The C5a Anaphylatoxin Receptor (C5aR1) Protects against Listeria monocytogenes Infection by Inhibiting Type 1 IFN Expression

Abstract

Listeria monocytogenes is a major cause of mortality resulting from food poisoning in the United States. In mice, the fifth complement component (C5) has been genetically linked to host resistance to listeriosis. Despite this genetic association, it remains poorly understood how C5 and its activation products, C5a and C5b, confer host protection to this Gram-positive intracellular bacterium. Here we show in a systemic infection model that the major receptor for C5a, C5aR1, is required for a normal robust host immune response against L. monocytogenes. In comparison to WT mice, C5aR1−/− mice had reduced survival and increased bacterial burden in their livers and spleens. Infected C5aR1−/− mice exhibited a dramatic reduction in all major subsets of splenocytes, which was associated with elevated caspase-3 activity and increased TUNEL staining. As Type 1 IFN has been reported to impede the host response to L. monocytogenes through the promotion of splenocyte death, we examined the effect of C5aR1 on type 1 IFN expression in vivo. Indeed, serum levels of IFN-α and IFN-β were significantly elevated in L. monocytogenes-infected C5aR1−/− mice. Similarly, the expression of TRAIL, a type 1 IFN target gene and a pro-apoptotic factor was elevated in NK cells isolated from infected C5aR1−/− mice. Treatment of C5aR1−/− mice with a type 1 IFN receptor blocking antibody resulted in near complete rescue of L. monocytogenes-induced mortality. Thus, these findings reveal a critical role for C5aR1 in host defense against L. monocytogenes through the suppression of type 1 IFN expression.

Innate and adaptive immunologic functions of complement in the host response to Listeria monocytogenes infection

“…Thus, deficiency of C5a was most likely responsible for the increased susceptibility of A/J mice. Our work in C5aR1 deficient mice now supports this hypothesis (Calame et al, 2014). C5aR1−/− mice were highly susceptible to L. monocytogenes infection, with higher bacterial burdens and reduced survival in comparison to WT mice.…”

“…Similarly, TRAIL, a downstream target of type 1 IFN and a major driver of L. monocytogenes -induced splenocyte apoptosis, was significantly upregulated in splenic NK cells in C5aR1−/− mice. Finally, blockade of the type 1 IFN receptor rescued C5aR1−/− mice from L. monocytogenes -induced mortality (Calame et al, 2014). Subsequent work from our lab has clarified the mechanism by which C3a and C5a regulate type 1 IFN expression.…”

Type I IFN Does Not Promote Susceptibility to Foodborne Listeria monocytogenes

“…Notably, previous measurements of IFNα concentrations in either serum or spleen ranged from 30–50 pg/mL of 24 hours after i.v. Lm infection (47, 48). This may indicate that IFNα is produced by cell types that we did not include in high numbers in our splenocyte cultures.…”

The Complement Anaphylatoxins C5a and C3a Suppress IFN-β Production in Response to Listeria monocytogenes by Inhibition of the Cyclic Dinucleotide–Activated Cytosolic Surveillance Pathway

“…C3aR and C5aR1 are expressed on both myeloid and lymphoid cells, as well as on multiple types of non-immune tissue cells (5). In our previous studies, we showed that C3aR (6) and C5aR1 (7) are protective during systemic Lm infection. Compared to WT mice, C3aR−/− mice and C5aR1−/− mice had decreased survival, increased bacterial burdens in the liver and spleen, increased cytokine production, including IFN-β, increased spleen and liver pathology, and increased apoptosis in the spleen.…”

“…Compared to WT mice, C3aR−/− mice and C5aR1−/− mice had decreased survival, increased bacterial burdens in the liver and spleen, increased cytokine production, including IFN-β, increased spleen and liver pathology, and increased apoptosis in the spleen. Pre-treatment of the C5aR1−/− mice with an antibody to the type I interferon receptor-1 (IFNAR-1) protected these mice from Lm -induced mortality (7), indicating that excess IFN-β production in the C5aR1−/− mice leads to increased susceptibility to Lm . Production of type I interferons during Lm infection is detrimental to the host (8–10).…”