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
View: Text | PDF
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

×

Figure 2

Deficiency in cGAS is associated with altered type I IFN signature.

Options: View larger image (or click on image) Download as PowerPoint
Deficiency in cGAS is associated with altered type I IFN signature. (A) ...
(A) Quantitative real-time PCR of indicated gene mRNA in bulk spleen tissue. Quantification was performed using the delta-delta CT method and normalized to a naive mouse, with HPRT as the designated housekeeping gene. Experiments were performed using 2 technical replicates of at least 6 biological samples with 2–3 separate experiments per time point. One representative experiment is shown. Since the data were nonparametric, statistical significance was assessed via Mann-Whitney U test. *P < 0.05, **P < 0.01. (B) Mean fluorescent intensity of PDCA-1 (CD317) on CD11b+ dendritic cells in representative flow plot. See Supplemental Figure 2 for full gating scheme. Representative data are shown. Statistical significance was assessed via Mann-Whitney U test. *P < 0.05. (C) L929-ISRE cells were plated at 5 × 104 cells per well and cocultured for 6 hours at a ratio of 100 splenocytes to 1 reporter cell in a 96-well plate (mean ± SD). Cells were lysed and luciferase activity was measured. Statistical analysis was performed using Student’s t test.