Fatal Disseminated Cryptococcus gattii Infection in New Mexico

Walraven, Carla; Gerstein, Wendy H.; Hardison, Sarah E.; Wormley, Floyd L.; Lockhart, Shawn R.; Harris, Julie; Fothergill, Annette W.; Wickes, Brian L.; Gober-Wilcox, Julie; Massie, Larry; Ku, Tsun Sheng N.; Firacative, Carolina; Meyer, Wieland; Lee, Samuel A.

doi:10.1371/journal.pone.0028625

Cited by 41 publications

(41 citation statements)

References 38 publications

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“…Recently, three fatal cases of cryptococcosis caused by C. gattii molecular types VGI (two cases) and VGIII (one case), have been also reported from North America form otherwise healthy patients [12], [13], [17]. Moreover, human cases of meningitis caused by C. gattii molecular type VGIV, have been reported in Mexico (two patients) [22] and India (four patients) [18], as well as several cases in patients with AIDS in Sub-Saharan Africa, where the molecular type VGIV is more prevalent [20].…”

Section: Discussionmentioning

confidence: 99%

Galleria mellonella Model Identifies Highly Virulent Strains among All Major Molecular Types of Cryptococcus gattii

2014

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Cryptococcosis is mainly caused by Cryptococcus neoformans. However, the number of cases due to C. gattii is increasing, affecting mainly immunocompetent hosts. C. gattii is divided into four major molecular types, VGI to VGIV, which differ in their host range, epidemiology, antifungal susceptibility and geographic distribution. Besides studies on the Vancouver Island outbreak strains, which showed that the subtype VGIIa is highly virulent compared to the subtype VGIIb, little is known about the virulence of the other major molecular types. To elucidate the virulence potential of the major molecular types of C. gattii, Galleria mellonella larvae were inoculated with ten globally selected strains per molecular type. Survival rates were recorded and known virulence factors were studied. One VGII, one VGIII and one VGIV strain were more virulent (p <0.05) than the highly virulent Vancouver Island outbreak strain VGIIa (CDCR265), 11 (four VGI, two VGII, four VGIII and one VGIV) had similar virulence (p >0.05), 21 (five VGI, five VGII, four VGIII and seven VGIV) were less virulent (p <0.05) while one strain of each molecular type were avirulent. Cell and capsule size of all strains increased markedly during larvae infection (p <0.001). No differences in growth rate at 37°C were observed. Melanin synthesis was directly related with the level of virulence: more virulent strains produced more melanin than less virulent strains (p <0.05). The results indicate that all C. gattii major molecular types exhibit a range of virulence, with some strains having the potential to be more virulent. The study highlights the necessity to further investigate the genetic background of more and less virulent strains in order to recognize critical features, other than the known virulence factors (capsule, melanin and growth at mammalian body temperature), that maybe crucial for the development and progression of cryptococcosis.

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Section: Discussionmentioning

confidence: 99%

Galleria mellonella Model Identifies Highly Virulent Strains among All Major Molecular Types of Cryptococcus gattii

2014

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“…Smoking was also an independent risk factor, occurring in 36% of cases in a recent Australian study (130). Other cases of C. gattii cryptococcosis have been reported in smokers (231,272). Pregnancy has been proposed to be a risk factor, and in two studies, 2 of 26 and 1 of 49 patients were pregnant (29,130); however, the proportion of pregnant patients in a recent Australian study of C. gattii infections was not higher than that in the general female population of reproductive age.…”

Section: Epidemiology Of Human Infectionmentioning

confidence: 95%

“…Theories on how these VGII subtypes may have arisen in North America are discussed above (see Epidemiology, Origin, and Evolution, above). Infection outside the Pacific Northwest has been caused by VGI and VGIII (242,243,251,272) as well as by subtype VGIIb and other, nonoutbreak subtypes of VGII (251).…”

Section: Epidemiology Of Human Infectionmentioning

confidence: 99%

Cryptococcus gattii Infections

2014

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SUMMARY Understanding of the taxonomy and phylogeny of Cryptococcus gattii has been advanced by modern molecular techniques. C. gattii probably diverged from Cryptococcus neoformans between 16 million and 160 million years ago, depending on the dating methods applied, and maintains diversity by recombining in nature. South America is the likely source of the virulent C. gattii VGII molecular types that have emerged in North America. C. gattii shares major virulence determinants with C. neoformans , although genomic and transcriptomic studies revealed that despite similar genomes, the VGIIa and VGIIb subtypes employ very different transcriptional circuits and manifest differences in virulence phenotypes. Preliminary evidence suggests that C. gattii VGII causes severe lung disease and death without dissemination, whereas C. neoformans disseminates readily to the central nervous system (CNS) and causes death from meningoencephalitis. Overall, currently available data indicate that the C. gattii VGI, VGII, and VGIII molecular types more commonly affect nonimmunocompromised hosts, in contrast to VGIV. New, rapid, cheap diagnostic tests and imaging modalities are assisting early diagnosis and enabling better outcomes of cerebral cryptococcosis. Complications of CNS infection include increased intracranial pressure, severe neurological sequelae, and development of immune reconstitution syndrome, although the mortality rate is low. C. gattii VGII isolates may exhibit higher fluconazole MICs than other genotypes. Optimal therapeutic regimens are yet to be determined; in most cases, initial therapy with amphotericin B and 5-flucytosine is recommended.

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“…In contrast, C. gattii molecular type VGIII is responsible for ongoing infections in immunocompromised HIV/AIDS patients in Southern California and the Southwestern US [18], [22], [37], [44], [45]. Outside the US VGIII has been associated with sporadic infections in Brazil, Colombia, Mexico, India, Germany, and Korea [14], [23], [37], [46]–[51].…”

Section: Introductionmentioning

confidence: 99%

Cryptococcus gattii VGIII Isolates Causing Infections in HIV/AIDS Patients in Southern California: Identification of the Local Environmental Source as Arboreal

et al. 2014

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Ongoing Cryptococcus gattii outbreaks in the Western United States and Canada illustrate the impact of environmental reservoirs and both clonal and recombining propagation in driving emergence and expansion of microbial pathogens. C. gattii comprises four distinct molecular types: VGI, VGII, VGIII, and VGIV, with no evidence of nuclear genetic exchange, indicating these represent distinct species. C. gattii VGII isolates are causing the Pacific Northwest outbreak, whereas VGIII isolates frequently infect HIV/AIDS patients in Southern California. VGI, VGII, and VGIII have been isolated from patients and animals in the Western US, suggesting these molecular types occur in the environment. However, only two environmental isolates of C. gattii have ever been reported from California: CBS7750 (VGII) and WM161 (VGIII). The incongruence of frequent clinical presence and uncommon environmental isolation suggests an unknown C. gattii reservoir in California. Here we report frequent isolation of C. gattii VGIII MATα and MAT a isolates and infrequent isolation of VGI MATα from environmental sources in Southern California. VGIII isolates were obtained from soil debris associated with tree species not previously reported as hosts from sites near residences of infected patients. These isolates are fertile under laboratory conditions, produce abundant spores, and are part of both locally and more distantly recombining populations. MLST and whole genome sequence analysis provide compelling evidence that these environmental isolates are the source of human infections. Isolates displayed wide-ranging virulence in macrophage and animal models. When clinical and environmental isolates with indistinguishable MLST profiles were compared, environmental isolates were less virulent. Taken together, our studies reveal an environmental source and risk of C. gattii to HIV/AIDS patients with implications for the >1,000,000 cryptococcal infections occurring annually for which the causative isolate is rarely assigned species status. Thus, the C. gattii global health burden could be more substantial than currently appreciated.

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Fatal Disseminated Cryptococcus gattii Infection in New Mexico

Cited by 41 publications

References 38 publications

Galleria mellonella Model Identifies Highly Virulent Strains among All Major Molecular Types of Cryptococcus gattii

Galleria mellonella Model Identifies Highly Virulent Strains among All Major Molecular Types of Cryptococcus gattii

Cryptococcus gattii Infections

Cryptococcus gattii VGIII Isolates Causing Infections in HIV/AIDS Patients in Southern California: Identification of the Local Environmental Source as Arboreal

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