Host Immunity in Sepsis-Induced Systemic Infection

总结 脓毒症仍然是一个持续和普遍的公共卫生问题， 脓毒症的治疗尚未成功。因此，迫切需要扩大我们的 这些知识可以导致更好的治疗策略。多器官损伤，包括急性肺 脓毒症中的急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是由宿主失调引起的 对细菌感染的反应和先天免疫提供了关键的早期保护， 感染虽然中性粒细胞（PMN）向组织的剧烈募集是先天性免疫的关键， 机制，过度流入会导致附带损害。中性粒细胞产生于造血系统。 在感染期间，通过紧急粒细胞生成来清除细菌病原体。先天免疫 细菌的识别通过膜结合的Toll样受体（TLR）和细胞溶质NOD样受体（NOD样受体）发生。 受体（NLR）。一种类型的NLR是炎性小体，一种多蛋白平台， 半胱天冬酶-1，以激活细胞因子IL-1 β和IL-18。我们拟议工作的长期目标是 了解炎性小体激活如何整合到有效的抗菌素耐药性中， 在这种反应中减轻器官损伤的可能性。在这种情况下，宿主靶向治疗是 因为出现了耐药性和超强毒力的细菌菌株。我们主要 重点是腹膜作为感染部位和肺部作为受累器官的全身感染。我们使用E。 由于其在革兰氏阴性细菌败血症中的重要性，因此将其用于体外实验。的假设 NLRP 10活化是脓毒症诱导的系统性免疫应答过程中宿主防御的关键决定因素， 感染提出了四个目标来解决这一假设：目标1将评估 NLRP 10对宿主防御的作用，目的2将阐明NLRP 10在紧急粒细胞生成中的作用，目的3 将描述NLRP 10在巨噬细胞中的作用，Aim 4将检查是否增强NLRP 10在巨噬细胞中的作用。 NLRP 10信号传导改善肺免疫。将使用体外和体内方法的组合。 这些目标的发现将揭示一种新的先天免疫分子模型， NLRP 10在脓毒症中的作用，并将促进识别增强细菌感染的新治疗靶点。 清除并恢复脓毒症引起的全身感染中受损器官的完整性。

SUMMARY Sepsis remains a persistent and pervasive public health problem and clinical trials for evaluating specific therapies for sepsis have not been successful. Therefore, there is an immediate need to broaden our knowledge that can result in better treatment strategies. Multiple organ damage, including Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS), in sepsis is caused by dysregulated host response to bacterial infection and the innate immunity provides critical and early protection against infection. Although vigorous recruitment of neutrophils (PMN) to tissues is a key innate immune mechanism, excessive influx can induce collateral damage. PMN are produced in the hematopoietic compartment during infection via emergency granulopoiesis to clear bacterial pathogens. Innate immune recognition of bacteria occurs through membrane-bound toll-like receptors (TLRs) and cytosolic NOD-like receptors (NLRs). One type of NLR is the inflammasomes, a multiprotein platform that can activate caspase-1 in order to activate cytokines IL-1 and IL-18. The long-term goal of our proposed work is to understand how inflammasome activation is integrated into effective antimicrobial resistance and if it is possible to mitigate organ damage during this response. In this context, host targeted therapies are warranted because of the emergence of drug-resistant and hypervirulent bacterial strains. We primarily focus on peritoneum as the site of infection and lung as the affected organ systemic infection. We use E. coli for in vitro experiments because of its importance in Gram-negative bacterial sepsis. The hypothesis is that NLRP10 activation is a critical determinant of host defense during sepsis-induced systemic infection. Four aims have been proposed to address the hypothesis: Aim 1 will evaluate the effects of NLRP10 on host defense, Aim 2 will elucidate the role of NLRP10 in emergency granulopoiesis, Aim 3 will characterize the role of NLRP10 in macrophages, and Aim 4 will examine whether enhancing NLRP10 signaling improves lung immunity. A combination of in vitro and in vivo approaches will be used. The findings in these aims will unveil a new molecular model of innate immunity relating to the role of the NLRP10 in sepsis and will foster the identification of novel therapeutic targets that enhance bacterial clearance and restores the integrity of the injured organs in sepsis-induced systemic infection.