The role of serotonin in cooperative defenses during polymicrobial sepsis

项目摘要 我们如何在感染期间促进健康和生存？在临床上，大多数患者使用的药物 努力消除病原体：抗生素、抗病毒药、抗真菌药等，但这种方法往往是不够的。 感染期间存活的主要决定因素是宿主预防、承受或修复损伤的能力。 因此，消除病原体并不一定足以生存。这一点尤其重要， 脓毒症是一种感染，在这种感染中，宿主的反应比微生物本身造成的损害要大得多。解决 这种脱节，在过去的十年里，艾尔斯实验室开创了合作防御，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。合作防御 包括抗毒性策略，其在病原体或宿主来源毒性信号引起 宿主中的损伤（例如，防止适应不良的细胞因子产生）和疾病耐受策略， 在存在毒力信号的情况下防止生理损伤（例如，防止损伤的代谢变化 过量的细胞因子产生）。艾尔斯实验室建立了一种识别合作的新方法 通过利用几十年前的致死剂量50（LD 50）现象来增强防御机制。LD 50是 一种病原体的剂量，杀死50%的基因相同的宿主群体，而其他50%的人存活。 引人注目的是，对于许多感染，存活和死亡的LD 50感染小鼠表现出相同的病原体负荷 在整个感染过程中，表明LD 50感染的存活小鼠存活是由于 他们进行合作防御的能力LD 50多微生物细菌脓毒症模型已经确定 5-羟色胺中和作为脓毒症期间的候选协同防御机制。初步数据 证明在多微生物败血症期间抑制外周血清素可通过以下方式促进健康和存活： 合作防御机制。虽然血清素最常被研究的是其作为神经递质的作用， 人体95%的血清素存在于外周，主要由循环中的血小板携带。最近 研究已经开始阐明这种外周血清素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。在败血症期间发生广泛的血小板活化， 诱导血小板5-羟色胺释放，但这种5-羟色胺的作用和处理它的方法， 没有很好地理解。三个具体目标将被解决：1）确定血清素的影响， 脓毒症期间的协同防御，2）确定5-羟色胺信号传导的抑制如何促进健康， 在多微生物败血症期间的存活率，和3）确定5-羟色胺被中和的机制 在败血症的协同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提高 科学指导和沟通技能。

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.