Three phylogenetic groups have driven the recent population expansion of Cryptococcus neoformans

Abstract

Cryptococcus neoformans ( C. neoformans var. grubii ) is an environmentally acquired pathogen causing 181,000 HIV-associated deaths each year. We sequenced 699 isolates, primarily C. neoformans from HIV-infected patients, from 5 countries in Asia and Africa. The phylogeny of C. neoformans reveals a recent exponential population expansion, consistent with the increase in the number of susceptible hosts. In our study population, this expansion has been driven by three sub-clades of the C. neoformans VNIa lineage; VNIa-4, VNIa-5 and VNIa-93. These three sub-clades account for 91% of clinical isolates sequenced in our study. Combining the genome data with clinical information, we find that the VNIa-93 sub-clade, the most common sub-clade in Uganda and Malawi, was associated with better outcomes than VNIa-4 and VNIa-5, which predominate in Southeast Asia. This study lays the foundation for further work investigating the dominance of VNIa-4, VNIa-5 and VNIa-93 and the association between lineage and clinical phenotype.

The virulence of theCryptococcus neoformansVNIa-5 lineage is highly plastic and associated with isolate background

“…These data suggest that VNIa-5 isolates have increased pathogenic potential. Of note, we do not observe clustering of isolates within the VNIa-5 lineage according to host immune status, signifying that the entire lineage has the potential to cause disease in immunocompetent people 2 .…”

“…We have previously shown that the VNIa-5 lineage is strongly associated with disease in apparently immunocompetent patients 2,3 . Both VNIa-5 and VNIa-4 frequently affect our (severely immunosuppressed) HIV-infected patients 2,3 . VNIa-4 rarely causes disease in HIV-uninfected patients, and when it does, the patients are significantly more likely to have underlying diseases associated with immunosuppression 9 .…”

“…A number of lineages of Cryptococcus neoformans cause meningitis in humans in Vietnam, but the vast majority of cases are due to either VNIa-4 or VNIa-5 2 . We have previously shown that the VNIa-5 lineage is strongly associated with disease in apparently immunocompetent patients 2,3 . Both VNIa-5 and VNIa-4 frequently affect our (severely immunosuppressed) HIV-infected patients 2,3 .…”

“…Contrary to other locations in tropical and sub-tropical areas 10,11 , most infections in these patients (80%) are due to C. neoformans , rather than C. gattii 12 . We previously identified an association between the C. neoformans VNIa-5 lineage and disease in these apparently immunocompetent patients, it accounting for approximately 90% of meningitis due to C. neoformans 2,3,12 . Furthermore, HIV-uninfected patients with cryptococcal meningitis due to other lineages were significantly more likely to have co-morbidities associated with immune compromise 12 .…”

“…Disease in HIV-infected patients has been driven by the clonal expansion of a small number of well-defined lineages. These lineages are widely dispersed globally, but a single lineage predominates in most countries 2 . However, Vietnam is atypical and has two co-dominant circulating lineages (VNIa-5 and VNIa-4), each accounting for approximately 35-40% of cases of meningitis in HIV-infected patients 2-4 .…”