IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

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Sebina, Ismail
James, Kylie R
Soon, Megan SF
Fogg, Lily G
Best, Shannon E
Rivera, Fabian de Labastida
de Oca, Marcela Montes
Amante, Fiona H
Thomas, Bryce S
Beattie, Lynette
Souza-Fonseca-Guimaraes, Fernando
Smyth, Mark J
Hertzog, Paul J
Hill, Geoffrey R
Hutloff, Andreas
Engwerda, Christian R
Haque, Ashraful
Griffith University Author(s)
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2016
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Abstract

Parasite-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.

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PLOS Pathogens

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12

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11

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© 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.

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Microbiology

Immunology

Medical microbiology

Science & Technology

Life Sciences & Biomedicine

Microbiology

Parasitology

Virology

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Sebina, 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)

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