cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses
William O. Hahn, Noah S. Butler, Scott E. Lindner, Holly M. Akilesh, D. Noah Sather, Stefan H.I. Kappe, Jessica A. Hamerman, Michael Gale Jr., W. Conrad Liles, Marion Pepper
William O. Hahn, Noah S. Butler, Scott E. Lindner, Holly M. Akilesh, D. Noah Sather, Stefan H.I. Kappe, Jessica A. Hamerman, Michael Gale Jr., W. Conrad Liles, Marion Pepper
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Research Article Immunology Infectious disease

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

Abstract

Sensing of pathogens by host pattern recognition receptors is essential for activating the immune response during infection. We used a nonlethal murine model of malaria (Plasmodium yoelii 17XNL) to assess the contribution of the pattern recognition receptor cyclic GMP-AMP synthase (cGAS) to the development of humoral immunity. Despite previous reports suggesting a critical, intrinsic role for cGAS in early B cell responses, cGAS-deficient (cGAS–/–) mice had no defect in the early expansion or differentiation of Plasmodium-specific B cells. As the infection proceeded, however, cGAS–/– mice exhibited higher parasite burdens and aberrant germinal center and memory B cell formation when compared with littermate controls. Antimalarial drugs were used to further demonstrate that the disrupted humoral response was not B cell intrinsic but instead was a secondary effect of a loss of parasite control. These findings therefore demonstrate that cGAS-mediated innate-sensing contributes to parasite control but is not intrinsically required for the development of humoral immunity. Our findings highlight the need to consider the indirect effects of pathogen burden in investigations examining how the innate immune system affects the adaptive immune response.

Authors

William O. Hahn, Noah S. Butler, Scott E. Lindner, Holly M. Akilesh, D. Noah Sather, Stefan H.I. Kappe, Jessica A. Hamerman, Michael Gale Jr., W. Conrad Liles, Marion Pepper

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Figure 8

Clearance of parasite with atovaquone restores germinal center CD4+ T cells and B cell responses.

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Clearance of parasite with atovaquone restores germinal center CD4+ T ce...
(A) WT and cGAS–/– mice were infected with 106 Plasmodium yoelii 17XNL–infected erythrocytes via the intraperitoneal route. Starting at day 7, mice were treated with atovaquone for 5 days via daily intraperitoneal injection. GP66+CD4+ T cells enriched from spleen and lymph nodes were examined for GC Tfh differentiation using antibodies against CXCR5 and PD1. Because data were nonparametric with different SDs, statistical analysis for both number and percentage was performed using a Kruskal-Wallis test with Dunn’s post-hoc comparison. WT mice were selected as the comparator group. *P < 0.05, ***P < 0.001. (B) MSP1+ B cells were identified and CD138+ plasmablasts were quantified. Statistical analysis was performed using Kruskal-Wallis test with Dunn’s post-hoc comparison. WT mice were selected as the comparator group. In cGAS–/– mice treated with atovaquone, there were CD138+MSP1+ 3.169% ± 3.6% (P = 0.92). *P < 0.05, ***P < 0.001. (C) MSP1+ GC B cells were quantified. *P < 0.05, ***P < 0.001. Statistical analysis was performed using Kruskal-Wallis test with Dunn’s post-hoc comparison. WT mice were selected as the comparator group. Data represent at least 6 biological replicates from 2 separate experiments. Error bars represent SD.