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Piotr L. Pierog
Molecular Pathology and Immunology ProgramB.S. 2007, Montclair State University
Thesis Advisor: Patricia Fitzgerald-Bocarsly, Ph.D.
Department of Pathology and Laboratory Medicine
Monday, April 30, 2012
12:00 P.M., MSB B-554
pDC are the major producers of IFN-á, an antiviral cytokine involved in control of HIV replication, while T.gondii is a life-threatening opportunistic infection (OI) in AIDS patients. In this study, we investigated pDC responses in the context of virus and T.gondii co-infection. T.gondii invaded but did not induce IFN-á or TNF-á in human pDC. However, Type I, II and III strains of T.gondii inhibited IFN-á and TNF-á in response to HSV and HIV, thus functionally inactivating pDC. Within the T. gondii exposed pDC population, IFN-á production was inhibited only in cells infected by T. gondii, whereas TNF-á was inhibited in both the infected and to a lesser extent, uninfected pDC. 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 was abolished by the parasite; however, the parasite failed to inhibit phosphorylation of IRF7. Moreover T. gondii infection of pDC abolished the co-localization of TLR-9 with CD107a + late endosomes. Taken together, these data indicate that the block of the intracellular signaling cascade by T.gondii occurs at the event of IRF7 translocation that is initiated in the CD107a + late endosomes.
Unexpectedly, T.gondii did not inhibit HSV-1nduced nuclear translocation of NF-êB. Obstruction of IRF7 nuclear translocation and inhibition of IFN-á was reversed by knocking out Rop16 kinase, known to directly phosphorylate STAT3 thus mimicking IL-10 anti-inflammatory signaling. Our results strongly support the hypothesis that Rop16 kinase is partially responsible for parasite mediated inhibition of IFN-á and responsible for inhibition of IRF7 nuclear translocation. In addition to Rop16 kinase, T.gondii employs an unidentified mechanism for inhibition of TNF-á production which is independent of inhibition of NF-êB nuclear translocation. Furthermore, T.gondii altered the virus-induced maturation profile of pDC. These findings imply a novel mechanism of inhibition of TLR signaling by T.gondii and suggest potential negative consequences of HIV/T. gondii co-infection.