Nervous system control of immunity to C. difficile

项目总结(项目3) 艰难梭状芽胞杆菌是美国主要的医院感染，其特点是反复感染 以及较差的抗菌抗体反应。艰难梭菌如何逃避获得性免疫 该系统对于开发艰难梭菌感染的合理治疗方法和防止复发至关重要。 有趣的是，艰难梭菌感染的主要危险因素(广谱抗生素使用、质子泵抑制剂 治疗、炎症性肠病)都会导致肠道神经丧失或功能障碍。感染 艰难梭菌还导致小鼠结肠神经严重丧失。目前尚不清楚是否会损失 肠道的神经支配可能是CDI易感性的主要驱动因素。此外，还有越来越多的人意识到 神经系统在促进免疫功能方面的巨大作用。感觉神经直接感知病原体， 细胞损伤和有毒化学物质，以使有机体作出反应并消除损害。 脾和淋巴结中的肾上腺素能神经是疫苗和疫苗最佳B细胞反应所必需的 感染。我们假设来自感染或疫苗接种部位的感觉神经信号通过 神经系统向淋巴器官中的肾上腺素能神经促进免疫反应。给定 神经元信号在促进免疫中的重要作用，也许这并不奇怪，许多病原体 横跨种类繁多的物种，专门针对神经系统。值得注意的是，艰难梭菌的外毒素 TcdA和TcdB除了在Rho失活中发挥众所周知的作用外，还具有神经元活性 糖基化的GTP酶。在与Mark Lang博士的合作中，我们发现TcdA抑制了 在疫苗接种期间抗原特异性抗体反应的发展，这种抑制依赖于 感觉神经信号；在疫苗接种期间对这些神经进行脱敏，甚至可以恢复抗体反应 在TCDA在场的情况下。结合我们的发现，CDI会导致肠道内严重的神经元丢失，我们 假设TcdA和TcdB操纵和删除神经对于艰难梭菌感染和 免疫逃避。在特定的目标1中，我们将确定神经元信号在艰难梭菌感染和 免疫逃避。在特定的目标2中，我们将确定TcdA过度激活感觉的机制 神经损害体液免疫。这些研究将通过揭示特定的艰难梭菌疫苗接种领域 限制对疫苗接种和感染的成功体液免疫反应的机制，并确定 神经保护是否是CDI保护的关键因素。

Project Summary (Project 3) Clostridioides difficile is the leading nosocomial infection in the US, and is characterized by recurrent infection and poor generation of antibacterial antibody responses. Identifying how C. difficile evades the adaptive immune system is critical to develop rational treatments for patients with C. difficile infections and to prevent recurrence. Interestingly, the major risk factors for C. difficile infection (broad spectrum antibiotic usage, proton pump inhibitor treatment, inflammatory bowel disease) all result in either a loss or dysfunction of nerves in the gut. Infection with C. difficile also results in a profound loss of nerves in the colon of mice. It is currently unknown if a loss of innervation in the gut can be a primary driver of CDI susceptibility. Additionally, there is increasing awareness of the outsized role of the nervous system in promoting immune function. Sensory nerves directly sense pathogens, cellular damage, and noxious chemicals in order to allow organisms to respond and eliminate damage. Adrenergic nerves in the spleen and lymph nodes are necessary for optimal B cell responses to vaccination and infection. We posit that sensory nerve signaling from the site of infection or vaccination communicates through the nervous system to the adrenergic nerves in lymphoid organs to promote immune responses. Given the important role for neuronal signaling in promoting immunity, is it perhaps unsurprising that numerous pathogens across a wide diversity of species specifically target the nervous system. Significantly, the C. difficile exotoxins TcdA and TcdB both have neuronal activity in addition to their well described function in the inactivation of Rho GTPases by glucosylation. In collaboration with Dr. Mark Lang, we have found that TcdA inhibits the development of antigen-specific antibody responses during vaccination, and this inhibition was dependent upon sensory nerve signaling; desensitization of these nerves during vaccination restored antibody responses even in the presence of TcdA. Combined with our finding that CDI induces profound neuronal loss in the gut, We hypothesize that TcdA and TcdB manipulation and deletion of nerves is necessary for C. difficile infection and immune evasion. In Specific Aim 1 we will determine the role of neuronal signaling in C. difficile infection and immune evasion. In Specific Aim 2 we will identify the mechanism by which TcdA hyperactivation of sensory nerves impairs humoral immunity. These studies will advance the C. difficile vaccination field by revealing specific mechanisms that limit successful humoral immune responses to vaccination and infection, and determining whether neuropreservation is a critical correlate of protection for CDI.