The Receptor for the Complement C3a Anaphylatoxin (C3aR) Provides Host Protection against Listeria monocytogenes–Induced Apoptosis

Abstract

Listeria monocytogenes (LM) is a Gram-positive intracellular bacterium that is acquired through tainted food and may lead to systemic infection and possible death. Despite the importance of the innate immune system in fighting LM infection, little is known about the role of complement and its activation products, including the potent C3a anaphylatoxin. In a model of systemic LM infection, we show here that mice lacking the receptor for C3a (C3aR-/-) are significantly more sensitive to infection compared to WT mice as demonstrated by decreased survival, increased bacterial burden, and increased damage to their livers and spleens. The inability of the C3aR-/- mice to clear the bacterial infection was not caused by defective macrophages or by reduction of cytokines/chemokines known to be critical in the host response to LM, including IFN-γ and TNF-α. Instead, TUNEL staining together with Fas, active caspase-3, and Bcl-2 expression data indicate that the increased susceptibility of C3aR-/- mice to LM infection was largely caused by increased LM-induced apoptosis of myeloid and lymphoid cells in the spleen that are required for ultimate clearance of LM, including neutrophils, macrophages, dendritic cells, and T cells. These findings reveal an unexpected function of C3a/C3aR signaling during the host immune response that suppresses Fas expression and caspase-3 activity while increasing Bcl-2 expression, thereby providing protection to both myeloid and lymphoid cells against LM-induced apoptosis.

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

“…This splenocyte depletion was not restricted to T cells as nearly all splenocyte subsets were affected. In line with the work of Strainic et al, this increased susceptibility to apoptosis in C3aR−/− splenocytes was associated with lower levels of the anti-apoptotic molecule Bcl-2 and higher levels of the pro-apoptotic receptor Fas (Mueller-Ortiz et al, 2014). To test whether the elevated apoptosis seen in C3aR−/− mice was responsible for the phenotype, C3aR−/− mice were treated with the apoptosis inhibitor Z-VAD before infection.…”

“…Since C3aR and C5aR1 have been reported to promote splenocyte and T-cell survival under homeostatic conditions (Liszewski et al, 2013) and during T cell activation (Lalli et al, 2008; Strainic et al, 2008), it was reasoned that C3aR might protect against L. monocytogenes -induced splenocyte death. In accordance with this hypothesis, splenocyte apoptosis was significantly increased and total splenocyte numbers were significantly reduced in L. monocytogenes -infected C3aR−/− mice (Mueller-Ortiz et al, 2014). This splenocyte depletion was not restricted to T cells as nearly all splenocyte subsets were affected.…”

“…While C5aR1’s function has been extensively probed in various infectious disease models, few studies have assessed the importance of C3aR during infection (Mueller-Ortiz et al, 2006). Recently, the work of Mueller-Ortiz et al has demonstrated a novel protective role for C3aR during listeriosis (Mueller-Ortiz et al, 2014). C3aR−/− mice were found to have impaired resistance to L. monocytogenes , with increased bacterial burden and reduced survival in comparison with WT mice.…”

“…To test whether the elevated apoptosis seen in C3aR−/− mice was responsible for the phenotype, C3aR−/− mice were treated with the apoptosis inhibitor Z-VAD before infection. Indeed, Z-VAD reduced bacterial burden in the liver, splenocyte apoptosis and serum cytokines including IL-10 to levels comparable to that of WT mice (Mueller-Ortiz et al, 2014). Thus, C3aR protects the host against listeriosis by inhibiting splenocyte death.…”

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

“…L. monocytogenes triggers the alternative pathway of complement activation, resulting in its opsonization by C3b and release of the complement anaphylatoxins C3a and C5a (18–20). Several studies have shown an important role for C3 and its cleavage polypeptides in the host response to L. monocytogenes (19–24). In contrast, little is known about the contribution of C5 and its major activation fragments C5a and C5b.…”