Chlamydia trachomatis is a major cause of pelvic inflammatory disease, ectopic pregnancy, and infertility among women. Further, ocular trachoma caused by chlamydiae continues to be the leading cause of preventable blindness in the world. Chlamydial infection is cleared by a T-cell-mediated adaptive immune response that depends on the initial innate immune response. Recently, the important role of type I interferons (IFNs), an innate response, during bacterial infection is being recognized. Type I IFN response occurs predominantly through activation of pathogen recognition receptors (PRR) such as Toll-like receptors (TLR) and other cytosolic PRR such as RIG-1, MDA5, that recognize specific molecular patterns associated with the pathogen (PAMP). We have observed an important role for type I IFNs in increasing bacterial shedding and inducing oviduct pathology during C. muridarum infection. The overall objective of this proposal is to delineate the TLR/PRR pathways involved in the induction of type I IFNs (IFNa/ ) during chlamydial infection. Specifically, we will determine, 1. The mechanism by which type I IFN promotes infection and oviduct pathology in the murine genital tract model, 2. Determine the TLRs/PRRs involved in the induction of IFNa/ and interferon response genes (IRG) during chlamydial infection, 3. Determine the downstream signaling events that induce IFNa/ during chlamydial infection, and 4. Determine the contribution of the chlamydial inclusion to generation of the host IFNa/ response and the interactions of intracellular TLR/PRR with Chlamydia. We have determined that induction of host type I IFNs during Chlamydia trachomatis infection could be a mechanism by which chlamydiae may achieve slower clearance and increase its transmission. The present study addresses the basic mechanisms of how type I IFNs induced in the host, delay chlamydial clearance. We will also determine the cellular and molecular mechanism(s) of IFN induction during chlamydial infection. These studies are essential to understand chlamydial pathogenesis and immunity, and eventually develop a vaccine against this pathogen.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Hiltke, Thomas J
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University of Pittsburgh
Schools of Medicine
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Nagarajan, Uma M; Tripathy, Manoj; Kollipara, Avinash et al. (2018) Differential signaling pathways are initiated in macrophages during infection depending on the intracellular fate of Chlamydia spp. Immunol Cell Biol 96:246-256
Zhang, Yugen; Yeruva, Laxmi; Marinov, Anthony et al. (2014) The DNA sensor, cyclic GMP-AMP synthase, is essential for induction of IFN-? during Chlamydia trachomatis infection. J Immunol 193:2394-404
Pokrovskaya, I D; Szwedo, J W; Goodwin, A et al. (2012) Chlamydia trachomatis hijacks intra-Golgi COG complex-dependent vesicle trafficking pathway. Cell Microbiol 14:656-68
Nagarajan, Uma M; Sikes, James D; Yeruva, Laxmi et al. (2012) Significant role of IL-1 signaling, but limited role of inflammasome activation, in oviduct pathology during Chlamydia muridarum genital infection. J Immunol 188:2866-75
Prantner, Daniel; Sikes, James D; Hennings, Leah et al. (2011) Interferon regulatory transcription factor 3 protects mice from uterine horn pathology during Chlamydia muridarum genital infection. Infect Immun 79:3922-33
Nagarajan, Uma (2011) Induction and function of IFN? during viral and bacterial infection. Crit Rev Immunol 31:459-74
Nagarajan, Uma M; Sikes, James; Prantner, Daniel et al. (2011) MyD88 deficiency leads to decreased NK cell gamma interferon production and T cell recruitment during Chlamydia muridarum genital tract infection, but a predominant Th1 response and enhanced monocytic inflammation are associated with infection resolution. Infect Immun 79:486-98
Prantner, Daniel; Darville, Toni; Nagarajan, Uma M (2010) Stimulator of IFN gene is critical for induction of IFN-beta during Chlamydia muridarum infection. J Immunol 184:2551-60
Rank, Roger G; Lacy, H Marie; Goodwin, Anna et al. (2010) Host chemokine and cytokine response in the endocervix within the first developmental cycle of Chlamydia muridarum. Infect Immun 78:536-44
Prantner, Daniel; Nagarajan, Uma M (2009) Role for the chlamydial type III secretion apparatus in host cytokine expression. Infect Immun 77:76-84

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