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

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

Research output: Contribution to journalArticle

22 Citations (Scopus)
3 Downloads (Pure)

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.
Original languageEnglish
Article numbere1005999
JournalPLoS Pathogens
Volume12
Issue number11
DOIs
Publication statusPublished - 3 Nov 2016

Fingerprint

Humoral Immunity
Malaria
B-Lymphocytes
Parasites
T-Lymphocytes
Germinal Center
Antibodies
Immunoglobulin Class Switching
Communicable Disease Control
Antigenic Variation
Interferon Type I
Plasmodium
Immunologic Factors
Helper-Inducer T-Lymphocytes
Infection
Dendritic Cells
Antibody Formation
Immunoglobulin M
Spleen
Immunoglobulin G

Cite this

Sebina, I., James, K. R., Soon, M., Fogg, L. G., Best, S. E., de Labastida Rivera, F., ... Haque, A. (2016). IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection. PLoS Pathogens, 12(11), [e1005999]. https://doi.org/10.1371/journal.ppat.1005999

IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection. / Sebina, Ismail; James, Kylie R (Corresponding Author); Soon, Megan (Corresponding Author); Fogg, Lily G (Corresponding Author); Best, Shannon E (Corresponding Author); de Labastida Rivera, Fabian (Corresponding Author); Montes de Oca, Marcela (Corresponding Author); Amante, Fiona (Corresponding Author); Thomas, Bryce (Corresponding Author); Beattie, Lynette (Corresponding Author); Souza-Fonsec-Guimaraes, Fernando (Corresponding Author); Smyth, Mark J (Corresponding Author); Hertzog, Paul J (Corresponding Author); Hill, Geoffrey R (Corresponding Author); Hutloff, Andreas (Corresponding Author); Engwerda, Christian R (Corresponding Author); Haque, Ashraful (Corresponding Author).

In: PLoS Pathogens, Vol. 12, No. 11, e1005999, 03.11.2016.

Research output: Contribution to journalArticle

Sebina, I, James, KR, Soon, M, Fogg, LG, Best, SE, de Labastida Rivera, F, Montes de Oca, M, Amante, F, Thomas, B, Beattie, L, Souza-Fonsec-Guimaraes, F, Smyth, MJ, Hertzog, PJ, Hill, GR, Hutloff, A, Engwerda, CR & Haque, A 2016, 'IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection', PLoS Pathogens, vol. 12, no. 11, e1005999. https://doi.org/10.1371/journal.ppat.1005999
Sebina, Ismail ; James, Kylie R ; Soon, Megan ; Fogg, Lily G ; Best, Shannon E ; de Labastida Rivera, Fabian ; Montes de Oca, Marcela ; Amante, Fiona ; Thomas, Bryce ; Beattie, Lynette ; Souza-Fonsec-Guimaraes, Fernando ; Smyth, Mark J ; Hertzog, Paul J ; Hill, Geoffrey R ; Hutloff, Andreas ; Engwerda, Christian R ; Haque, Ashraful. / IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection. In: PLoS Pathogens. 2016 ; Vol. 12, No. 11.
@article{6242307644b24990985f02a3d70ff7e1,
title = "IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection",
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.",
author = "Ismail Sebina and James, {Kylie R} and Megan Soon and Fogg, {Lily G} and Best, {Shannon E} and {de Labastida Rivera}, Fabian and {Montes de Oca}, Marcela and Fiona Amante and Bryce Thomas and Lynette Beattie and Fernando Souza-Fonsec-Guimaraes and Smyth, {Mark J} and Hertzog, {Paul J} and Hill, {Geoffrey R} and Andreas Hutloff and Engwerda, {Christian R} and Ashraful Haque",
note = "Funding: This work was funded by a Career Development Fellowship (1028634) and a project grant (GRNT1028641) awarded to AHa by the Australian National Health & Medical Research Council (NHMRC). IS was supported by The University of Queensland Centennial and IPRS Scholarships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",
year = "2016",
month = "11",
day = "3",
doi = "10.1371/journal.ppat.1005999",
language = "English",
volume = "12",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "11",

}

TY - JOUR

T1 - IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

AU - Sebina, Ismail

AU - James, Kylie R

AU - Soon, Megan

AU - Fogg, Lily G

AU - Best, Shannon E

AU - de Labastida Rivera, Fabian

AU - Montes de Oca, Marcela

AU - Amante, Fiona

AU - Thomas, Bryce

AU - Beattie, Lynette

AU - Souza-Fonsec-Guimaraes, Fernando

AU - Smyth, Mark J

AU - Hertzog, Paul J

AU - Hill, Geoffrey R

AU - Hutloff, Andreas

AU - Engwerda, Christian R

AU - Haque, Ashraful

N1 - Funding: This work was funded by a Career Development Fellowship (1028634) and a project grant (GRNT1028641) awarded to AHa by the Australian National Health & Medical Research Council (NHMRC). IS was supported by The University of Queensland Centennial and IPRS Scholarships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2016/11/3

Y1 - 2016/11/3

N2 - 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.

AB - 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.

U2 - 10.1371/journal.ppat.1005999

DO - 10.1371/journal.ppat.1005999

M3 - Article

VL - 12

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 11

M1 - e1005999

ER -