Plasmacytoid dendritic cells (pDCs) are the major producers of IFN-α, an antiviral cytokine involved in immunomodulation and control of HIV type 1 replication, whereas Toxoplasma gondii is a life-threatening opportunistic infection in AIDS patients. During infection with HIV type 1, human pDCs decrease in circulation and remaining pDC produce lower amounts of IFN-α in response to viral stimulation. In this study, we investigated the impact of coinfection with T. gondii on the innate virus-directed responses of human pDCs. Using intracellular flow cytometry and fluorescence microscopy, we determined that T. gondii invaded but did not induce IFN-α or TNF-α in human pDC. However, T. gondii inhibited IFN-α and TNF-α produced in response to HSV and HIV, thus functionally inactivating pDC. IFN-α production was inhibited only in cells infected by T. gondii, which inhibited neither uptake of GFP-HSV nor localization of TLR9 in CD71+ endosomes, directing us to investigate downstream events. Using imaging flow cytometry, we found that both T. gondii and IL-10 inhibited virus-induced nuclear translocation, but not phosphorylation, of IFN response factor 7. Blockade of IFN response factor 7 nuclear translocation and inhibition of the IFN-α response was partially reversed by a deficiency in the T. gondii–derived ROP16 kinase, known to directly phosphorylate STAT3, a critical mediator of IL-10’s anti-inflammatory effects. Taken together, our results indicate that T. gondii suppresses pDC activation by mimicking IL-10’s regulatory effects through an ROP16 kinase-dependent mechanism. Our findings further imply a convergent mechanism of inhibition of TLR signaling by T. gondii and IL-10 and suggest potential negative consequences of HIV/T. gondii coinfection.
This work was supported by grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (R01AI062806 and R01AI106125 to P.F.-B. and R56AI124691 and R01AI083405 to G.S.Y.) and National Institute for Research Resources Grant S10ODO18103 to P.F.-B. P.L.P. was supported by a predoctoral fellowship from the New Jersey Commission on Cancer Research.
Abbreviations used in this article:
- HIV type 1
- HSV type 1
- IFN response factor
- multiplicity of infection
- opportunistic infection
- plasmacytoid dendritic cell
- parasitophorous vacuole membrane.
- Received July 19, 2017.
- Accepted October 20, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.