Molecular Mechanisms of Type I IFN Induction during Chlamydia Infection

描述（由申请人提供）：沙眼衣原体生殖器感染是盆腔炎（PID）的主要原因，导致女性异位妊娠和不孕。PID是由上生殖道明显的炎症反应引起的。引发这种经常具有毁灭性的疾病的特定免疫机制和效应物还不清楚。小鼠模型是研究这些输卵管炎症反应的有用工具。使用该模型，我们已经证明了宿主受体IFNAR （IFNα/ß受体）和IL-1R （IL-1受体）的信号传导导致生殖器衣原体感染期间的输卵管病理。然而，衣原体发起这些反应的确切机制以及宿主分子的参与尚不清楚。本应用的中心假设是I型IFN和IL-1信号通过激活细胞死亡途径和增加PMN浸润，协同驱动感染期间的输卵管损伤。我们的总体目标是：(1)描述导致病理的IFN和IL-1R信号的上游激活因子和下游效应因子，以及(2)使用小鼠模型治疗性地阻断IL-1R信号诱导的输卵管损伤的下游介质。为了验证我们的假设并实现我们的目标，我们将确定宿主DNA传感器和衣原体效应物之间在感染期间启动IFNß表达的特定分子相互作用（目的1）。我们将验证caspase-11介导的细胞死亡激活在病理和I型IFN信号导致感染期间caspase-11激活的假设（目的2）。我们将探索损伤相关分子模式（DAMPs），如HMGB-1和IL-1α存在于感染小鼠的生殖器分泌物中，在输卵管病理学中的作用（目的3）。我们还建议在体外输卵管外植体和小鼠模型中使用抑制剂特异性靶向IL-1R信号的损伤臂，以防止病理（Aim 4）。本应用的中心主题是，这些信号事件可能进化为减少输卵管中的病原体负荷，但导致细胞死亡和组织损伤，从而以不利的生殖健康为代价。描述先天免疫途径以分离损伤和保护成分，促进靶向治疗以预防疾病而不影响感染的解决。该研究的具体结果包括鉴定感染过程中参与炎症反应扩增的宿主分子，这些分子将作为预防衣原体感染妇女生殖后遗症的生物标志物和治疗靶点。

DESCRIPTION (provided by applicant): 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 (IFNα/ß 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 IFNß 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-1α 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.