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.

Fig. 1

A whole-genome single-nucleotide polymorphism (SNP) phylogeny of all VNI in this study and Desjardins et al., constructed from 325,812 variable positions. Nodes with <80% bootstrap support are highlighted by a blue circle. Scale bar is genetic distance in number of substitutions per site

Fig. 2

Within sub-clade phylogenetic trees for a VNIa-4, b VNIa-5 and c VNIa-93. Rings are numbered and coloured according to Fig. 1. Nodes with <80% bootstrap support are denoted with blue circles. Trees were constructed from 24,956 (VNIa-4), 22,894 (VNIa-5) and 11,056 (VNIa-93) variable positions. Scale bar is genetic distance in number of substitutions per site

Fig. 3

Kaplan–Meier survival estimates up to 6 months for all 530-HIV infected patients enroled in one of two clinical trials (Day et al.; Beardsley et al.) with whole-genome sequencing results for their infecting isolate