcosis outbreak induce less protective inflammation in a murine model of infection than Cryptococcus neoformans. Infect Immun. 2009;77(10):4284–94. Epub 2009/07/29. pmid:19635827; PubMed Central PMCID: PMC2747943.
  85. 85. Decote-Ricardo D, LaRocque-de-Freitas IF, Rocha JDB, Nascimento DO, Nunes MP, Morrot A, et al. Immunomodulatory Role of Capsular Polysaccharides Constituents of Cryptococcus neoformans. Front Med (Lausanne). 2019;6:129. pmid:31275938.
  86. 86. Okagaki LH, Nielsen K. Titan cells confer protection from phagocytosis in Cryptococcus neoformans infections. Eukaryot Cell. 2012;11(6):820–6. Epub 2012/05/01. pmid:22544904; PubMed Central PMCID: PMC3370461.
  87. 87. Maxson ME, Cook E, Casadevall A, Zaragoza O. The volume and hydration of the Cryptococcus neoformans polysaccharide capsule. Fungal Genet Biol. 2007;44(3):180–6. Epub 2006/09/12. pmid:16963294.
  88. 88. McFadden DC, Fries BC, Wang F, Casadevall A. Capsule structural heterogeneity and antigenic variation in Cryptococcus neoformans. Eukaryot Cell. 2007;6(8):1464–73. Epub 2007/07/03. pmid:17601878; PubMed Central PMCID: PMC1951120.
  89. 89. Frases S, Nimrichter L, Viana NB, Nakouzi A, Casadevall A. Cryptococcus neoformans capsular polysaccharide and exopolysaccharide fractions manifest physical, chemical, and antigenic differences. Eukaryot Cell. 2008;7(2):319–27. Epub 2007/12/25. pmid:18156290; PubMed Central PMCID: PMC2238165.
  90. 90. Freitas GJ, Santos DA. Cryptococcus gattii polysaccharide capsule: An insight on fungal-host interactions and vaccine studies. Eur J Immunol. 2021;51(9):2206–2209. pmid:34396521
  91. 91. Feldmesser M, Kress Y, Casadevall A. Dynamic changes in the morphology of Cryptococcus neoformans during murine pulmonary infection. Microbiology. 2001;147(Pt 8):2355–65. Epub 2001/08/10. pmid:11496012.
  92. 92. Okagaki LH, Strain AK, Nielsen JN, Charlier C, Baltes NJ, Chretien F, et al. Cryptococcal cell morphology affects host cell interactions and pathogenicity. PLoS Pathog. 2010;6(6):e1000953. Epub 2010/06/30. pmid:20585559; PubMed Central PMCID: PMC2887476.
  93. 93. Altamirano S, Li Z, Fu MS, Ding M, Fulton SR, Yoder JM, et al. The cyclin Cln1 controls polyploid titan cell formation following a stress-induced G2 arrest in <em>Cryptococcus</em&gt. bioRxiv. 2021:2021.08.24.457603.
  94. 94. Zhou X, Ballou ER. The Cryptococcus neoformans titan cell: from in vivo phenomenon to in vitro model. Curr Clin Microbiol. 2018;5(4):252–260.
  95. 95. Lin X. Cryptococcus neoformans: morphogenesis, infection, and evolution. Infect Genet Evol. 2009;9(4):401–16. Epub 2009/05/23. pmid:19460306.
  96. 96. Alspaugh JA, Davidson RC, Heitman J. Morphogenesis of Cryptococcus neoformans. Contrib Microbiol. 2000;5:217–238. pmid:10863675
  97. 97. da Silva-Junior EB, Firmino-Cruz L, Guimarães-de-Oliveira JC, De-Medeiros JVR, de Oliveira Nascimento D, Freire-de-Lima M, et al. The role of Toll-like receptor 9 in a murine model of Cryptococcus gattii infection. Sci Rep. 2021;11(1):1–11.
  98. 98. Probert M, Zhou X, Goodall M, Johnston SA, Bielska E, Ballou ER, et al. A Glucuronoxylomannan Epitope Exhibits Serotype-Specific Accessibility and Redistributes towards the Capsule Surface during Titanization of the Fungal Pathogen Cryptococcus neoformans. Infect Immun. 2019;87(4). Epub 2019/01/24. pmid:30670549; PubMed Central PMCID: PMC6434129.
  99. 99. Dos Santos MH, Machado MP, Kumaresan PR, da Silva TA. Titan Cells and Yeast Forms of Cryptococcus neoformans and Cryptococcus gattii Are Recognized by GXMR-CAR. Microorganisms. 2021;9(9). Epub 2021/09/29. pmid:34576780; PubMed Central PMCID: PMC8467747.
  100. 100. Liebana-Jordan M, Brotons B, Falcon-Perez JM, Gonzalez E. Extracellular vesicles in the fungi kingdom. Int J Mol Sci. 2021;22(13):7221. pmid:34281276
  101. 101. Gill S, Catchpole R, Forterre P. Extracellular membrane vesicles in the three domains of life and beyond. FEMS Microbiol Rev. 2019;43(3):273–303. pmid:30476045
  102. 102. de Oliveira HC, Castelli RF, Reis FCG, Rizzo J, Rodrigues ML. Pathogenic Delivery: The Biological Roles of Cryptococcal Extracellular Vesicles. Pathogens. 2020;9(9). Epub 2020/09/20. pmid:32948010; PubMed Central PMCID: PMC7557404.
  103. 103. Oliveira DL, Freire-de-Lima CG, Nosanchuk JD, Casadevall A, Rodrigues ML, Nimrichter L. Extracellular vesicles from Cryptococcus neoformans modulate macrophage functions. Infect Immun. 2010;78(4):1601–1609. pmid:20145096
  104. 104. Rodrigues ML, Nakayasu ES, Oliveira DL, Nimrichter L, Nosanchuk JD, Almeida IC, et al. Extracellular vesicles produced by Cryptococcus neoformans contain protein components associated with virulence. Eukaryot Cell. 2008;7(1):58–67. pmid:18039940
  105. 105. Rizzo J, Wong SSW, Gazi AD, Moyrand F, Chaze T, Commere PH, et al. Cryptococcus extracellular vesicles properties and their use as vaccine platforms. J Extracell Vesicles. 2021;10(10):e12129. pmid:34377375
  106. 106. Rizzo J, Taheraly A, Janbon G. Structure, composition and biological properties of fungal extracellular vesicles. microLife. 2021:2.
  107. 107. Wolf JM, Espadas-Moreno J, Luque-Garcia JL, Casadevall A. Interaction of Cryptococcus neoformans extracellular vesicles with the cell wall. Eukaryot Cell. 2014;13(12):1484–1493. pmid:24906412
  108. 108. Hu G, Caza M, Cadieux B, Bakkeren E, Do E, Jung WH, et al. The endosomal sorting complex required for transport machinery influences haem uptake and capsule elaboration in C ryptococcus neoformans. Mol Microbiol. 2015;96(5):973–992. pmid:25732100
  109. 109. Chang YC, Kwon-Chung K. Complementation of a capsule-deficient mutation of Cryptococcus neoformans restores its virulence. Mol Cell Biol. 1994;14(7):4912–4919. pmid:8007987
  110. 110. García-Rivera J, Chang YC, Kwon-Chung K, Casadevall A. Cryptococcus neoformans CAP59 (or Cap59p) is involved in the extracellular trafficking of capsular glucuronoxylomannan. Eukaryot Cell. 2004;3(2):385–392. pmid:15075268
  111. 111. Grijpstra J, Tefsen B, van Die I, de Cock H. The Cryptococcus neoformans cap10 and cap59 mutant strains, affected in glucuronoxylomannan synthesis, differentially activate human dendritic cells. FEMS Immunol Med Microbiol. 2009;57(2):142–50. Epub 2009/08/22. pmid:19694810.
  112. 112. Chang YC, Penoyer LA, Kwon-Chung KJ. The second capsule gene of cryptococcus neoformans, CAP64, is essential for virulence. Infect Immun. 1996;64(6):1977–83. Epub 1996/06/01. pmid:8675296; PubMed Central PMCID: PMC174025.
  113. 113. Chang Y, Kwon-Chung K. Isolation of the third capsule-associated gene, CAP60, required for virulence in Cryptococcus neoformans. Infect Immun. 1998;66(5):2230–2236. pmid:9573112
  114. 114. Moyrand F, Fontaine T, Janbon G. Systematic capsule gene disruption reveals the central role of galactose metabolism on Cryptococcus neoformans virulence. Mol Microbiol. 2007;64(3):771–81. Epub 2007/04/28. pmid:17462022.
  115. 115. García-Rodas R, Cordero RJ, Trevijano-Contador N, Janbon G, Moyrand F, Casadevall A, et al. Capsule growth in Cryptococcus neoformans is coordinated with cell cycle progression. mBio. 2014;5(3):e00945–14. Epub 2014/06/19. pmid:24939886; PubMed Central PMCID: PMC4056547.
  116. 116. O’Meara TR, Norton D, Price MS, Hay C, Clements MF, Nichols CB, et al. Interaction of Cryptococcus neoformans Rim101 and protein kinase A regulates capsule. PLoS Pathog. 2010;6(2):e1000776. pmid:20174553
  117. 117. Hommel B, Mukaremera L, Cordero RJB, Coelho C, Desjardins CA, Sturny-Leclere A, et al. Titan cells formation in Cryptococcus neoformans is finely tuned by environmental conditions and modulated by positive and negative genetic regulators. PLoS Pathog. 2018;14(5):e1006982. Epub 2018/05/19. pmid:29775480; PubMed Central PMCID: PMC5959062.
  118. 118. Gong J, Grodsky JD, Zhang Z, Wang P. A Ric8/synembryn homolog promotes Gpa1 and Gpa2 activation to respectively regulate cyclic AMP and pheromone signaling in Cryptococcus neoformans. Eukaryot Cell. 2014;13(10):1290–9. Epub 2014/08/01. pmid:25084863.
  119. 119. García-Rodas R, Trevijano-Contador N, Román E, Janbon G, Moyrand F, Pla J, et al. Role of Cln1 during melanization of Cryptococcus neoformans. Front Microbiol. 2015;6:798. pmid:26322026
  120. 120. Chen LC, Blank ES, Casadevall A. Extracellular proteinase activity of Cryptococcus neoformans. Clin Diagn Lab Immunol. 1996;3(5):570–4. Epub 1996/09/01. pmid:8877137; PubMed Central PMCID: PMC170408.
  121. 121. Seoane PI, May RC. Vomocytosis: what we know so far. Cell Microbiol. 2020;22(2):e13145. pmid:31730731
  122. 122. Olszewski MA, Noverr MC, Chen G-H, Toews GB, Cox GM, Perfect JR, et al. Urease expression by Cryptococcus neoformans promotes microvascular sequestration, thereby enhancing central nervous system invasion. Am J Pathol. 2004;164(5):1761–1771. pmid:15111322