Chlamydia trachomatis genital infection is a major cause of pelvic inflammatory disease (PID), resulting in ectopic pregnancy and infertility among women. PID is caused by an overt inflammatory response in the upper genital tract. The specific immune mechanisms and effectors that trigger this often-devastating condition are poorly defined. The mouse model is a useful tool to study these inflammatory responses in the oviduct. Using this model, we have shown that signaling from the host receptors IFNAR (IFNa/b receptor) and IL-1R (IL-1 receptor) leads to oviduct pathology during genital chlamydial infection. However, the exact mechanisms by which chlamydiae initiate these responses, and the host molecules engaged, are unknown. The central hypothesis of this application is that type I IFN and IL-1 signaling synergistically drive oviduct damage during infection by activating cell death pathways and increasing PMN infiltration. Our overall objectives are to (1) delineate the upstream activators and downstream effectors of IFN and IL-1R signaling which lead to pathology, and (2) therapeutically block the downstream mediators of IL-1R signaling-induced oviduct damage, using the mouse model. To test our hypothesis and achieve our objectives, we will identify the specific molecular interaction between host DNA sensor and chlamydial effector that initiate IFNb expression during infection (Aim 1). We will test the hypothesis that caspase-11 mediated cell death activation is a major player in pathology and type I IFN signaling results in caspase-11 activation during infection (Aim 2). We will explore the role of damage associated molecular patterns (DAMPs), such as HMGB-1 and IL-1a present in genital secretions of infected mice, in oviduct pathology (Aim 3). We also propose to specifically target the damaging arm of IL-1R signaling using inhibitors in ex vivo Fallopian tube explants and in the mouse model to protect from pathology (Aim 4). The central theme of this application is that these signaling events likely evolved to reduce pathogen load in the oviduct, but lead to cell death and tissue damage, thereby come at an expense of adverse reproductive health in women. Delineating the innate immune pathways to segregate the damaging and protective constituents, facilitates therapeutic targeting to prevent disease without affecting resolution of infection. Specific outcomes of the proposed study include identification of host molecules involved in amplification of the inflammatory response during infection, which would serve as biomarkers and therapeutic targets to prevent reproductive sequelae in women infected with Chlamydia.
This study will provide a direct link of key host molecules involved in oviduct pathology during genital chlamydial infection and provide therapeutic targets to ameliorate disease in the mouse model. These studies can be extended to provide potential diagnostic tools for identifying infected women with greater risk of developing PID and identify novel therapeutics that could be co-administered with antibiotic therapy to reduce the risk of long term reproductive sequelae.
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|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|
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