Dataset Information

Cutting Edge: IFN-? Produced by Brain-Resident Cells Is Crucial To Control Cerebral Infection with Toxoplasma gondii.

ABSTRACT: In vitro studies demonstrated that microglia and astrocytes produce IFN-? in response to various stimulations, including LPS. However, the physiological role of IFN-? production by brain-resident cells, including glial cells, in resistance against cerebral infections remains unknown. We analyzed the role of IFN-? production by brain-resident cells in resistance to reactivation of cerebral infection with Toxoplasma gondii using a murine model. Our study using bone marrow chimeric mice revealed that IFN-? production by brain-resident cells is essential for upregulating IFN-?-mediated protective innate immune responses to restrict cerebral T. gondii growth. Studies using a transgenic strain that expresses IFN-? only in CD11b(+) cells suggested that IFN-? production by microglia, which is the only CD11b(+) cell population among brain-resident cells, is able to suppress the parasite growth. Furthermore, IFN-? produced by brain-resident cells is pivotal for recruiting T cells into the brain to control the infection. These results indicate that IFN-? produced by brain-resident cells is crucial for facilitating both the protective innate and T cell-mediated immune responses to control cerebral infection with T. gondii.

SUBMITTER: Sa Q

PROVIDER: S-EPMC4520543 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Cutting Edge: IFN-γ Produced by Brain-Resident Cells Is Crucial To Control Cerebral Infection with Toxoplasma gondii.

Sa Qila Q Ochiai Eri E Tiwari Ashish A Perkins Sara S Mullins Jeremi J Gehman Marie M Huckle William W Eyestone Willard H WH Saunders Thomas L TL Shelton Brent J BJ Suzuki Yasuhiro Y

Journal of immunology (Baltimore, Md. : 1950) 20150619 3

In vitro studies demonstrated that microglia and astrocytes produce IFN-γ in response to various stimulations, including LPS. However, the physiological role of IFN-γ production by brain-resident cells, including glial cells, in resistance against cerebral infections remains unknown. We analyzed the role of IFN-γ production by brain-resident cells in resistance to reactivation of cerebral infection with Toxoplasma gondii using a murine model. Our study using bone marrow chimeric mice revealed th ...[more]

PMID: 26091720

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Project description: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.

Dataset Information

Cutting Edge: IFN-? Produced by Brain-Resident Cells Is Crucial To Control Cerebral Infection with Toxoplasma gondii.

Publications

Cutting Edge: IFN-γ Produced by Brain-Resident Cells Is Crucial To Control Cerebral Infection with Toxoplasma gondii.

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