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dc.contributor.authorSebina, Ismail
dc.contributor.authorJames, Kylie R
dc.contributor.authorSoon, Megan SF
dc.contributor.authorFogg, Lily G
dc.contributor.authorBest, Shannon E
dc.contributor.authorRivera, Fabian de Labastida
dc.contributor.authorde Oca, Marcela Montes
dc.contributor.authorAmante, Fiona H
dc.contributor.authorThomas, Bryce S
dc.contributor.authorBeattie, Lynette
dc.contributor.authorSouza-Fonseca-Guimaraes, Fernando
dc.contributor.authorSmyth, Mark J
dc.contributor.authorHertzog, Paul J
dc.contributor.authorHill, Geoffrey R
dc.contributor.authorHutloff, Andreas
dc.contributor.authorEngwerda, Christian R
dc.contributor.authorHaque, Ashraful
dc.date.accessioned2021-05-06T04:44:26Z
dc.date.available2021-05-06T04:44:26Z
dc.date.issued2016
dc.identifier.issn1553-7366en_US
dc.identifier.doi10.1371/journal.ppat.1005999en_US
dc.identifier.urihttp://hdl.handle.net/10072/404200
dc.description.abstractParasite-specific antibodies protect against blood-stage Plasmodium infection. However, in malaria-endemic regions, it takes many months for naturally-exposed individuals to develop robust humoral immunity. Explanations for this have focused on antigenic variation by Plasmodium, but have considered less whether host production of parasite-specific antibody is sub-optimal. In particular, it is unclear whether host immune factors might limit antibody responses. Here, we explored the effect of Type I Interferon signalling via IFNAR1 on CD4 T-cell and B-cell responses in two non-lethal murine models of malaria, P. chabaudi chabaudi AS (PcAS) and P. yoelii 17XNL (Py17XNL) infection. Firstly, we demonstrated that CD4 T-cells and ICOS-signalling were crucial for generating germinal centre (GC) B-cells, plasmablasts and parasite-specific antibodies, and likewise that T follicular helper (Tfh) cell responses relied on B cells. Next, we found that IFNAR1-signalling impeded the resolution of non-lethal blood-stage infection, which was associated with impaired production of parasite-specific IgM and several IgG sub-classes. Consistent with this, GC B-cell formation, Ig-class switching, plasmablast and Tfh differentiation were all impaired by IFNAR1-signalling. IFNAR1-signalling proceeded via conventional dendritic cells, and acted early by limiting activation, proliferation and ICOS expression by CD4 T-cells, by restricting the localization of activated CD4 T-cells adjacent to and within B-cell areas of the spleen, and by simultaneously suppressing Th1 and Tfh responses. Finally, IFNAR1-deficiency accelerated humoral immune responses and parasite control by boosting ICOS-signalling. Thus, we provide evidence of a host innate cytokine response that impedes the onset of humoral immunity during experimental malaria.en_US
dc.description.peerreviewedYesen_US
dc.languageEnglishen_US
dc.publisherPublic Library Scienceen_US
dc.relation.ispartofpagefrom1en_US
dc.relation.ispartofpageto26en_US
dc.relation.ispartofissue11en_US
dc.relation.ispartofjournalPLOS Pathogensen_US
dc.relation.ispartofvolume12en_US
dc.subject.fieldofresearchMicrobiologyen_US
dc.subject.fieldofresearchImmunologyen_US
dc.subject.fieldofresearchMedical Microbiologyen_US
dc.subject.fieldofresearchcode0605en_US
dc.subject.fieldofresearchcode1107en_US
dc.subject.fieldofresearchcode1108en_US
dc.subject.keywordsScience & Technologyen_US
dc.subject.keywordsLife Sciences & Biomedicineen_US
dc.subject.keywordsMicrobiologyen_US
dc.subject.keywordsParasitologyen_US
dc.subject.keywordsVirologyen_US
dc.titleIFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infectionen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationSebina, I; James, KR; Soon, MSF; Fogg, LG; Best, SE; Rivera, FDL; de Oca, MM; Amante, FH; Thomas, BS; Beattie, L; Souza-Fonseca-Guimaraes, F; Smyth, MJ; Hertzog, PJ; Hill, GR; Hutloff, A; Engwerda, CR; Haque, A, IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection, PLOS PATHOGENS, 2016, 12 (11)en_US
dcterms.dateAccepted2016-10-13
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2021-05-06T04:41:00Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© 2016 Sebina et al. 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_US
gro.hasfulltextFull Text
gro.griffith.authorEngwerda, Christian R.


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