Nervous system control of immunity to C. difficile

神经系统对艰难梭菌免疫的控制

• 批准号: 10625177
• 负责人: Maureen Cox
• 金额: $ 32.57万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-25 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625177
• 关键词: Adaptive Immune System; Adrenergic Agents; Anti-Bacterial Agents; Antibiotics; Antibodies; Antibody Response; Antigens; Attenuated; Awareness; B-Cell Development; B-Lymphocytes; Bacterial Antibodies; Cells; Chemicals; Clostridium difficile; Collaborations; Colon; Communication; Critical Pathways; Development; Enteral; Exotoxins; Failure; Functional disorder; Generations; Human; Humoral Immunities; Immune; Immune Evasion; Immune response; Immunity; Immunoglobulin G; Immunoglobulin M; Impairment; Infection; Inflammatory Bowel Diseases; Injections; Intestines; Laboratories; Measures; Memory; Memory B-Lymphocyte; Mus; Nerve; Nervous System; Nervous System control; Neurons; Neuropeptides; Nosocomial Infections; Organism; Pathology; Patients; Predisposition; Proton Pump Inhibitors; Rattus; Recurrence; Risk Factors; Role; Signal Transduction; Site; Spleen; Staphylococcus aureus infection; T-Lymphocyte; TRPV1 gene; Testing; Toxic effect; Vaccination; Vaccines; Work; adaptive immune response; adaptive immunity; afferent nerve; cell injury; desensitization; immune function; lymph nodes; lymphoid organ; mouse model; nerve supply; neuron loss; neurotransmission; neurotransmitter release; neutralizing antibody; pathogen; prevent; programs; recurrent infection; response; rho GTP-Binding Proteins

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.

项目概要（项目3） 艰难梭菌是美国主要的医院感染，其特征是反复感染 以及抗菌抗体应答的产生差。如何识别C。艰难梭菌逃避适应性免疫 系统是制定合理治疗C.艰难的感染，并防止复发。 有趣的是，C.艰难梭菌感染（广谱抗生素使用，质子泵抑制剂 治疗、炎症性肠病）都导致肠道神经的损失或功能障碍。感染 梭艰难梭菌还导致小鼠结肠中神经的严重丧失。目前尚不清楚， 肠道中的神经支配可能是CDI易感性的主要驱动因素。此外，人们越来越认识到， 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，以使生物体作出反应并消除损伤。 脾和淋巴结中的肾上腺素能神经对于疫苗接种的最佳B细胞应答是必需的， 感染我们认为来自感染或接种部位的感觉神经信号通过 神经系统对淋巴器官中的肾上腺素能神经的作用，以促进免疫反应。鉴于 神经元信号在促进免疫中的重要作用，许多病原体 针对神经系统的病毒。值得注意的是，C.艰难杆菌外毒素 TcdA和TcdB除了在Rho失活中的功能外，还具有神经元活性 葡糖基化GTP酶。在与Mark Lang博士的合作中，我们发现TcdA抑制了 在疫苗接种期间产生抗原特异性抗体应答，这种抑制依赖于 感觉神经信号传导;在接种疫苗期间这些神经的脱敏恢复了抗体应答， 在TcdA的存在下。结合我们的发现，CDI诱导肠道神经元的严重损失，我们 假设TcdA和TcdB操纵和神经缺失是C.艰难梭菌感染， 免疫逃避在具体目标1中，我们将确定神经元信号在C。艰难梭菌感染， 免疫逃避在具体目标2中，我们将确定TcdA超激活感觉神经元的机制。 神经损害体液免疫。这些研究将促进C.艰难的疫苗接种领域，通过揭示具体 限制对疫苗接种和感染的成功体液免疫应答的机制， 神经保护是否是CDI保护的关键相关因素。