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.

项目摘要（项目3） 梭状芽胞杆菌艰难梭菌是美国的主要医院感染，其特征是复发性感染 以及抗菌抗体反应的差产生。确定艰难梭菌如何逃避适应性免疫 系统对于开发艰难梭菌感染患者并防止复发的患者至关重要。 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）均导致肠道中神经的损失或功能障碍。感染 艰难梭菌还导致小鼠结肠的神经丧失。目前尚不清楚是否丢失 肠道的神经可能是CDI敏感性的主要驱动力。此外，人们对 神经系统在促进免疫功能中的重要作用。感觉神经直接感知病原体， 细胞损伤和有害的化学物质，以使生物可以反应并消除损害。 对于最佳的B细胞疫苗接种反应和淋巴结中的肾上腺素神经是必要 感染。我们认为感染或疫苗接种部位的感觉神经信号通过 淋巴机器人中肾上腺能神经的神经系统以促进免疫反应。鉴于 神经元信号在促进免疫力中的重要作用，可能不足为奇的是许多病原体 在各种各样的物种中，专门针对神经系统。值得注意的是，艰难梭菌外毒素 TCDA和TCDB都具有神经元活性，除了在Rho失活中所描述的功能很好 GTPases通过葡萄糖基化。与马克·朗（Mark Lang）博士合作，我们发现TCDA抑制了 疫苗接种过程中抗原特异性抗体反应的发展，这种抑制作用取决于 感觉神经信号传导；疫苗接种期间这些神经的脱敏甚至恢复了抗体反应 在TCDA的情况下。结合我们的发现，CDI诱导了肠道中的深刻神经元丧失，我们 假设TCDA和TCDB操纵和神经缺失对于艰难梭菌感染和 免疫逃避。在特定目的1中，我们将确定神经元信号在艰难梭菌感染中的作用，并 免疫逃避。在特定目标2中，我们将确定TCDA感觉过度激活的机制 神经会损害体液免疫。这些研究将通过揭示特定 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 神经保存是否是CDI保护的关键相关性。