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

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dc.contributor.authorBeale, Mathew Aen_ZA
dc.contributor.authorSabiiti, Wilberen_ZA
dc.contributor.authorRobertson, Emma Jen_ZA
dc.contributor.authorFuentes-Cabrejo, Karen Men_ZA
dc.contributor.authorO'Hanlon, Simon Jen_ZA
dc.contributor.authorJarvis, Joseph Nen_ZA
dc.contributor.authorLoyse, Angelaen_ZA
dc.contributor.authorMeintjes, Graemeen_ZA
dc.contributor.authorHarrison, Thomas Sen_ZA
dc.contributor.authorMay, Robin Cen_ZA
dc.date.accessioned2015-12-28T06:47:47Z
dc.date.available2015-12-28T06:47:47Z
dc.date.issued2015en_ZA
dc.description.abstractCryptococcal 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.identifier.apacitationBeale, 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/11427/16052en_ZA
dc.identifier.chicagocitationBeale, 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/11427/16052en_ZA
dc.identifier.citationBeale, 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.0003847en_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
dc.identifier.urihttp://hdl.handle.net/11427/16052
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pntd.0003847
dc.identifier.vancouvercitationBeale 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.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis 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.holder© 2015 Beale et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLOS Neglected Tropical Diseasesen_ZA
dc.source.urihttp://journals.plos.org/plosntdsen_ZA
dc.subject.otherDNA sequence analysisen_ZA
dc.subject.otherHuman geneticsen_ZA
dc.subject.otherCryptococcusen_ZA
dc.subject.otherLaccasesen_ZA
dc.subject.otherPhenotypesen_ZA
dc.subject.otherCryptococcus neoformansen_ZA
dc.subject.otherFungal geneticsen_ZA
dc.subject.otherSequence alignmenten_ZA
dc.titleGenotypic diversity is associated with clinical outcome and phenotype in cryptococcal meningitis across Southern Africaen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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