Date of Graduation

8-2014

Document Type

Dissertation (PhD)

Program Affiliation

Biomedical Sciences

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Rick Wetsel, Ph.D.

Committee Member

Edgar Walters, Ph.D.

Committee Member

Brian Davis, Ph.D.

Committee Member

Barrett Harvey, Ph.D.

Committee Member

Amber Luong, M.D., Ph.D.

Abstract

Listeria monocytogenes (Lm) is a major cause of mortality resulting from food poisoning in the United States. While the complement component C5 is known to be protective in listeriosis, it is unknown how its cleavage fragment C5a participates. Here we show in a model of systemic Lm infection that the C5a receptor is essential for host defense. C5aR-/- mice have reduced survival and increased bacterial burden in the liver and spleen in comparison to WT mice. Surprisingly, C5aR-/- mice also have a dramatic reduction in splenocyte numbers resulting from elevated cell death as indicated by TUNEL staining and caspase 3 activity. This splenocyte depletion affected all major subsets of splenocytes, indicating a broad protective effect for C5aR. C5aR was not required for the production of protective cytokines such as TNF-α, IFN-γ and IL-6. As Type 1 IFN impedes the host response to Lm through the promotion of splenocyte death, we examined the effect of C5a and C5aR on type 1 IFN expression in vivo and in vitro. Serum levels of IFN-α and IFN-β are significantly higher in C5aR-/- mice than WT mice. The elevation of type 1 IFN in C5aR-/- mice correlated with increased expression of TRAIL, a downstream target of type 1 IFN and an important driver of splenocyte loss in listeriosis. Pre-stimulation with C5a directly represses LPS-induced IFN-β expression in the macrophage cell line J774A in vitro. Finally, treatment of C5aR-/- mice with a type 1 IFN receptor blocking antibody resulted in near complete rescue of Lm-induced mortality. Thus, these findings reveal for the first time a critical role for C5aR in host defense against Lm through the suppression of type 1 IFN expression.

Keywords

Listeria monocytogenes, C5aR, innate immunity, type 1 interferon

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