The emergence of Cryptococcus gattii in British Columbia and the Pacific Northwest

Bartlett, Karen H.; Kidd, Sarah; Kronstad, James W.

doi:10.1007/s11908-008-0011-1

Cited by 100 publications

(113 citation statements)

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“…Despite its medical importance, the treatment for cryptococcosis is limited. With increasing concerns of drug resistance and evolution of new virulent strains (6)(7)(8)(9), there is an urgent need to understand the molecular basis of cryptococcal infection in order to discover and develop safer and more effective antifungal drugs. Against this background of clinical need are the heroic research efforts toward understanding the mechanism of Cryptococcus development and virulence that have significantly advanced the field in the past several decades.…”

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Fbp1-Mediated Ubiquitin-Proteasome Pathway Controls Cryptococcus neoformans Virulence by Regulating Fungal Intracellular Growth in Macrophages

Liu

Xue

2014

Infect Immun

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Cryptococcus neoformans is a human fungal pathogen that often causes lung and brain infections in immunocompromised patients, with a high fatality rate. Our previous results showed that an F-box protein, Fbp1, is essential for Cryptococcus virulence independent of the classical virulence factors, suggesting a novel virulence control mechanism. In this study, we show that Fbp1 is part of the ubiquitin-proteasome system, and we further investigated the mechanism of Fbp1 function during infection. Time course studies revealed that the fbp1⌬ mutant causes little damage in the infected lung and that the fungal burden in the lung remains at a low but persistent level throughout infection. The fbp1⌬ mutant cannot disseminate to other organs following pulmonary infection in the murine inhalation model of cryptococcosis but still causes brain infection in a murine intravenous injection model, suggesting that the block of dissemination of the fbp1⌬ mutant is due to its inability to leave the lung. The fbp1⌬ mutant showed a defect in intracellular proliferation after phagocytosis in a Cryptococcus-macrophage interaction assay, which likely contributes to its virulence attenuation. To elucidate the molecular basis of the SCF(Fbp1) E3 ligase function, we analyzed potential Fbp1 substrates based on proteomic approaches combined with phenotypic analysis. One substrate, the inositol phosphosphingolipid-phospholipase C1 (Isc1), is required for fungal survival inside macrophage cells, which is consistent with the role of Fbp1 in regulating Cryptococcus-macrophage interaction and fungal virulence. Our results thus reveal a new determinant of fungal virulence that involves the posttranslational regulation of inositol sphingolipid biosynthesis.C ryptococcus neoformans is a major human fungal pathogen and the causative agent of fatal cryptococcal meningoencephalitis, which is considered an AIDS-defined condition (1-5). Despite its medical importance, the treatment for cryptococcosis is limited. With increasing concerns of drug resistance and evolution of new virulent strains (6-9), there is an urgent need to understand the molecular basis of cryptococcal infection in order to discover and develop safer and more effective antifungal drugs. Against this background of clinical need are the heroic research efforts toward understanding the mechanism of Cryptococcus development and virulence that have significantly advanced the field in the past several decades. Several virulence factors, including production of polysaccharide capsule and melanin and the ability to grow at body temperature (37°C), have been well characterized (10, 11). A number of signal pathways regulating these virulence factors and important for Cryptococcus pathogenesis have also been identified (5, 12-16). Systematic genetic analysis of genes involved in fungal virulence revealed a capsule-independent antiphagocytic mechanism, as well as a number of proteins regulating fungal virulence independent of the classical virulence factors (17, 18). These studies revealed tha...

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Fbp1-Mediated Ubiquitin-Proteasome Pathway Controls Cryptococcus neoformans Virulence by Regulating Fungal Intracellular Growth in Macrophages

Liu

Xue

2014

Infect Immun

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“…Cryptococcus is the most common systemic fungal pathogen of cats and can also cause severe disseminated disease in dogs (1). In humans, C. neoformans is opportunistic, usually infecting HIV/AIDS patients and other immunosuppressed individuals (2), whereas C. gattii is more likely to infect immunocompetent hosts (3). Cryptococcosis typically occurs in cats with no obvious underlying immunodeficiency, and infections are not associated with concurrent retroviral infection or other immunocompromised states (4,5).…”

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“…C. gattii strains that belong to molecular type VGII can be further categorized into a large number of subtypes. Of those VGIIa, VGIIb, and VGIIc have been implicated in disease in immunocompetent humans, cats, dogs, and other animal species in British Columbia and the Pacific Northwest of the United States (3,(13)(14)(15)). An epidemiological study of dogs and cats with cryptococcosis in California showed that cats were most often infected with C. gattii molecular type VGIII, whereas dogs were more likely to be infected with C. neoformans, possibly reflecting host differences in susceptibility (6).…”

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Antifungal Drug Susceptibility and Phylogenetic Diversity among Cryptococcus Isolates from Dogs and Cats in North America

et al. 2014

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f Molecular types of the Cryptococcus neoformans/Cryptococcus gattii species complex that infect dogs and cats differ regionally and with host species. Antifungal drug susceptibility can vary with molecular type, but the susceptibility of Cryptococcus isolates from dogs and cats is largely unknown. Cryptococcus isolates from 15 dogs and 27 cats were typed using URA5 restriction fragment length polymorphism analysis (RFLP), PCR fingerprinting, and multilocus sequence typing (MLST). Susceptibility was determined using a microdilution assay (Sensititre YeastOne; Trek Diagnostic Systems). MICs were compared among groups. The 42 isolates studied comprised molecular types VGI (7%), VGIIa (7%), VGIIb (5%), VGIIc (5%), VGIII (38%), VGIV (2%), VNI (33%), and VNII (2%), as determined by URA5 RFLP. The VGIV isolate was more closely related to VGIII according to MLST. All VGIII isolates were from cats. All sequence types identified from veterinary isolates clustered with isolates from humans. VGIII isolates showed considerable genetic diversity compared with other Cryptococcus molecular types and could be divided into two major subgroups. Compared with C. neoformans MICs, C. gattii MICs were lower for flucytosine, and VGIII MICs were lower for flucytosine and itraconazole. For all drugs except itraconazole, C. gattii isolates exhibited a wider range of MICs than C. neoformans. MICs varied with Cryptococcus species and molecular type in dogs and cats, and MICs of VGIII isolates were most variable and may reflect phylogenetic diversity in this group. Because sequence types of dogs and cats reflect those infecting humans, these observations may also have implications for treatment of human cryptococcosis.

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“…However, since 1999, an outbreak of C. gattii infections has been occurring in the temperate climate of Vancouver Island in British Columbia. This outbreak has resulted in at least 200 human cases and eight deaths (3,21). More recently, cases of cryptococcosis caused by C. gattii have occurred on the mainland in British Columbia as well as in Washington and Oregon in the United States.…”

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Cryptococcus gattiiIsolates from the British Columbia Cryptococcosis Outbreak Induce Less Protective Inflammation in a Murine Model of Infection thanCryptococcus neoformans

2009

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The fungal pathogen Cryptococcus neoformans causes approximately one million cases of cryptococcosis per year in people with AIDS. In contrast, the related species C. gattii is responsible for a much smaller number of cases, but these often occur in immunocompetent people. In fact, C. gattii has emerged in the last decade as the frequent cause of cryptococcosis in otherwise healthy people in British Columbia. We analyzed the immune responses elicited by three C. gattii strains and one C. neoformans strain in mice as a first step toward understanding why C. gattii is able to cause disease in immunocompetent hosts. The C. gattii strains all induced a less protective inflammatory response in C57BL/6 mice by inhibiting or failing to provoke the migration of neutrophils to sites of infection. The C. gattii strains also failed to elicit the production of protective cytokines, such as tumor necrosis factor alpha, compared to the ability of the C. neoformans strain. Despite these differences, the strain representing the major outbreak genotype from British Columbia showed a virulence equivalent to that of the C. neoformans strain, while two other C. gattii strains had reduced virulence. Taken together, our results indicate that C. gattii strains thrive in immunocompetent hosts by evading or suppressing the protective immune responses that normally limit the progression of disease caused by C. neoformans.

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The emergence of Cryptococcus gattii in British Columbia and the Pacific Northwest

Cited by 100 publications

References 46 publications

Fbp1-Mediated Ubiquitin-Proteasome Pathway Controls Cryptococcus neoformans Virulence by Regulating Fungal Intracellular Growth in Macrophages

Fbp1-Mediated Ubiquitin-Proteasome Pathway Controls Cryptococcus neoformans Virulence by Regulating Fungal Intracellular Growth in Macrophages

Antifungal Drug Susceptibility and Phylogenetic Diversity among Cryptococcus Isolates from Dogs and Cats in North America

Cryptococcus gattiiIsolates from the British Columbia Cryptococcosis Outbreak Induce Less Protective Inflammation in a Murine Model of Infection thanCryptococcus neoformans

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