C5aR1 Activation Drives Early IFN-gamma Production to Control ExperimentalToxoplasma gondiiInfection

Toxoplasma gondii (T. gondii) is a parasite infecting animals and humans. In intermediate hosts, such as humans or rodents, rapidly replicating tachyzoites drive vigorous innate and adaptive immune responses resulting in bradyzoites that survive within tissue cysts. Activation of the innate immune system is critical during the early phase of infection to limit pathogen growth and to instruct parasite-specific adaptive immunity. In rodents, dendritic cells (DCs) senseT. gondiithrough TLR11/12, leading to IL-12 production, which activates NK cells to produce IFN-gamma as an essential mechanism for early parasite control. Further, C3 can bind toT. gondiiresulting in limited complement activation. Here, we determined the role of C5a/C5aR1 axis activation for the early innate immune response in a mouse model of peritonealT. gondiiinfection. We found thatC5ar1(-/-)animals suffered from significantly higher weight loss, disease severity, mortality, and parasite burden in the brain than wild type control animals. Severe infection inC5ar1(-/-)mice was associated with diminished serum concentrations of IL-12, IL-27, and IFN-gamma. Importantly, the serum levels of pro-inflammatory cytokines, including IL-1 alpha, IL-6, and TNF-alpha, as well as several CXC and CC chemokines, were decreased in comparison to wt animals, whereas anti-inflammatory IL-10 was elevated. The defect in IFN-gamma production was associated with diminishedIfngmRNA expression in the spleen and the brain, reduced frequency of IFN-gamma+NK cells in the spleen, and decreasedNos2expression in the brain ofC5ar1(-/-)mice. Mechanistically, DCs from the spleen ofC5ar1(-/-)mice produced significantly less IL-12 in response to soluble tachyzoite antigen (STAg) stimulationin vivoandin vitro. Our findings suggest a model in which the C5a/C5aR1 axis promotes IL-12 induction in splenic DCs that is critical for IFN-gamma production from NK cells and subsequent iNOS expression in the brain as a critical mechanism to control acuteT. gondiiinfection