Reducing Infection Susceptibility by Immune Function Restoration in Spinal Cord Injury

通过恢复脊髓损伤的免疫功能来降低感染易感性

• 批准号: 10656433
• 负责人: Jan Schwab
• 金额: $ 36.76万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656433
• 关键词: Acute; Acute Pneumonia; Address; Adrenal Gland Hyperfunction; Adrenal Glands; Anatomy; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Applications Grants; Atrophic; Autonomic Dysfunction; Bacteria; Bacterial Pneumonia; Biological Assay; Biological Markers; Catecholamines; Cause of Death; Cells; Cessation of life; Characteristics; Clinical; Colony-forming units; Complement; Cre lox recombination system; Data; Development; Disinhibition; Drug Delivery Systems; Dysautonomias; Endocrine; Experimental Models; FDA approved; Failure; Functional disorder; Ganglia; Genetic; Goals; Host Defense; Immune; Immune system; Immunologic Deficiency Syndromes; Immunosuppression; Impairment; Individual; Infection; Infection prevention; Injury; Intervention; Lesion; Life; Lung; Lymphocyte Count; Lymphoid Tissue; Lymphopenia; Methodology; Molecular Target; Multicenter Studies; Nerve; Neurologic; Neurons; Neurosecretory Systems; Nosocomial pneumonia; Outcome; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Pneumonia; Predisposition; Prevention; Qualifying; Recovery; Recovery of Function; Reflex action; Regimen; Risk; Risk Factors; Sepsis; Series; Severities; Site; Spinal; Spinal cord injury; Spinal cord injury patients; Spleen; Streptococcus pneumoniae; Sympathetic Nerve Block; Synaptic Transmission; T-Lymphocyte; Technology; Testing; Thymus Gland; Tissues; Vertebral column; Whole Blood; adverse outcome; cholinergic; clinical application; clinically relevant; disability; drug repurposing; experimental study; gabapentin; gut dysbiosis; immune function; immune system function; improved; in vivo; insight; modifiable risk; mortality; neurological recovery; neuroregulation; novel; pharmacologic; presynaptic; prevent; restoration; septic; transmission process; treatment strategy; voltage

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.

抽象的 脊髓损伤（SCI）后获得性感染普遍存在，是患者死亡的主要原因 并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。 传统抗生素的感染治疗因 i) 谱/功效差距，ii) 早期发展而变得复杂 抗生素耐药性，以及 iii) 早期使用抗生素未能预防感染的患者 急性中枢神经系统病变。此外，新的证据表明抗生素会损害神经功能恢复，因为 它们导致肠道菌群失调的能力。迫切需要改进的抗感染治疗策略，这需要 考虑 SCI 后的免疫受损状态。最近的数据发现不受管制的交感神经 源自脊髓损伤部位下方的音调（脊髓产生的交感神经活动，SNA）作为 系统性脊髓损伤免疫缺陷综合征（SCI-IDS）的主要驱动因素。国民经济核算体系 (SNA) 已 被识别并独立证实为恢复体内免疫功能的机制目标。三个目标 建议回答一个主要且新颖的问题：免疫功能和宿主防御能否抵抗 肺炎是否可以通过 SNA 靶向免疫营养药理神经调节 (IPN) 来重建？ 目标 1 的实验将使用 FDA 批准的药物的新型组合，以促进免疫 系统功能并降低急性或 SCI 后 4 周对细菌性肺炎的易感性。目标2将 评估 IPN 使不同细胞 SCI-IDS 特征和交感神经正常化的能力 神经内分泌反射。无论是否有 SCI，感染都是众所周知的自主神经功能障碍的原因，这是一种 脓毒症转化的病理生理学途径。目标 3 解决 IPN 是否可以减弱感染相关性 自主神经功能障碍并中和败血症危险因素。如果成功的话，这些实验的数据将 直接告知 SCI 患者有效的非抗生素抗感染策略，以减少感染相关 死亡率和残疾。

项目成果

Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After Spinal Cord Injury.

病变抗体合成和补体沉积与脊髓损伤后从头抗神经元抗体合成相关。

• 发表时间: 2023-05
• 作者: Schwab, Jan M;Haider, Carmen;Kopp, Marcel A;Zrzavy, Tobias;Endmayr, Verena;Ricken, Gerda;Kubista, Helmut;Haider, Thomas;Liebscher, Thomas;Lübstorf, Tom;Blex, Christian;Serdani;Curt, Armin;Cinelli, Paolo;Scivoletto, Giorgio
• 通讯作者: Scivoletto, Giorgio

Profiling age-related muscle weakness and wasting: neuromuscular junction transmission as a driver of age-related physical decline.

分析与年龄相关的肌肉无力和消瘦：神经肌肉接头传输是与年龄相关的身体衰退的驱动因素。

• 发表时间: 2021-06
• 影响因子: 5.6
• 作者: Padilla, Carlos J;Harrigan, Markus E;Harris, Hallie;Schwab, Jan M;Rutkove, Seward B;Rich, Mark M;Clark, Brian C;Arnold, W David
• 通讯作者: Arnold, W David

Spinal Cord Injury Impairs Lung Immunity in Mice.

脊髓损伤会损害小鼠的肺部免疫力。

• 发表时间: 2022-07-01
• 作者: Mifflin, Katherine A;Brennan, Faith H;Guan, Zhen;Kigerl, Kristina A;Filous, Angela R;Mo, Xiaokui;Schwab, Jan M;Popovich, Phillip G
• 通讯作者: Popovich, Phillip G

A critical reappraisal of corticospinal tract somatotopy and its role in traumatic cervical spinal cord syndromes.

对皮质脊髓束躯体形态及其在创伤性颈脊髓综合征中的作用的批判性重新评估。

• 发表时间: 2022-04-01
• 作者: Levi, Allan D;Schwab, Jan M
• 通讯作者: Schwab, Jan M

Lesion level-dependent systemic muscle wasting after spinal cord injury is mediated by glucocorticoid signaling in mice.

小鼠脊髓损伤后损伤水平依赖性全身肌肉萎缩是由糖皮质激素信号介导的。

• 发表时间: 2023-12-20
• 影响因子: 17.1
• 作者: Harrigan, Markus E;Filous, Angela R;Vadala, Christopher P;Webb, Amy;Pietrzak, Maciej;Sahenk, Zarife;Prüss, Harald;Reiser, Peter J;Popovich, Phillip G;Arnold, W David;Schwab, Jan M
• 通讯作者: Schwab, Jan M