Host Immunity in Sepsis-Induced Systemic Infection

脓毒症引起的全身感染中的宿主免疫

基本信息

批准号：
10615084
负责人：
Samithamby Jeyaseelan
金额：
$ 58.66万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615084
关键词：
Ablation Acute Lung Injury Acute Respiratory Distress Syndrome Address Adoptive Transfer Affect Alveolar Macrophages Antimicrobial Resistance Attenuated Bacteremia Bacteria Bacterial Infections Binding Blocking Antibodies Blood Bone Marrow CASP1 gene CXCL1 gene Cause of Death Cells Clinical Trials Complication Data Drug resistance Emergency Situation Epithelial Cells Escherichia coli Escherichia coli Infections FDA approved Failure Fostering Functional disorder Goals Granulopoiesis Hematopoietic Host Defense Host Defense Mechanism Host resistance Human IL18 gene Immune Immune response Immunity In Vitro Infection Inflammasome Injury Innate Immune Response Innate Immune System Intensive Care Units Knockout Mice Knowledge Lung Lung infections Macrophage Marrow Mediating Membrane Multi-Drug Resistance Multiple Organ Failure Mus Myeloid Cells Natural Immunity Neutrophil Infiltration Organ Peritoneal Peritoneal Macrophages Peritoneum Predisposition Proteins Public Health Recombinants Role Sepsis Septic Shock Serum Signal Transduction Site Small Interfering RNA Spleen Stromal Cells Systemic infection TLR4 gene Testing Tissues Toll-like receptors Up-Regulation Work activated Protein C antagonist assault cecal ligation puncture cytokine drotrecogin alfa experimental study improved in vivo innate immune mechanisms knock-down microbial signature molecular modeling mortality neutrophil new therapeutic target novel therapeutic intervention organ injury overexpression pathogenic bacteria receptor recruit response septic systemic inflammatory response targeted treatment treatment strategy

项目摘要

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.

概括脓毒症仍然是一个持续存在且普遍存在的公共卫生问题，需要进行临床试验来评估具体情况脓毒症的治疗方法尚未成功，因此迫切需要扩大我们的治疗范围。可以产生更好的治疗策略的多器官损伤的知识。败血症中的损伤 (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尽管中性粒细胞（PMN）向组织的大量募集是一种关键的先天免疫。机制上，过度流入会导致造血系统产生附带损害。感染期间通过紧急粒细胞生成清除细菌病原体。细菌的识别通过膜结合 Toll 样受体 (TLR) 和胞质 NOD 样受体进行 NLR 的一种类型是炎症小体，它是一种可以激活的多蛋白平台。 caspase-1 以激活细胞因子 IL-1 和 IL-18 我们提出的工作的长期目标是了解炎症小体激活如何整合到有效的抗菌药物耐药性中，以及是否是这样在这种情况下，宿主靶向治疗可以减轻器官损伤。由于耐药性和高毒力细菌菌株的出现，这是有必要的。重点关注腹膜作为感染部位和肺部作为受影响的器官全身感染，我们使用大肠杆菌。大肠杆菌用于体外实验，因为它在革兰氏阴性细菌败血症中的重要性。 NLRP10 激活是脓毒症引起的全身性防御过程中宿主防御的关键决定因素为了解决这一假设，提出了四个目标：目标 1 将评估感染的影响。 NLRP10 对宿主防御的作用，目标 2 将阐明 NLRP10 在紧急粒细胞生成中的作用，目标 3 将描述 NLRP10 在巨噬细胞中的作用，目标 4 将检查是否增强 NLRP10 信号传导可改善肺部免疫力。这些目标的发现将揭示一种新的先天免疫分子模型，该模型与 NLRP10 在脓毒症中的应用将促进识别增强细菌感染的新治疗靶点在脓毒症引起的全身感染中清除并恢复受损器官的完整性。