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Cited by 531Fungal Infections and StudiesYeasts and Rust Fungi StudiesBacterial Infections and Vaccines

Cryptococcus neoformans and Cryptococcus gattii, the etiologic agents of cryptococcosis

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Kwon-Chung, K. J., Fraser, J. A., Doering, T. L., Wang, Z. A., Janbon, G., Idnurm, A., Bahn, Y.-S.·2014·Cold Spring Harbor Perspectives in Medicine
DOI 10.1101/cshperspect.a019760PMC PMC4066639
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Abstract

Cryptococcus neoformans and Cryptococcus gattii are the two etiologic agents of cryptococcosis.They belong to the phylum Basidiomycota and can be readily distinguished from other pathogenic yeasts such as Candida by the presence of a polysaccharide capsule, formation of melanin, and urease activity, which all function as virulence determinants.Infection proceeds via inhalation and subsequent dissemination to the central nervous system to cause meningoencephalitis.The most common risk for cryptococcosis caused by C. neoformans is AIDS, whereas infections caused by C. gattii are more often reported in immunocompetent patients with undefined risk than in the immunocompromised.There have been many chapters, reviews, and books written on C. neoformans.The topics we focus on in this article include species description, pathogenesis, life cycle, capsule, and stress response, which serve to highlight the specializations in virulence that have occurred in this unique encapsulated melanin-forming yeast that causes global deaths estimated at more than 600,000 annually. HISTORY OF THE ETIOLOGIC AGENTS AND CRYPTOCOCCOSISC ryptococcus neoformans was first isolated from peach juice by Sanfelice in 1894 in Italy and was named Saccharomyces neoformans (Sanfelice 1894).In the same year, Busse provided the first description of a case of cryptococcosis (Busse 1894) and isolated a yeast culture from a sarcoma-like lesion in the infected young woman's tibia.Busse called the fungus Saccharomyces, while naming the disease Sac-

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Written from the paper’s full text.

TL;DR

This review summarizes the biology, taxonomy, ecology, epidemiology, pathogenesis, and virulence determinants of *Cryptococcus neoformans* and *Cryptococcus gattii*, the two agents of cryptococcosis. It emphasizes the three classical virulence traits — polysaccharide capsule, melanin formation, and growth at mammalian body temperature — along with newer work on sensing/signaling and stress-response pathways.

Key findings

  • Cryptococcosis is acquired by inhalation of desiccated yeast cells or basidiospores (1.5–3.5 µm), which reach the distal airways; in immunocompromised hosts the fungus disseminates hematogenously across the blood–brain barrier to cause meningoencephalitis, which is uniformly fatal if untreated. The global burden is estimated at close to 1 million cases with 700,000 deaths annually (Park et al. 2009); the abstract cites global deaths estimated at more than 600,000 annually.
  • *C. neoformans* infection is predominantly associated with AIDS and other immunocompromising conditions, whereas *C. gattii* infection occurs more often in immunocompetent patients; pulmonary infection is considerably more common with *C. gattii*, and mouse studies show *C. neoformans*-infected mice die of CNS infection while *C. gattii*-infected mice die of pulmonary infection.
  • Worldwide, *C. neoformans* molecular type VNI predominates (63% of isolates), followed by VNII/VNIII (6% each) and VNIV (5%); *C. gattii* accounts for <20% of cryptococcosis globally, with VGI most common (9%), then VGII (7%), VGIII (3%), and VGIV (1%) among 2046 isolates.
  • Azole heteroresistance, caused by reversible disomy of chromosomes containing resistance genes (chromosome 1 always duplicating first, then chromosome 4 and others stepwise), is suggested to be the most common cause of azole treatment failure during suppression therapy in AIDS patients.

Methods

  • Narrative review article (Cold Spring Harbor Perspectives in Medicine) synthesizing historical, taxonomic, ecological, epidemiological, and molecular literature on *C. neoformans* and *C. gattii*.
  • No primary data collection; the paper compiles findings from cited studies, including molecular typing, genome comparisons, animal infection models, and clinical/epidemiological surveys.
  • Topics covered include species description, pathogenesis, life cycle, capsule, melanin, thermotolerance, degradation enzymes, metal/gas/light sensing, and stress-signaling pathways (HOG, Mpk1, calcineurin, cAMP/PKA, UPR).

Limitations

  • The paper states that a consensus on how to treat the *C. neoformans*/*C. gattii* species complex taxonomically has yet to be achieved, and that elevating the eight major haploid molecular types to species status is controversial.
  • The paper notes that understanding of the host response to cryptococci is mostly based on animal data, and that the genetic basis of capsule size regulation has not been elucidated; the glycosyltransferases mediating capsule synthesis are largely uncharacterized.
  • Evident from the text: several statements rest on single or few cited studies (e.g., the GM-CSF autoantibody finding in immunocompetent *C. gattii* patients), and the review repeatedly flags open questions (e.g., whether light-sensing mutants' virulence defect relates to known traits, whether ROS/RNS events in *C. gattii* occur in *C. neoformans*).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1101/cshperspect.a019760

Cites

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Statistics

Nothing to recompute.

Claims the paper makes

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  • Premisecitation

    Curtis' strain was later determined to be the first clinical isolate of C. gattii.

    “Curtis' strain was later determined to be the first clinical isolate of C. gattii (Kwon-Chung et al. 2002).”
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    • cites Kwon-Chung et al. 2002

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    C. neoformans and C. gattii can be readily distinguished from other pathogenic yeasts such as Candida by the presence of a polysaccharide capsule, formation of melanin, and urease activity.

    “They belong to the phylum Basidiomycota and can be readily distinguished from other pathogenic yeasts such as Candida by the presence of a polysaccharide capsule, formation of melanin, and urease activity, which all function as virulence determinants.”
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    • cites Seeliger 1956

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    • cites Staib 1962b

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  • Premisecitation

    The complete life cycles of C. neoformans and C. gattii became known by the mid-1970s when heterothallic sexuality was discovered in both species.

    “By the mid-1970s, the complete life cycles of C. neoformans and C. gattii became known when heterothallic sexuality was discovered in both species (Kwon-Chung 1975, 1976b).”
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    • cites Kwon-Chung 1975, 1976b

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  • Premisecitation

    Distribution of the four major molecular types of C. gattii strains among 2046 cryptococcal isolates from clinical and veterinary sources indicates that the VGI type is most common (9%) followed by VGII (7%), VGIII (3%), and VGIV (1%).

    “Distribution of the four major molecular types of C. gattii strains among 2046 cryptococcal isolates from clinical and veterinary sources indicat that the VGI type is most common (9%) followed by VGII (7%), VGIII (3%), and VGIV (1%) in decreasing order (Meyer et al. 2011).”
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  • Premisecitation

    Each species of C. neoformans and C. gattii is composed of at least four major genetically diverse subgroups.

    “Genotyping of numerous C. neoformans and C. gattii global strains revealed that each species is composed of at least four major genetically diverse subgroups (Meyer et al. 2011).”
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    Premisecitation

    Evans identified three serotypes A, B, and C in 1950.

    “Cryptococcal antigenic heterogeneity was confirmed in 1950 by Evans who identified three serotypes: A, B, and C (Evans 1950).”
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    Premisecitation

    The characteristic neurotropism of C. neoformans was first recognized in 1914 by Verse and 2 years later by Stoddard and Cutler.

    “The characteristic neurotropism of C. neoformans was first recognized in 1914 by Verse ´(1914), and 2 years later by Stoddard and Cutler (1916).”
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    • cites Stoddard and Cutler 1916

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    Premisenone given

    The most common risk for cryptococcosis caused by C. neoformans is AIDS.

    “The most common risk for cryptococcosis caused by C. neoformans is AIDS, whereas infections caused by C. gattii are more often reported in immunocompetent patients with undefined risk than in the immunocompromised.”
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    Premisecitation

    A fourth serotype, D, was discovered in 1968.

    “A fourth serotype, D, was discovered in 1968 (Wilson et al. 1968).”
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    • cites Wilson et al. 1968

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    Premisecitation

    The polysaccharide capsule, melanin formation, and urease activity of C. neoformans and C. gattii all function as virulence determinants.

    “They belong to the phylum Basidiomycota and can be readily distinguished from other pathogenic yeasts such as Candida by the presence of a polysaccharide capsule, formation of melanin, and urease activity, which all function as virulence determinants.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Seeliger 1956

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    • cites Staib 1962b

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    Premisenone given

    Cryptococcus neoformans and Cryptococcus gattii are the two etiologic agents of cryptococcosis.

    “Cryptococcus neoformans and Cryptococcus gattii are the two etiologic agents of cryptococcosis.”
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    Premisenone given

    Infection with C. neoformans and C. gattii proceeds via inhalation and subsequent dissemination to the central nervous system to cause meningoencephalitis.

    “Infection proceeds via inhalation and subsequent dissemination to the central nervous system to cause meningoencephalitis.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Busse provided the first description of a case of cryptococcosis in 1894 and isolated a yeast culture from a sarcoma-like lesion in the infected young woman's tibia.

    “In the same year, Busse provided the first description of a case of cryptococcosis (Busse 1894) and isolated a yeast culture from a sarcoma-like lesion in the infected young woman's tibia.”
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    • cites Busse 1894

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    Infections caused by C. gattii are more often reported in immunocompetent patients with undefined risk than in the immunocompromised.

    “The most common risk for cryptococcosis caused by C. neoformans is AIDS, whereas infections caused by C. gattii are more often reported in immunocompetent patients with undefined risk than in the immunocompromised.”
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    Premisereasoning

    Because the propagules are small (1.5-3.5 mm), they reach the distal airways and come into contact with alveolar macrophages.

    “Because the propagules are small (1.5 -3.5 mm), they reach the distal airways and come into contact with alveolar macrophages.”
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    Premisecitation

    Serologic evidence indicates that cryptococcal infection in humans is prevalent but disease is rare.

    “Serologic evidence indicates that cryptococcal infection in humans is prevalent (Goldman et al. 2001) but disease is rare.”
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    • cites Goldman et al. 2001

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    Premisecitation

    C. neoformans contains molecular types VNI-VNIV and VNB with var. grubii VNI, VNII, and VNB strains, estimated to have diverged from the single var. neoformans molecular type VNIV (serotype D) approximately 25 million years ago, and serotype AD (VNIII) strains representing hybrids of the two varieties.

    “C. neoformans contains molecular types VNI-VNIV and VNB with var.grubii VNI, VNII, and VNB strains, estimated to have diverged from the single var.neoformans molecular type VNIV (serotype D) approximately 25 million years ago, and serotype AD (VNIII) strains representing hybrids of the two varieties.”
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    • cites Meyer et al. 2011

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    Premisecitation

    Regardless of molecular type, global clinical isolates of C. neoformans are almost always mating type a (MATa) except for certain areas in Africa such as Botswana, where MATa can be as common as 10% of strains.

    “Regardless of molecular type, global clinical isolates are almost always mating type a (MATa) except for certain areas in Africa such as Botswana, where MATa can be as common as 10% of strains (Litvintseva et al. 2003).”
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    Premisecitation

    Elevating the eight major haploid molecular types to separate species status is controversial at present and a consensus on how to treat the C. neoformans/C. gattii species complex taxonomically has yet to be achieved among medical mycologists.

    “However, elevating the eight major haploid molecular types to separate species status is controversial at present and a consensus on how to treat the C. neoformans/C.gattii species complex taxonomically has yet to be achieved among medical mycologists (de Hoog et al. 2013).”
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    Premisereasoning

    Upon loss of immunity, the dormant yeast cells are activated and begin to multiply in the pulmonary-lymph node complex and disseminate into extrapulmonary sites.

    “Upon this loss of immunity, the dormant yeast cells are activated and begin to multiply in the pulmonary -lymph node complex and disseminate into extrapulmonary sites.”
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    Premisereasoning

    C. neoformans can survive in amoebae and the fungus can utilize the same pathogenic strategy in human macrophages.

    “C. neoformans can survive in amoebae and the fungus can utilize the same pathogenic strategy in human macrophages, which in some respect provides a similar environment.”
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    Premisenone given

    An unprecedented rate of increase in cryptococcosis began in the early 1980s, with AIDS becoming the leading risk factor of the disease.

    “The importance of understanding the pathogen became even more pressing as an unprecedented rate of increase in cryptococcosis began in the early 1980s, with AIDS becoming the leading risk factor of the disease.”
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    Premisecitation

    The teleomorph names have been abandoned as of 2013 and only Cryptococcus is used in accordance with the new fungal nomenclatural rule of one name for one fungus.

    “its use has been abandoned as of 2013 and only Cryptococcus is used in accordance with the new fungal nomenclatural rule of one name for one fungus (Hawksworth et al. 2011).”
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    Cryptococcosis had been considered a rare disease until immunosuppressive therapy came into wide use starting in the 1970s.

    “These discoveries were timely, as cryptococcosis had been considered a rare disease until immunosuppressive therapy came into wide use starting in the 1970s.”
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    Premisenone given

    Although the vast majority of patients with disseminated cryptococcosis are immunocompromised, C. neoformans also causes disease in apparently normal hosts.

    “Although the vast majority of patients with disseminated cryptococcosis are immunocompromised, C. neoformans also causes disease in apparently normal hosts.”
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    Interpretationnone given

    Importation of Eucalyptus trees from Australia, the accelerated rate of human international travel, and climate changes may all have contributed to the spread of C. gattii to temperate zones.

    “Importation of Eucalyptus trees from Australia, the accelerated rate of human international travel, and climate changes may all have contributed to the spread of C. gattii to temperate zones.”
    Quote in the paperNot a substantial claim

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    Premisenone given

    Serotype AD hybrids are common but sterile, and hybrids between other molecular types are rare.

    “Although serotype AD hybrids are common, these are sterile, and hybrids between other molecular types are rare, raising the possibility that each haploid type may in fact represent different species.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    C. gattii molecular types VGI and VGII usually correspond with serotype B, and molecular types VGIII and VGIV with serotype C; these molecular types have been estimated to have diverged over 8.5-12.5 million years.

    “C. gattii molecular types VGI and VGII usually correspond with serotype B, and molecular types VGIII and VGIV with serotype C; these molecular types have been estimated to have diverged over 8.5 -12.5 million years.”
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    • cites Meyer et al. 2011

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    Premisenone given

    Infection of the central nervous system is the most common clinical manifestation of cryptococcosis and the most common cause of death.

    “Although virtually every organ in the body can be involved, infection of the central nervous system (CNS) is the most common clinical manifestation of cryptococcosis and the most common cause of death.”
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    Premisecitation

    In 2000, C. neoformans var. gattii was elevated to a species, C. gattii, and the taxon C. neoformans was reserved for the varieties neoformans and grubii.

    “In 2000, C. neoformans var.gattii was elevated to a species, C. gattii (Kwon-Chung et al. 2002) and the taxon C. neoformans was reserved for the varieties neoformans and grubii.”
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    Premisenone given

    Cryptococcosis caused by C. gattii is significantly less frequent globally (<20%) than C. neoformans (80%), and the major risk factors for C. gattii infection remain unclear.

    “Cryptococcosis caused by C. gattii is significantly less frequent globally (,20%) than C. neoformans (80%), and the major risk factors for C. gattii infection remain unclear.”
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    Premisecitation

    The global burden of cryptococcosis is estimated to be close to 1 million cases with 700,000 deaths annually.

    “The global burden of the disease is estimated to be close to 1 million cases with 700,000 deaths annually (Park et al. 2009).”
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    • cites Park et al. 2009

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    Premisecitation

    C. gattii has 14 chromosomes, and predicted centromere locations are conserved with C. neoformans, but the chromosomes have been rearranged by inversions and balanced translocations.

    “Like C. neoformans, C. gattii has 14 chromosomes, and although the predicted centromere locations are conserved, the chromosomes have been rearranged by inversions and balanced translocations.”
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    • cites D 'Souza et al. 2011

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    Premisenone given

    The capsule may also include mannoproteins, hyaluronic acid, and sialic acid.

    “The capsule may also include mannoproteins, hyaluronic acid, and sialic acid.”
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    Premisecitation

    Basidiospores can cause infection in a mouse model just as efficiently as vegetative yeast cells, and may play the role of infectious particles.

    “These basidiospores can cause infection in a mouse model just as efficiently as vegetative yeast cells, and may play the role of infectious particles (Giles et al. 2009).”
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    • cites Giles et al. 2009

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    Premisecitation

    A majority of the clinical isolates obtained before the birth of azoles had an LHF of 16 mg/mL or lower, whereas the LHF of C. gattii was generally higher.

    “A majority of the clinical isolates obtained before the birth of azoles had an LHF of 16 mg/mL or lower (Sionov et al. 2009), whereas the LHF of C. gattii was generally higher (Varma and Kwon-Chung 2010).”
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    Premisecitation

    Animal studies supported these differences in the primary target organs between the two species; mice infected with C. neoformans succumbed to infection by CNS infection, whereas mice infected with C. gattii died by pulmonary infection.

    “Animal studies supported these differences in the primary target organs between the two species; mice infected with C. neoformans succumbed to infection by CNS infection, whereas mice infected with C. gattii died by pulmonary infection (Ngamskulrungroj et al. 2012c).”
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    The morphology of the two teleomorphs are even more different: rough-walled oblong to elliptical basidiospores are produced in C. neoformans, whereas the basidiospores produced by C. gattii are in bacillary form with smooth walls.

    “The morphology of the two teleomorphs are even more different: rough-walled oblong to eliptical basidiospores are produced in C. neoformans, whereas the basidiospores produced by C. gattii, as suggested by the original teleomorph designation of F. bacillispora, are in bacillary form with smooth walls (Fig. 3A) (Kwon-Chung 1975, 1976b).”
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    • cites Kwon-Chung 1975, 1976b

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    The morphology of C. neoformans yeast cells is almost uniformly globose, whereas those of C. gattii are a mixture of globose and oblong to elliptical cells; the proportion of globose to oblong cells in C. gattii is strain dependent.

    “Although the morphology of C. neoformans yeast cells are almost uniformly globose, those of C. gattii are a mixture of globose and oblong to elliptical cells (Kwon-Chung et al. 1982a); this proportion of globose to oblong cells in C. gattii is strain dependent (Fig. 3B -D).”
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    • cites Kwon-Chung et al. 1982a

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    Premisecitation

    Since divergence of var. grubii and var. neoformans, few genomic rearrangements have occurred in the var. grubii lineage and more in var. neoformans.

    “It has subsequently been shown that since the divergence of var.grubii and var.neoformans, few genomic rearrangements have occurred in the var.grubii lineage and even more in var.neoformans”
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    • cites Sun and Xu 2009

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    • cites Morrow et al. 2012

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    Premisenone given

    C. neoformans and C. gattii are both heterothallic haploid yeasts that exist in two mating types, MATa and MATα.

    “C. neoformans (Fig. 2) and C. gattii (Fig. 3) are both heterothallic haploid yeasts that exist in two mating types, MATa and MATa.”
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    Premisecitation

    It became common in the early 1980s to use amphotericin B in combination with flucytosine for induction therapy.

    “Although sometimes used alone, it be-came common in the early 1980s to use this polyene in combination with flucytosine, a fluorinated pyrimidine analog (Bennett et al. 1979).”
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    • cites Bennett et al. 1979

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    Premisecitation

    Amphotericin B has been the major therapeutic agent for cryptococcal meningoencephalitis since the late 1960s.

    “Amphotericin B, a secondary metabolite of Streptomyces nodosus, has been the major therapeutic agent for cryptococcal meningoencephalitis since the late 1960s (Sarosi et al. 1969).”
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    • cites Sarosi et al. 1969

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    Premisenone given

    The C. neoformans genome contains approximately 6500 genes with an average size of 1.9 kb.

    “With .6500genes with an average size of 1.9 kb”
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    Premisecitation

    A recent report indicates that monokaryotic hyphal production unrelated to unisexual reproduction can be induced by high-temperature arrest of yeast cell cycle in the G2 stage.

    “Furthermore, a recent report indicates that monokaryotic hyphal production unrelated to unisexual reproduction can be induced by high-temperature arrest of yeast cell cycle in the G 2 stage (Fu et al. 2013).”
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    • cites Fu et al. 2013

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    Premisecitation

    The treatment strategy for cryptococcosis may vary depending on the different categories of risk groups: HIV-infected patients, organ transplant recipients, non-HIV-infected, and nontransplant patients.

    “More important, the treatment strategy for cryptococcosis may vary depending on the different categories of risk groups: HIV-infected patients, organ transplant recipients, non-HIV-infected, and nontransplant patients.”
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    • cites Perfect et al. 2010

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    Premisenone given

    The capsule is displayed on the cryptococcal surface and component polysaccharides are also shed into the environment.

    “The capsule is displayed on the cryptococcal surface and component polysaccharides are also shed into the environment.”
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    Premisecitation

    The lowest level of fluconazole at which the heteroresistant minor subpopulation emerges (LHF) and the frequency of resistant subpopulation varies depending on the strain.

    “The lowest level of fluconazole at which the heteroresistant minor subpopulation emerges (LHF) and the frequency of resistant subpopulation varies depending on the strain.”
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    Premisecitation

    The cryptococcal capsule is anchored by the cell wall, which is composed of glucans, chitin, chitosan, and glycoprotein.

    “The cryptococcal capsule is anchored by the cell wall, which is composed of glucans, chitin, chitosan, and glycoprotein”
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    • cites Doering 2009

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    • cites Gilbert et al. 2011

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    Premisecitation

    Activation of the cAMP/PKA pathway can be triggered by altered CO2 levels, low glucose, low nitrogen, or low iron, resulting in direct activation of Nrg1, and can also result in regulation of Hog1 and/or Rim101 in response to pH alteration and osmotic stress.

    “Activation of the cAMP/ PKA pathway, which can be triggered by altered CO 2 levels, low glucose, low nitrogen, or low iron resulting in direct activation of the transcription factor Nrg1, can also result in the regulation of Hog1 and/or Rim101 in response to pH alteration and osmotic stress, respectively”
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    • cites Bahn et al. 2005b

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    Premisecitation

    Rim101 plays a central role in pH response and capsule regulation.

    “Rim101 also plays a central role in pH response and capsule regulation”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites O'Meara et al. 2010

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Although the genome encodes other putative nucleotide sugar transporters, they have not been matched to specific functions required for capsule synthesis.

    “Although the genome encodes other putative nucleotide sugar transporters, they have not been matched to specific functions required for capsule synthesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Calcineurin, encoded by CNA1, is essential for cryptococcal growth at 37°C but not at 24°C.

    “calcineurin, the highly conserved Ca 2þ / calmodulin-activated serine/threonine-specific phosphatase encoded by CNA1, to be essential for growth at 37 ˚C but not at 24 ˚C.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Odom et al. 1997

      Not checked in the free run.

    • cites Fox et al. 2001

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C. neoformans contains two laccase genes, LAC1 and LAC2, but only LAC1 is expressed significantly under most conditions, and virulence is reduced only when LAC1 is deleted.

    “C. neoformans contains two laccase genes, LAC1 and LAC2, in the genome but only LAC1 is expressed significantly under most conditions and virulence is reduced only when the LAC1 gene is deleted”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Zhu and Williamson 2004

      Not checked in the free run.

    • cites Pukkila-Worley et al. 2005

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Melanin is produced by a wide variety of fungal species and the pigment deposited in the cell wall plays an important protective role against environmental stress.

    “Melanin is produced by a wide variety of fungal species and the pigment deposited in the cell wall is known to play an important protective role against environmental stress”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nosanchuk and Casadevall 2006

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Secretion of the capsule and the genetics of its regulation have not been studied extensively.

    “However, secretion of the capsule and the genetics of its regulation have not been studied extensively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Whether the interaction between cell wall α-glucan and capsule is direct or indirect has not been determined.

    “although whether this is a direct or indirect interaction has not been determined.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lack of the capsule synthetic proteins reduces capsule production and virulence in animal models, except for the enzyme responsible for UDP-galactofuranose synthesis.

    “The lack of these proteins reduces capsule produc-tion and virulence in animal models, except for the enzyme responsible for UDP-galactofuranose synthesis”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Heiss et al. 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Enzymes required for synthesis of GDP-mannose, UDP-glucuronate, UDP-xylose, and UDP-galactofuranose have been biochemically characterized, and genes encoding synthetic machinery for all five sugar donors have been identified and deleted.

    “Enzymes required for synthesis of the first four have been biochemically characterized, and genes encoding synthetic machinery for all five have been identified and deleted to assess the impact on cells”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bar-Peled et al. 2001, 2004

      Not checked in the free run.

    • cites Wills et al. 2001

      Not checked in the free run.

    • cites Moyrand et al. 2002

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Multiple transduction pathways respond to each environmental signal and a single transduction cascade can respond to multiple signals.

    “Thus, multiple transduction pathways respond to each environmental signal and a single transduction cascade can respond to multiple signals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The transcription factors Cir1 and HapX are necessary for iron homeostasis and are specifically induced under low iron conditions.

    “the genes that encode the transcription factors Cir1 and HapX are necessary for iron homeostasis and are specifically induced under low iron conditions”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kronstad et al. 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Melanization is regulated by a number of different pathways, as is capsule formation.

    “As in the case of capsule formation, melanization is regulated by number of different pathways”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liu et al. 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C. neoformans senses iron levels and regulates a suite of genes using the Cir1 transcription factor.

    “C. neoformans senses iron levels, and regulates a suite of genes using the Cir1 transcription factor”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jung et al. 2006

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Two carbonic anhydrase homologs are expressed in C. neoformans, with Can2 having the major function.

    “Two homologs are expressed in C. neoformans, with Can2 having the major function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Other factors, such as the siderophore transporter Sit1, are not required for pathogenesis, although this may reflect gene redundancy.

    “Other factors, such as the siderophore transporter Sit1, are not required for pathogenesis although this may reflect gene redundancy”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tangen et al. 2007

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Scp1 cleaves the inactive Sre1 into an active transcription factor that is shuttled into the nucleus.

    “Scp1 cleaves the inactive Sre1 into an active transcription factor that is shuttled into the nucleus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Effects of iron limitation on C. neoformans have been known since the early 1990s, and one consequence is enhancement of capsule formation.

    “Effects of iron limitation on C. neoformans have been known since the early 1990s, because one consequence is the enhancement of capsule formation”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vartivarian et al. 1993

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Strains harboring an intact URE1 but disrupted accessory proteins disseminated to the brain at rates similar to the ure1 mutant, indicating that urease activity and not the Ure1 protein is a virulence factor in C. neoformans.

    “Strains harboring an intact URE1 but disrupted accessory proteins disseminated to the brain at rates similar to the ure1 mutant, which indicates that it is the urease activity and not the Ure1 protein that is a virulence factor in C. neoformans”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Singh et al. 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Carbonic anhydrases are zinc proteins that convert CO2 to bicarbonate.

    “Carbonic anhydrases are zinc proteins that convert CO 2 to bicarbonate (HCO3 -).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Although genes for heme biosynthesis and iron uptake are induced by light, the light-sensing mutants do not have phenotypes that indicate any change in these properties.

    “Although genes for heme biosynthesis and iron uptake are induced by light, the light-sensing mutants do not have phenotypes that indicate any change in these properties”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Idnurm and Heitman 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Another source of iron for C. neoformans is heme, yet use of this iron source is currently less well established.

    “Another source of iron for C. neoformans is heme, yet use of this iron source is currently less well established”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Jung et al. 2010

      Not checked in the free run.

    • cites Cadieux et al. 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C. neoformans produces many degradation enzymes, some of which have been confirmed as virulence determinants.

    “C. neoformans produces many degradation enzymes; some of them have been confirmed as virulence determinants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    MAC1 (CUF1) encodes a copper-response transcription factor that regulates target genes.

    “MAC1 (CUF1) encodes a copper-response transcription factor that regulates target genes”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ding et al. 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The cryptococcal urease is a nickel enzyme and requires accessory proteins Ure4, Ure6, and Ure7, which are homologs of bacterial accessory proteins UreD, UreF, and UreG, respectively.

    “the cryptococcal urease is a nickel enzyme and requires the accessory proteins, Ure4, Ure6, and Ure7, which are homologs of the bacterial accessory proteins UreD, UreF, and UreG, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Deletion of CAN2 prevents growth under low CO2 concentrations; however, virulence is unaffected presumably because of the high CO2 concentrations within the host.

    “Deletion of CAN2 prevents growth under low CO 2 concen-trations; however, virulence is unaffected presumably because of the high CO 2 concentrations within the host”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bahn et al. 2005a

      Not checked in the free run.

    • Rests on an assumption: O2 and CO2 vary in concentration in different parts of the body, lower or higher, respectively, than the natural environment in which Cryptococcus species reside.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Zinc is a cofactor in many proteins, including zinc finger transcription factors, so loss of virulence may reflect an impact on a number of key processes.

    “Zinc is a cofactor in many proteins, including zinc finger transcription factors, so loss of virulence may reflect an impact on a number of key processes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Those genes include an adjacent pair of genes for iron oxidation and high-affinity uptake, which are also required for full virulence.

    “Those genes include an adjacent pair of genes for iron oxidation and high-affinity uptake, which are also required for full virulence”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Jung et al. 2008

      Not checked in the free run.

    • cites Jung et al. 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of either Scp1 or Sre1 reduces the ability of C. neoformans to grow at <3% oxygen levels and reduces virulence.

    “Deletion of either gene reduces the ability of C. neoformans to grow at ,3% oxygen levels, and reduces virulence”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chang et al. 2007

      Not checked in the free run.

    • cites Chun et al. 2007

      Not checked in the free run.

    • Rests on an assumption: O2 and CO2 vary in concentration in different parts of the body, lower or higher, respectively, than the natural environment in which Cryptococcus species reside.

  • May combine two claims.

    Premisenone given

    Copper is a cofactor for multicopper oxidases, which include the ferroxidase Cfo1 for iron uptake and laccase for melanin synthesis.

    “Copper is a cofactor for multicopper oxidases, which include the ferroxidase Cfo1 for iron uptake and laccase for melanin synthesis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The link between copper and melanization has been known for two decades.

    “The link between copper and melanization has also been known for two decades.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Carbonic anhydrases do not affect virulence of Cryptococcus within the host, but may influence its survival on the outer surface (e.g., the skin) of the host and in the natural environment.

    “Therefore, carbonic anhydrases do not affect virulence of Cryptococcus within the host, but may influence its survival on the outer surface (e.g., the skin) of the host and in the natural environment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Upon entering the host, Cryptococcus is subjected to drastic changes in CO2 levels from 0.0036% (ambient air) to 5%.

  • May combine two claims.

    Premisecitation

    Itraconazole (but not fluconazole) and amphotericin B induce ROS and RNS production in C. gattii.

    “In C. gattii, ROS and RNS defense systems are also important for antifungal drug resistance because itraconazole (but not fluconazole) and amphotericin B induce ROS and RNS production, which causes lipid peroxidation and oxidative degradation of lipid membranes (Ferreira et al. 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ferreira et al. 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Several studies comparing stress management between C. neoformans and C. gattii have revealed both redundant and distinct roles of the diverse signaling pathways.

    “Several studies comparing the stress management between C. neoformans and C. gattii have revealed both redundant and distinct roles of the diverse signaling pathways.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The three best-established virulence traits and growth or stress phenotypes are unaffected by light-sensing mutants, and further analysis may enable discoveries about virulence factors operating in Cryptococcus species.

    “Hence, the three best-established virulence traits and growth or stress phenotypes are unaffected, and further analysis may enable discoveries about virulence factors operating in Cryptococcus species.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Inhibition of the calcineurin pathway is fungistatic against the highly virulent C. gattii VGIIa strain R265 at 37°C, whereas it is fungicidal against the less virulent C. gattii VGIIb strain R272 and C. neoformans.

    “inhibition of the calcineurin pathway is fungistatic against the highly virulent C. gattii VGIIa strain R265 at 37 ˚C, whereas it is fungicidal against the less virulent C. gattii VGIIb strain R272 and C. neoformans”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chen et al. 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Comparative microarray analysis revealed MPK1 to be more up-regulated in R265 than in R272, and its deletion caused temperature sensitivity, defects in cell wall integrity, and reduced production of melanin and capsule.

    “Comparative microarray analysis revealed MPK1 to be more up-regulated in R265 than in R272 and its deletion caused temperature sensitivity, defects in cell wall integrity, and a reduced production of melanin and capsule”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ngamskulrungroj et al. 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ena1 (Na+/ATPase) plays an essential role in osmotic stress response, survival under alkaline pH conditions, and plasma membrane potential in C. neoformans.

    “In fact, a key cation transporter, Ena1 (Na þ / ATPase), which plays an essential role in osmotic stress response, survival under alkaline pH conditions and plasma membrane potential, is required for virulence of C. neoformans (Idnurm et al. 2009;Jung et al. 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Idnurm et al. 2009

      Not checked in the free run.

    • cites Jung et al. 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The trehalose pathway modulates production of melanin and capsule as well as cell wall integrity in C. gattii, but not in C. neoformans.

    “the trehalose pathway modulates production of melanin and capsule as well as cell wall integrity in C. gattii, but not in C. neoformans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ngamskulrungroj et al. 2009b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In C. gattii, Sod1 not only counteracts superoxide anions, but also promotes production of virulence factors such as melanin, urease, and phospholipase.

    “In C. gattii, Sod1 not only counteracts superoxide anions, but also promotes production of virulence factors such as melanin, urease, and phospholipase”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Narasipura et al. 2003

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Accurate identification of the subspecies is not only of taxonomic interest but may be clinically relevant because patients infected by these subspecies could have varying risk factors.

    “Accurate identification of the subspecies is not only of taxonomic interest but may be clinically relevant because patients infected by these subspecies could have varying risk factors.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: There are a number of genetically diverged subspecies within each agent of cryptococcosis.
85 of 85

  • The paper relies on this without support.

    The ability to grow at 37°C is essential for any microbial pathogen to cause invasive disease.

    “Although the ability to grow at 37 ˚C is not sufficient by itself to be a mammalian pathogen, it is essential for any microbial pathogen to be able to cause invasive disease.”

  • The paper relies on this without support.

    Iron can be either limiting or in excess in a host depending on health status.

    “Iron can be either limiting or in excess in a host depending on health status.”

  • The paper relies on this without support.

    O2 and CO2 vary in concentration in different parts of the body, lower or higher, respectively, than the natural environment in which Cryptococcus species reside.

    “O 2 and CO 2 vary in concentration in different parts of the body, lower or higher, respectively, than the natural environment in which Cryptococcus species reside.”

  • The paper relies on this without support.

    There are a number of genetically diverged subspecies within each agent of cryptococcosis.

    “There are a number of genetically diverged subspecies within each agent of cryptococcosis.”

  • The paper relies on this without support.

    Upon entering the host, Cryptococcus is subjected to drastic changes in CO2 levels from 0.0036% (ambient air) to 5%.

    “Finally, upon entering the host, Cryptococcus is subjected to drastic changes in CO 2 levels from 0.0036% (ambient air) to 5%.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

1 of the 257 references couldn’t be matched to a known paper.

Research works printed but not linked: 5

  1. Kurtzman CP, Fell JW, Boekhout T), pp. 1661-1745. Elsevier, Amsterdam.
  2. Hsueh YP, Lin X, Kwon-Chung KJ, Heitman J. 2011b. Sexual reproduction of Cryptococcus. In Cryptococcus: From hu- man pathogen to model yeast (ed. Heitman J, et al.), pp. 81-96. ASM, Washington, DC.
  3. Mitchell TG, Castaneda E, Niersen K, Wanke BMSL. 2011. Environmental niches for Cryptococcus neoformans and Cryptococcus gattii. In Cryptococcus: From human patho- gen to model yeast (ed. Heitman J, et al.), pp. 237-259.
  4. Perfect JR. 2010. Cryptococcus neoformans In Principles and practice of infectious diseases (ed. Mandell GL, et al.), pp. 3287-3303. Churchill Livingstone, Philadelphia.
  5. C. neoformans and C. gattii in Cryptococcosis Cite this article as Cold Spring Harb Perspect Med 2014;4:a019760 2014; doi: 10.1101/cshperspect.a019760 Cold Spring Harb Perspect Med

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Authors
Kwon-Chung, K. J., Fraser, J. A., Doering, T. L., Wang, Z. A., Janbon, G., Idnurm, A., & Bahn, Y.-S.
Affiliations
  • National Institutes of Health (US)
  • The University of Queensland (AU)
  • Washington University in St. Louis (US)
  • Institut Pasteur (FR)
  • University of Missouri–Kansas City (US)
  • Yonsei University (KR)
ORCID
Venue
Cold Spring Harbor Perspectives in Medicine
Publisher
Cold Spring Harbor Laboratory
Published
2014-07-01
Volume
4
Issue
7
Pages
a019760-a019760
ISSN
2157-1422 (ISSN-L)
DOI
10.1101/cshperspect.a019760
PMC
PMC4066639
OpenAlex
W2160571905
Semantic Scholar
b424d63f850032f2753f4a64cb25fe91c4fe102b
Cited by
531
References
257
Citations by year
2026: 28 · 2025: 42 · 2024: 50 · 2023: 70 · 2022: 53 · 2021: 53 · 2020: 64 · 2019: 47 · 2018: 45 · 2017: 36 · 2016: 21 · 2015: 16 · 2014: 4
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Research Foundation (109623)
  • National Research Foundation of Korea
  • National Institutes of Health
  • U.S. Public Health Service (87794, 102882, 78795, 109623)
  • National Institute of Allergy and Infectious Diseases (R01AI087794, R01AI102882, R21AI109623, R01AI078795)
Topics
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Yeasts and Rust Fungi Studies
  • Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
Keywords
Cryptococcus neoformans, Cryptococcus gattii, cryptococcosis, fungal pathogenesis, virulence factors, polysaccharide capsule, melanin, urease activity, meningoencephalitis, AIDS, immunocompetent patient, life cycle, stress response
MeSH terms
Cryptococcosis, Cryptococcus neoformans, Enzymes, Genotype, Humans, Life Cycle Stages, Melanins, Terminology as Topic, Phenotype, Stress, Physiological, Signal Transduction, Drug Resistance, Multiple, Fungal, Virulence Factors, Host-Pathogen Interactions, Cryptococcus gattii, Fungal Capsules

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

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