Low Diversity Cryptococcus neoformans Variety grubii Multilocus Sequence Types from Thailand Are Consistent with an Ancestral African Origin

PLoS Pathogens, Apr 2011

The global burden of HIV-associated cryptococcal meningitis is estimated at nearly one million cases per year, causing up to a third of all AIDS-related deaths. Molecular epidemiology constitutes the main methodology for understanding the factors underpinning the emergence of this understudied, yet increasingly important, group of pathogenic fungi. Cryptococcus species are notable in the degree that virulence differs amongst lineages, and highly-virulent emerging lineages are changing patterns of human disease both temporally and spatially. Cryptococcus neoformans variety grubii (Cng, serotype A) constitutes the most ubiquitous cause of cryptococcal meningitis worldwide, however patterns of molecular diversity are understudied across some regions experiencing significant burdens of disease. We compared 183 clinical and environmental isolates of Cng from one such region, Thailand, Southeast Asia, against a global MLST database of 77 Cng isolates. Population genetic analyses showed that Thailand isolates from 11 provinces were highly homogenous, consisting of the same genetic background (globally known as VNI) and exhibiting only ten nearly identical sequence types (STs), with three (STs 44, 45 and 46) dominating our sample. This population contains significantly less diversity when compared against the global population of Cng, specifically Africa. Genetic diversity in Cng was significantly subdivided at the continental level with nearly half (47%) of the global STs unique to a genetically diverse and recombining population in Botswana. These patterns of diversity, when combined with evidence from haplotypic networks and coalescent analyses of global populations, are highly suggestive of an expansion of the Cng VNI clade out of Africa, leading to a limited number of genotypes founding the Asian populations. Divergence time testing estimates the time to the most common ancestor between the African and Asian populations to be 6,920 years ago (95% HPD 122.96 - 27,177.76). Further high-density sampling of global Cng STs is now necessary to resolve the temporal sequence underlying the global emergence of this human pathogen.

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Low Diversity Cryptococcus neoformans Variety grubii Multilocus Sequence Types from Thailand Are Consistent with an Ancestral African Origin

et al. (2011) Low Diversity Cryptococcus neoformans Variety grubii Multilocus Sequence Types from Thailand Are Consistent with an Ancestral African Origin. PLoS Pathog 7(4): e1001343. doi:10.1371/journal.ppat.1001343 Low Diversity Cryptococcus neoformans Variety grubii Multilocus Sequence Types from Thailand Are Consistent with an Ancestral African Origin Sitali P. Simwami Kantarawee Khayhan Daniel A. Henk David M. Aanensen Teun Boekhout Ferry Hagen Annemarie E. Brouwer Thomas S. Harrison Christl A. Donnelly Matthew C. Fisher Joseph Heitman, Duke University Medical Center, United States of America The global burden of HIV-associated cryptococcal meningitis is estimated at nearly one million cases per year, causing up to a third of all AIDS-related deaths. Molecular epidemiology constitutes the main methodology for understanding the factors underpinning the emergence of this understudied, yet increasingly important, group of pathogenic fungi. Cryptococcus species are notable in the degree that virulence differs amongst lineages, and highly-virulent emerging lineages are changing patterns of human disease both temporally and spatially. Cryptococcus neoformans variety grubii (Cng, serotype A) constitutes the most ubiquitous cause of cryptococcal meningitis worldwide, however patterns of molecular diversity are understudied across some regions experiencing significant burdens of disease. We compared 183 clinical and environmental isolates of Cng from one such region, Thailand, Southeast Asia, against a global MLST database of 77 Cng isolates. Population genetic analyses showed that Thailand isolates from 11 provinces were highly homogenous, consisting of the same genetic background (globally known as VNI) and exhibiting only ten nearly identical sequence types (STs), with three (STs 44, 45 and 46) dominating our sample. This population contains significantly less diversity when compared against the global population of Cng, specifically Africa. Genetic diversity in Cng was significantly subdivided at the continental level with nearly half (47%) of the global STs unique to a genetically diverse and recombining population in Botswana. These patterns of diversity, when combined with evidence from haplotypic networks and coalescent analyses of global populations, are highly suggestive of an expansion of the Cng VNI clade out of Africa, leading to a limited number of genotypes founding the Asian populations. Divergence time testing estimates the time to the most common ancestor between the African and Asian populations to be 6,920 years ago (95% HPD 122.96 - 27,177.76). Further high-density sampling of global Cng STs is now necessary to resolve the temporal sequence underlying the global emergence of this human pathogen. - Competing Interests: The authors have declared that no competing interests exist. Introduction Cryptococcus neoformans (Cn) is an encapsulated basidiomycetous yeast, and the etiological agent of the invasive fungal infection cryptococcosis. The first clinical discovery of Cn was in 1894, and this pathogen has since become one of the leading causes of mycotic morbidity and mortality worldwide [1,2,3]. Capable of causing disease among both immunocompetent and immunocompromised individuals, the most common manifestation of cryptococcosis is cryptococcal meningitis (CM) [4,5]. The HIV/AIDS epidemic has driven increased Cryptococcus infection rates via the rapid increase of immunosuppressed populations [1,6,7]. Patients with HIV-related CM must undergo maintenance anti-fungal therapy life-long or until immunoreconstitution is reached by antiretroviral therapy [8], and mortality rates remain unacceptably high [3]. Originally believed to be a single species, two distinct varieties of Cn have been described, corresponding to three serotypes: Cn var grubii (serotype A; henceforth Cng), Cn var neoformans (serotype D) and AD hybrids [9]. C. gattii, a second species of the genus Cryptococcus, consists of serotypes B and C [10], and is also capable of forming hybrids with Cn [11,12,13]. Molecular typing has resulted in these two species being further subdivided into eight major molecular types: VNI and VNII (serotype A; var grubii), VNIII (hybrid serotype AD; var neoformans), VNIV (serotype D; var neoformans), VGI, VGII, VGIII and VGIV (serotypes B and C; var gattii) [12,13,14,15]. Within Cng, VNI predominates worldwide, including in Southeast Asian countries such as Thailand [16] and Malaysia [17]. Cn has two mating types, MATa and MATa, controlled by a single locus, two allele mating system [18]. Globally, there is a predominance of mating-type MATa among Cryptococcus neoformans is a species complex of often highly pathogenic fungi that cause significant disease in humans. Cryptococcus is notable in the degree that virulence differs amongst genotypes, and highly-virulent emerging lineages are changing patterns of disease in time and space. Cryptococcus neoformans variety grubii (Cng) causes meningitis (...truncated)


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Sitali P. Simwami, Kantarawee Khayhan, Daniel A. Henk, David M. Aanensen, Teun Boekhout, Ferry Hagen, Annemarie E. Brouwer, Thomas S. Harrison, Christl A. Donnelly, Matthew C. Fisher. Low Diversity Cryptococcus neoformans Variety grubii Multilocus Sequence Types from Thailand Are Consistent with an Ancestral African Origin, PLoS Pathogens, 2011, Volume 7, Issue 4, DOI: 10.1371/journal.ppat.1001343