Reducing Infection Susceptibility by Immune Function Restoration in Spinal Cord Injury

摘要 脊髓损伤(Sci)后的获得性感染非常普遍，是患者死亡的主要原因。 已被确定为与神经和功能恢复不良相关的可改变的危险因素。 用正统抗生素治疗感染的复杂性是：1)光谱/疗效差距，2)早期发展 抗生素耐药性，以及iii)早期应用抗生素未能预防感染 急性中枢神经系统损害。此外，新的证据表明，抗生素会损害神经恢复，因为 它们导致肠道生物失调的能力。迫切需要改进的抗感染治疗策略，这采取了 考虑脊髓损伤后的免疫功能低下状态。最近的数据表明，未受监管的同情心 起源于脊髓损伤部位下方的音调(脊髓产生的交感神经活动，SNA) 全身性脊髓损伤免疫缺陷综合征(SCI-IDS)的主要驱动力。SNA一直是 被确定并被独立证实为体内恢复免疫功能的机械性靶点。三个目标 提出了回答一个主要而新颖的问题：免疫功能和宿主防御能否针对 以SNA为靶向的免疫营养药理神经调节(IPN)能否重建肺炎？ AIM 1的实验将使用FDA批准的一种新的药物组合来促进免疫 在急性或脊髓损伤后4周，改善系统功能，降低细菌性肺炎的易感性。目标2将 评估IPN对不同细胞SCI-IDs特征和交感神经的正常化能力 神经内分泌反射。不考虑脊髓损伤，感染是众所周知的自主神经障碍的原因，这是一种 败血症转换的病理生理管道。目标3解决IPN是否可以钝化感染相关的问题 自主神经功能障碍和中和败血症的危险因素。如果成功，这些实验的数据将 直接告知脊髓损伤患者有效的非抗生素抗感染策略以减少感染相关 死亡率和伤残。

Abstract Acquired infections after spinal cord injury (SCI) are prevalent, constitute the main cause of death in patients and have been identified as a modifiable risk factor associated with poor neurological and functional recovery. Infection treatment by orthodox antibiotics is complicated by i) spectrum/efficacy gaps, ii) early development of antibiotic resistancies, and iii) failure of antibiotics to prevent infections when applied early in patients with acute CNS lesions. Moreover, new evidence indicates that antibiotics can impair neurological recovery, due to their ability to cause gut dysbiosis. Improved anti-infective treatment strategies are critically needed, which take the immune-compromised status after SCI into account. Recent data have identified unregulated sympathetic tone originating from below the spinal cord injury site (spinally generated sympathetic nerve activity, SNA) as a major driver of the systemic spinal cord injury immune deficiency syndrome (SCI-IDS). SNA has been identified and independently confirmed as a mechanistic target to restore immune function in vivo. Three aims are proposed to answer one main and novel question: Can immune function and host-defense against pneumonia be re-established with SNA-targeting immunotrophic pharmacological neuromodulation (IPN)? Experiments in Aim 1 will use a novel combination of FDA-approved drugs selected to promote immune system function and reduce susceptibility to bacterial pneumonia acutely or at 4 weeks post SCI. Aim 2 will assess the capacity of IPN to normalize different cellular SCI-IDS characteristics and the sympathetic neuroendocrine reflex. Irrespective of SCI, infections are well-known causes of dysautonomia, which is a pathophysiological conduit for septic conversions. Aim 3 addresses whether IPN can blunt infection-associated autonomic dysfunction and neutralize a sepsis risk factor. If successful, data from these experiments will directly inform effective non-antibiotic anti-infective strategies for SCI patients to reduce infection-associated mortality and disability.