Abstract
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.
Highlights
Cryptococcus neoformans (Cn) is an encapsulated basidiomycetous yeast, and the etiological agent of the invasive fungal infection cryptococcosis
Cryptococcus neoformans variety grubii (Cng) causes meningitis among HIV/AIDS patients, up to 1 million cases/year resulting in over 600,000 mortalities. Despite these rates of mortality being comparable to those caused by malaria, cryptococcal meningitis receives only a fraction of the attention, funding and control granted to more widely recognised diseases
This study uses multilocus sequence typing to compare the genetic diversity of Cng in a largely unstudied country with an emerging HIV epidemic, Thailand, against the diversity seen elsewhere
Summary
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]. The HIV/AIDS epidemic has driven increased Cryptococcus infection rates via the rapid increase of immunosuppressed populations [1,6,7]. 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]. The ISHAM group has selected multi-locus sequence typing (MLST) using seven loci as the method of choice for global molecular epidemiological typing of Cryptococcus species
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