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dc.contributor.authorSabiiti, Wilber
dc.contributor.authorRobertson, Emma
dc.contributor.authorBeale, Mathew A
dc.contributor.authorJohnston, Simon A
dc.contributor.authorBrouwer, Annemarie E
dc.contributor.authorLoyse, Angela
dc.contributor.authorJarvis, Joseph N
dc.contributor.authorGilbert, Andrew S
dc.contributor.authorFisher, Matthew C
dc.contributor.authorHarrison, Thomas S
dc.contributor.authorMay, Robin C
dc.contributor.authorBicanic, Tihana
dc.date.accessioned2014-05-15T15:01:04Z
dc.date.available2014-05-15T15:01:04Z
dc.date.issued2014-05-01
dc.identifier.citationSabiiti , W , Robertson , E , Beale , M A , Johnston , S A , Brouwer , A E , Loyse , A , Jarvis , J N , Gilbert , A S , Fisher , M C , Harrison , T S , May , R C & Bicanic , T 2014 , ' Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis ' , The Journal of Clinical Investigation , vol. 124 , no. 5 , pp. 2000-2008 . https://doi.org/10.1172/JCI72950en
dc.identifier.issn0021-9738
dc.identifier.otherPURE: 118740732
dc.identifier.otherPURE UUID: 4abe2795-1a86-453e-a17a-5d9c3e2511ed
dc.identifier.otherPubMed: 24743149
dc.identifier.otherScopus: 84899712756
dc.identifier.otherORCID: /0000-0002-4742-2791/work/60196328
dc.identifier.otherWOS: 000335424500016
dc.identifier.urihttp://hdl.handle.net/10023/4803
dc.descriptionThis work was made possible by funding from the Wellcome Trust (WT088148MF), the Medical Research Council (MR/J008176/1), the NIHR Surgical Reconstruction and Microbiology Research Centre and the Lister Institute for Preventive Medicine (to R.C. May), and a Wellcome Trust Intermediate fellowship (089966, to T. Bicanic). The C. neoformans isolates were collected within clinical trials funded by the British Infection Society (fellowship to T. Bicanic), the Wellcome Trust (research training fellowships WT069991, to A.E. Brouwer and WT081794, to J.N. Jarvis), and the Medical Research Council, United Kingdom (76201).en
dc.description.abstractBackground. Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality globally. High fungal burden in cerebrospinal fluid (CSF) at diagnosis and poor fungal clearance during treatment are recognized adverse prognostic markers; however, the underlying pathogenic factors that drive these clinical manifestations are incompletely understood. We profiled a large set of clinical isolates for established cryptococcal virulence traits to evaluate the contribution of C. neoformans phenotypic diversity to clinical presentation and outcome in human cryptococcosis. Methods. Sixty-five C. neoformans isolates from clinical trial patients with matched clinical data were assayed in vitro to determine murine macrophage uptake, intracellular proliferation rate (IPR), capsule induction, and laccase activity. Analysis of the correlation between prognostic clinical and host immune parameters and fungal phenotypes was performed using Spearman's r, while the fungal-dependent impact on long-term survival was determined by Cox regression analysis. Results. High levels of fungal uptake by macrophages in vitro, but not the IPR, were associated with CSF fungal burden (r = 0.38, P = 0.002) and long-term patient survival (hazard ratio [HR] 2.6, 95% CI 1.2-5.5, P = 0.012). High-uptake strains were hypocapsular (r = -0.28, P = 0.05) and exhibited enhanced laccase activity (r = 0.36, P = 0.003). Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF (r = 0.49, P P = 0.05) and exhibited enhanced laccase activity (r = 0.36, P = 0.003). Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF (r = 0.49, P < 0.0001) and resistance to clearance following patient antifungal treatment (r = 0.39, P = 0.003). Conclusion. These findings underscore the contribution of cryptococcal-phagocyte interactions and laccase-dependent melanin pathways to human clinical presentation and outcome. Furthermore, characterization of fungal-specific pathways that drive clinical manifestation provide potential targets for the development of therapeutics and the management of CM.
dc.format.extent9
dc.language.isoeng
dc.relation.ispartofThe Journal of Clinical Investigationen
dc.rightsCopyright © 2014, American Society for Clinical Investigation. This work has been made available online in accordance with publisher policies or with permission. Permission for further reuse of this content should be sought from the publisher or the rights holder. This is the final published version of the work, which was originally published at https://doi.org/10.1172/JCI72950en
dc.subjectQR355 Virologyen
dc.subjectBDCen
dc.subjectR2Cen
dc.subject.lccQR355en
dc.titleEfficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosisen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.contributor.institutionUniversity of St Andrews.Gillespie Groupen
dc.identifier.doihttps://doi.org/10.1172/JCI72950
dc.description.statusPeer revieweden


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