ID: 223 : Toxoplasma gondii inhibits virus-induced IFN-α production in pDC through functional IL-10 mimicry

Abstract

Plasmacytoid dendritic cells (pDC) are major producers of IFN- α , an antiviral cytokine with immunomodulatory and anti-viral activity. IFN- α production in pDC is inhibited by IL-10. Toxoplasma gondii is a life-threatening opportunistic infection in HIV-infected individuals, with areas with high incidence of HIV also endemic for T. gondii. We investigated human pDC responses with virus and T. gondii co-infection. Using flow cytometry and fluorescence microscopy, we determined that T. gondii invaded but did not induce IFN- α or TNF- α in pDC. However, T. gondii inhibited both IFN- α and TNF- α produced in response to HSV and HIV, thus functionally inactivating pDC. Within the T. gondii-exposed pDC population, IFN- α production was inhibited only in cells infected by T. gondii, demonstrating the inhibition occurs in cis. T. gondii inhibited neither uptake of GFP-HSV nor localization of TLR-9 in CD71+ endosomes. Using imaging flow cytometry, we found that virus-induced nuclear translocation of IRF7 but not phosphorylation was abolished by the parasite, similar to what we observed with IL-10 treatment of pDC. Taken together, these data indicate that the block of the intracellular signaling cascade by T. gondii occurs downstream of TLR9 recruitment but upstream of IRF7 translocation. Obstruction of IRF7 nuclear translocation and inhibition of IFN- α were partially reversed by knocking out T. gondii-derived ROP16 kinase, known to directly phosphorylate STAT3, further mimicking IL-10 anti-inflammatory signaling. These findings describe a novel mechanism of inhibition of TLR signaling by T. gondii whereby the pathogen mimics IL-10 signaling and suggest potential negative consequences of HIV/T. gondii co-infection.