Abstract
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) sense T. gondii 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 T. gondii 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 T. gondii infection. We found that C5ar1−/− animals suffered from significantly higher weight loss, disease severity, mortality, and parasite burden in the brain than wild type control animals. Severe infection in C5ar1−/− 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 Ifng mRNA expression in the spleen and the brain, reduced frequency of IFN-γ+ NK cells in the spleen, and decreased Nos2 expression in the brain of C5ar1−/− mice. Mechanistically, DCs from the spleen of C5ar1−/− mice produced significantly less IL-12 in response to soluble tachyzoite antigen (STAg) stimulation in vivo and in vitro. 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 T. gondii infection.
Highlights
T. gondii is an obligate intracellular apicomplexan parasite capable of infecting virtually all nucleated animal cells [1]
Immune recognition of T. gondii occurs through binding of profilin to the intracellular toll-like receptor (TLR) 11/12 dimers in CD8α+ splenic dendritic cells (DCs), which act as a primary source for IL-12 [4,5,6,7,8]
The number of parasite cysts in the brain of those C5ar1−/− animals that survived the T. gondii infection for 30 days was significantly higher than that of wt mice (Figure 1D). These data suggest that parasite-sensing by the complement system and consecutive C5a generation is critical for the development of appropriate innate immune responses during the first 30 days after T. gondii infection
Summary
T. gondii is an obligate intracellular apicomplexan parasite capable of infecting virtually all nucleated animal cells [1]. Infection occurs after ingestion of oocysts or tissue cysts that release the fast-replicating form of the parasite—the tachyzoites, which multiply asexually and spread through the host [reviewed in [2]]. Following successful immune system activation, the parasite converts into the slowly replicating bradyzoites and persists asymptomatically as a latent infection in the central nervous system or muscle tissue in the form of cysts [2]. Secreted IL-12, together with TNFα and IL-18, stimulate NK and T cells to produce IFN-γ [9,10,11]. Such IFN-γ primes infected cells to express immunity-related GTPases (IRGs) and inducible nitric oxide synthase (iNOS, NOS2) as important effector agents [reviewed in [12]]. Reactive nitrogen species synthesized by iNOS exert microbicidal activity in macrophages and microglia and are essential for the control of T. gondii in the brain during the chronic stage of infection [13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
