AUTHOR=Briukhovetska Daria , Ohm Birte , Mey Fabian T. , Aliberti Julio , Kleingarn Marie , Huber-Lang Markus , Karsten Christian M. , Köhl Jörg 

TITLE=C5aR1 Activation Drives Early IFN-γ Production to Control Experimental Toxoplasma gondii Infection

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01397

DOI=10.3389/fimmu.2020.01397

ISSN=1664-3224

ABSTRACT=<p><italic>Toxoplasma gondii</italic> (<italic>T. gondii</italic>) 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) sense <italic>T. gondii</italic> through TLR11/12, leading to IL-12 production, which activates NK cells to produce IFN-γ as an essential mechanism for early parasite control. Further, C3 can bind to <italic>T. gondii</italic> resulting 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 peritoneal <italic>T. gondii</italic> infection. We found that <italic>C5ar1</italic><sup>−/−</sup> animals suffered from significantly higher weight loss, disease severity, mortality, and parasite burden in the brain than wild type control animals. Severe infection in <italic>C5ar1</italic><sup>−/−</sup> mice was associated with diminished serum concentrations of IL-12, IL-27, and IFN-γ. Importantly, the serum levels of pro-inflammatory cytokines, including IL-1α, IL-6, and TNF-α, 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-γ production was associated with diminished <italic>Ifng</italic> mRNA expression in the spleen and the brain, reduced frequency of IFN-γ<sup>+</sup> NK cells in the spleen, and decreased <italic>Nos2</italic> expression in the brain of <italic>C5ar1</italic><sup>−/−</sup> mice. Mechanistically, DCs from the spleen of <italic>C5ar1</italic><sup>−/−</sup> mice produced significantly less IL-12 in response to soluble tachyzoite antigen (STAg) stimulation <italic>in vivo</italic> and <italic>in vitro</italic>. Our findings suggest a model in which the C5a/C5aR1 axis promotes IL-12 induction in splenic DCs that is critical for IFN-γ production from NK cells and subsequent iNOS expression in the brain as a critical mechanism to control acute <italic>T. gondii</italic> infection.</p>