Genotypic diversity is associated with clinical outcome and phenotype in cryptococcal meningitis across Southern Africa

 

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dc.contributor.author Beale, Mathew A en_ZA
dc.contributor.author Sabiiti, Wilber en_ZA
dc.contributor.author Robertson, Emma J en_ZA
dc.contributor.author Fuentes-Cabrejo, Karen M en_ZA
dc.contributor.author O'Hanlon, Simon J en_ZA
dc.contributor.author Jarvis, Joseph N en_ZA
dc.contributor.author Loyse, Angela en_ZA
dc.contributor.author Meintjes, Graeme en_ZA
dc.contributor.author Harrison, Thomas S en_ZA
dc.contributor.author May, Robin C en_ZA
dc.date.accessioned 2015-12-28T06:47:47Z
dc.date.available 2015-12-28T06:47:47Z
dc.date.issued 2015 en_ZA
dc.identifier.citation Beale, M. A., Sabiiti, W., Robertson, E. J., Fuentes-Cabrejo, K. M., O’Hanlon, S. J., Jarvis, J. N., ... & Fisher, M. C. (2015). Genotypic diversity is associated with clinical outcome and phenotype in cryptococcal meningitis across Southern Africa. PLoS Negl Trop Dis, 9(6), e0003847. doi:10.1371/journal.pntd.0003847 en_ZA
dc.identifier.uri http://hdl.handle.net/11427/16052
dc.identifier.uri http://dx.doi.org/10.1371/journal.pntd.0003847
dc.description.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. en_ZA
dc.language.iso eng en_ZA
dc.publisher Public Library of Science en_ZA
dc.rights This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. en_ZA
dc.rights.uri http://creativecommons.org/licenses/by/4.0 en_ZA
dc.source PLOS Neglected Tropical Diseases en_ZA
dc.source.uri http://journals.plos.org/plosntds en_ZA
dc.subject.other DNA sequence analysis en_ZA
dc.subject.other Human genetics en_ZA
dc.subject.other Cryptococcus en_ZA
dc.subject.other Laccases en_ZA
dc.subject.other Phenotypes en_ZA
dc.subject.other Cryptococcus neoformans en_ZA
dc.subject.other Fungal genetics en_ZA
dc.subject.other Sequence alignment en_ZA
dc.title Genotypic diversity is associated with clinical outcome and phenotype in cryptococcal meningitis across Southern Africa en_ZA
dc.type Journal Article en_ZA
dc.rights.holder © 2015 Beale et al en_ZA
uct.type.publication Research en_ZA
uct.type.resource Article en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Health Sciences en_ZA
dc.publisher.department Institute of Infectious Disease and Molecular Medicine en_ZA
uct.type.filetype Text
uct.type.filetype Image
dc.identifier.apacitation Beale, M. A., Sabiiti, W., Robertson, E. J., Fuentes-Cabrejo, K. M., O'Hanlon, S. J., Jarvis, J. N., ... May, R. C. (2015). Genotypic diversity is associated with clinical outcome and phenotype in cryptococcal meningitis across Southern Africa. <i>PLOS Neglected Tropical Diseases</i>, http://hdl.handle.net/11427/16052 en_ZA
dc.identifier.chicagocitation Beale, Mathew A, Wilber Sabiiti, Emma J Robertson, Karen M Fuentes-Cabrejo, Simon J O'Hanlon, Joseph N Jarvis, Angela Loyse, Graeme Meintjes, Thomas S Harrison, and Robin C May "Genotypic diversity is associated with clinical outcome and phenotype in cryptococcal meningitis across Southern Africa." <i>PLOS Neglected Tropical Diseases</i> (2015) http://hdl.handle.net/11427/16052 en_ZA
dc.identifier.vancouvercitation Beale MA, Sabiiti W, Robertson EJ, Fuentes-Cabrejo KM, O'Hanlon SJ, Jarvis JN, et al. Genotypic diversity is associated with clinical outcome and phenotype in cryptococcal meningitis across Southern Africa. PLOS Neglected Tropical Diseases. 2015; http://hdl.handle.net/11427/16052. en_ZA
dc.identifier.ris TY - Journal Article AU - Beale, Mathew A AU - Sabiiti, Wilber AU - Robertson, Emma J AU - Fuentes-Cabrejo, Karen M AU - O'Hanlon, Simon J AU - Jarvis, Joseph N AU - Loyse, Angela AU - Meintjes, Graeme AU - Harrison, Thomas S AU - May, Robin C AB - 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. DA - 2015 DB - OpenUCT DO - 10.1371/journal.pntd.0003847 DP - University of Cape Town J1 - PLOS Neglected Tropical Diseases LK - https://open.uct.ac.za PB - University of Cape Town PY - 2015 T1 - Genotypic diversity is associated with clinical outcome and phenotype in cryptococcal meningitis across Southern Africa TI - Genotypic diversity is associated with clinical outcome and phenotype in cryptococcal meningitis across Southern Africa UR - http://hdl.handle.net/11427/16052 ER - en_ZA


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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Except where otherwise noted, this item's license is described as This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.