Abstract

C. neoformans var. grubii (C. neoformans) is an environmentally acquired pathogen causing 181 000 HIV-associated deaths each year. We used whole genome sequencing (WGS) to characterise 699 isolates, primarily C. neoformans from HIV-infected patients, from 5 countries in Asia and Africa. We found that 91% of our clinical isolates belonged to one of three highly clonal sub-clades of VNIa, which we have termed VNIa-4, VNIa-5 and VNIa-93. Parsimony analysis revealed frequent, long distance transmissions of C. neoformans; international transmissions took place on 13% of VNIa-4 branches, and intercontinental transmissions on 7% of VNIa-93 branches. The median length of within sub-clade internal branches was 3-6 SNPs, while terminal branches were 44.5-77.5 SNPs. The short median internal branches were partly driven by the large number (12-15% of internal branches) of polytomies in the within-sub-clade trees. To simultaneously explain our observation of no apparent molecular clock, short internal branches and frequent polytomies we hypothesise that C. neoformans VNIa spends much of its time in the environment in a quiescent state, while, when it is sampled, it has almost always undergone an extended period of growth. Infections with VNIa-93 were associated with a significantly reduced risk of death by 10 weeks compared with infections with VNIa-4 (Hazard Ratio = 0.45, p = 0.003). We detected a recombination in the mitochondrial sequence of VNIa-5, suggesting that mitochondria could be involved in the propensity of this sub-clade to infect HIV-uninfected patients. These data highlight the insight into the biology and epidemiology of pathogenic fungi which can be gained from WGS data.

Details

Title
Genomics of Cryptococcus neoformans
Author
Ashton, Philip M; Lam, Tuan Thanh; Phan, Hai Trieu; Duong Van Anh; Nguyen Mai Trinh; Beardsley, Justin; Kibengo, Freddie; Chierakul, Wirongrong; David Ab Dance; Le Quoc Hung; Nguyen Van Vinh Chau; Nguyen Le Nhu Tung; Chan, Adrienne K; Thwaites, Guy E; Lalloo, David G; Anscombe, Catherine; Le Thanh Hoang Nhat; Perfect, John; Dougan, Gordon; Baker, Stephen; Harris, Simon; Day, Jeremy N
University/institution
Cold Spring Harbor Laboratory Press
Section
New Results
Publication year
2018
Publication date
Jun 28, 2018
Publisher
Cold Spring Harbor Laboratory Press
ISSN
2692-8205
Source type
Working Paper
Language of publication
English
ProQuest document ID
2068570708
Copyright
�� 2018. This article is published under http://creativecommons.org/licenses/by/4.0/ (���the License���). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.