Abstract
Cryptococcal meningitis is a major cause of mortality throughout the
developing world, yet little is known about the genetic markers
underlying Cryptococcal virulence and patient outcome. We studied a
cohort of 230 Cryptococcus neoformans (Cn) isolates
from HIV-positive South African clinical trial patients with detailed
clinical follow-up using multi-locus sequence typing and in vitro phenotypic virulence assays, correlating these data with clinical and fungal markers of disease in the patient. South African Cn
displayed high levels of genetic diversity and locus variability
compared to globally distributed types, and we identified 50 sequence
types grouped within the main molecular types VNI, VNII and VNB, with
72% of isolates typed into one of seven 'high frequency' sequence types.
Spatial analysis of patients’ cryptococcal genotype was not shown to be
clustered geographically, which might argue against recent local
acquisition and in favour of reactivation of latent infection. Through
comparison of MLST genotyping data with clinical parameters, we found a
relationship between genetic lineage and clinical outcome, with patients
infected with the VNB lineage having significantly worse survival (n=8,
HR 3.35, CI 1.51-7.20, p=0.003), and this was maintained even after
adjustment for known prognostic indicators and treatment regimen.
Comparison of fungal genotype with in vitro phenotype
(phagocytosis, laccase activity and CSF survival) performed on a subset
of 89 isolates revealed evidence of lineage-associated virulence
phenotype, with the VNII lineage displaying increased laccase activity
(p=0.001) and ex vivo CSF survival (p=0.0001). These findings show that Cryptococcus neoformans
is a phenotypically heterogeneous pathogen, and that lineage plays an
important role in cryptococcal virulence during human infection.
Furthermore, a detailed understanding of the genetic diversity in
Southern Africa will support further investigation into how genetic
diversity is structured across African environments, allowing assessment
of the risks different ecotypes pose to infection.
Original language | English |
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Article number | e0003847 |
Number of pages | 18 |
Journal | PLoS Neglected Tropical Diseases |
Volume | 9 |
Issue number | 6 |
DOIs | |
Publication status | Published - 25 Jun 2015 |
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Wilber Sabiiti
- School of Medicine - Principal Research Fellow
- Infection and Global Health Division
Person: Academic - Research
Datasets
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Genotypic diversity is associated with clinical outcome and phenotype in cryptococcal meningitis across Southern Africa (dataset)
Beale, M. A. (Creator), Sabiiti, W. (Creator), Robertson, E. J. (Creator), Fuentes-Cabrejo, K. M. (Creator), O'Hanlon, S. J. (Creator), Jarvis, J. N. (Creator), Loyse, A. (Creator), Meintjes, G. (Creator), Harrison, T. S. (Creator), May, R. C. (Creator), Fisher, M. C. (Creator) & Bicanic, T. (Creator), The European Bioinformatics Institute, 11 Jun 2015
Dataset