The role of serotonin in cooperative defenses during polymicrobial sepsis

血清素在多种微生物败血症期间协同防御中的作用

• 批准号: 10607955
• 负责人: Robert Marc Gallant
• 金额: $ 4.25万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607955
• 关键词: Acceleration; Address; Antibiotic Resistance; Antibiotics; Antifungal Agents; Antiviral Agents; Bacteremia; Biological; Blood Platelets; Circulation; Clinical; Communication; Data; Defense Mechanisms; Development; Disease; Dose; Enzyme-Linked Immunosorbent Assay; Enzymes; Escherichia coli; Exhibits; Flow Cytometry; Fractionation; Genes; Goals; Health; Health Promotion; High Pressure Liquid Chromatography; Host Defense; Immune; Immune response; Immune system; Individual; Infection; Inflammation; Interleukin-10; Intraperitoneal Injections; Kidney; Knock-out; Knowledge; Lethal Dose 50; Lipids; Liver; Lung; Mentors; Metabolic; Metabolism; Microbe; Modeling; Molecular; Monoamine Oxidase A; Mus; Neurotransmitters; Organ; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Platelet Activation; Population; Process; Production; Regulation; Research; Resistance; Role; Scintillation Counting; Sepsis; Serotonin; Signal Transduction; Staphylococcus aureus; Therapeutic; Training; Triglyceride Metabolism; Viral Vector; Virulence; Work; cytokine; defense response; experimental study; genetic approach; improved; new pandemic; new therapeutic target; novel; novel strategies; novel therapeutic intervention; overexpression; pathogen; pharmacologic; polymicrobial sepsis; prevent; repaired; skills; transcriptome; uptake

Project Summary How can we promote health and survival during infection? Clinically, most patients are treated with drugs that work to eliminate the pathogen: antibiotics, antivirals, antifungals, etc., but this approach is often insufficient. The primary determinant of survival during infection is the host’s ability to prevent, withstand, or repair damage. Thus, eliminating the pathogen is not necessarily sufficient for survival. This is particularly relevant during sepsis, an infection in which the host response causes much more damage than the microbe itself. To address this disconnect, over the past decade the Ayres lab has pioneered cooperative defenses, a new infection defense framework focused on promoting health independent of pathogen burden. Cooperative defenses include anti-virulence strategies which neutralize pathogen- or host-derived virulence signals before they cause damage in the host (e.g. preventing maladaptive cytokine production) and disease tolerance strategies which prevent physiological damage in the presence of virulence signals (e.g. metabolic shifts that prevent damage from excess cytokine production). The Ayres lab has established a novel approach to identifying cooperative defense mechanisms by leveraging the decades-old phenomenon of the lethal dose 50 (LD50). LD50 is the dose of a pathogen that kills 50% of a genetically identical host population while the other 50% survives. Strikingly, for many infections, surviving and dying LD50-infected mice exhibit the same pathogen burden throughout the course of the infection, indicating that LD50-infected surviving mice survive due to differences in their ability to engage cooperative defenses. An LD50 polymicrobial bacterial sepsis model has identified serotonin neutralization as a candidate cooperative defense mechanism during sepsis. Preliminary data demonstrates inhibiting peripheral serotonin during polymicrobial sepsis promotes health and survival through cooperative defense mechanisms. While serotonin is most commonly studied in its role as a neurotransmitter, 95% of the body’s serotonin is found in the periphery, largely carried by platelets in circulation. Recent research has begun to elucidate the role of this peripheral serotonin in regulating a wide variety of processes: chief among these are inflammation and metabolism. Widespread platelet activation occurs during sepsis, inducing platelet serotonin release, yet the effects of this serotonin and the means by which it is handled are not well understood. Three specific aims will be addressed: 1) Determine the impact of serotonin on cooperative defenses during sepsis, 2) Determine how inhibition of serotonin signaling promotes health and survival during polymicrobial sepsis, and 3) Determine the mechanisms by which serotonin is neutralized during a cooperative defense response to sepsis. This research will take place at the Salk Institute for Biological Studies. In addition to these research objectives, the proposed training goals include improving scientific mentoring and communication skills.

项目摘要 我们如何才能在感染期间促进健康和生存？临床上，大多数患者使用的药物是 努力消除病原体：抗生素、抗病毒药物、抗真菌药物等，但这种方法往往是不够的。 在感染期间存活的主要决定因素是宿主预防、抵御或修复损伤的能力。 因此，消灭病原体不一定是生存的充分条件。这一点在以下方面尤其相关 败血症，一种宿主反应比微生物本身造成更大损害的感染。致信地址 这种脱节，在过去的十年里，艾尔斯实验室开创了合作防御的先河，一种新的感染 防御框架侧重于促进健康，不受病原体负担的影响。协同防御 包括抗毒力策略，其在病原体或寄主产生毒力信号之前将其中和 寄主的损害(例如，防止不适应的细胞因子的产生)和疾病耐受策略 在毒力信号存在的情况下防止生理损伤(例如，防止损伤的代谢变化 由于细胞因子的过度产生)。艾尔斯实验室已经建立了一种新的方法来识别合作 通过利用数十年来的致死剂量50(LD50)现象来防御机制。半数致死剂量是 一种病原体的剂量，它杀死了50%的遗传相同的宿主群体，而另50%存活了下来。 令人惊讶的是，对于许多感染，存活和死亡的LD50感染小鼠表现出相同的病原体负担 在整个感染过程中，表明LD50感染的存活小鼠存活下来是由于 他们参与合作防御的能力。一种LD50多菌细菌败血症模型已确定 5-羟色胺中和作为脓毒症候选协同防御机制。初步数据 证明在多菌败血症期间抑制外周5-羟色胺可通过 合作防御机制。虽然5-羟色胺最常被研究的是它作为神经递质的作用， 人体内95%的5-羟色胺存在于外周，主要由循环中的血小板携带。近期 研究已经开始阐明这种外周5-羟色胺在调节多种过程中的作用： 其中最主要的是炎症和新陈代谢。在脓毒症期间会发生广泛的血小板激活， 诱导血小板释放5-羟色胺，然而这种5-羟色胺的影响和它的处理方式是 不是很清楚。将解决三个具体目标：1)确定5-羟色胺对 脓毒症期间的合作防御，2)确定5-羟色胺信号的抑制如何促进健康和 多菌败血症期间的存活，以及3)确定5-羟色胺被中和的机制 在对脓毒症的合作防御反应中。这项研究将在索尔克研究所进行 生物学研究。除了这些研究目标外，拟议的培训目标还包括改进 科学的指导和沟通技巧。