Host Immunity in Sepsis-Induced Systemic Infection

脓毒症引起的全身感染中的宿主免疫

• 批准号: 10400027
• 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
• 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/10400027
• 关键词: Ablation; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Adoptive Transfer; Affect; Alveolar Macrophages; Antimicrobial Resistance; Attenuated; Bacteremia; Bacteria; Bacterial Infections; 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 Infections; FDA approved; Failure; Fostering; Functional disorder; Goals; Granulopoiesis; Hematopoietic; Host Defense; Host Defense Mechanism; Host resistance; Human; Immune; Immune response; Immunity; Infection; Inflammasome; Injury; Innate Immune Response; Innate Immune System; Intensive Care Units; Interleukin-1; Interleukin-18; Knockout Mice; Knowledge; Lung; Lung infections; Marrow; Mediating; Membrane; Multi-Drug Resistance; Multiple Organ Failure; Mus; Myeloid Cells; Natural Immunity; Neutrophil Infiltration; Organ; Peritoneal; Peritoneal Macrophages; Peritoneum; Predisposition; 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; macrophage; microbial signature; molecular modeling; mortality; neutrophil; new therapeutic target; organ injury; overexpression; pathogenic bacteria; receptor; recruit; response; septic; systemic inflammatory response; targeted treatment; treatment strategy

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 败血症仍然是一个持久而普遍的公共卫生问题和临床试验，用于评估特定的特定问题 败血症的疗法尚未成功。因此，迫切需要扩大我们的 可以带来更好治疗策略的知识。多器官损伤，包括急性肺 损伤（ALI）和急性呼吸窘迫综合征（ARDS），败血症是由失调的宿主引起的 对细菌感染和先天免疫的反应提供了至关重要的早期保护 感染。尽管急剧募集中性粒细胞（PMN）是组织是一种关键的先天免疫 机制，过度影响会导致附带损害。 PMN在造血中产生 通过紧急颗粒膜片感染期间的隔室清除细菌病原体。先天免疫 通过膜结合的Toll样受体（TLR）和胞质Nod-like发生识别细菌的识别 受体（NLR）。一种类型的NLR是炎性症，这是一种可以激活的多蛋白平台 caspase-1为了激活细胞因子IL-1和IL-18。我们提议的工作的长期目标是 了解如何将炎性体激活整合到有效的抗菌耐药性中 在此响应中可能会减轻器官损伤。在这种情况下，宿主的靶向疗法是 由于出现了耐药性和高毒性细菌菌株，因此被保证。我们主要 专注于腹膜作为感染部位和肺部作为影响的有机系统感染。我们使用E。 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。假设 是，NLRP10激活是败血症诱导的全身性期间宿主防御的关键确定剂 感染。提出了四个目标来解决该假设：AIM 1将评估 NLRP10在主机防御上，AIM 2将阐明NLRP10在紧急粒子中的作用，AIM 3 将表征NLRP10在巨噬细胞中的作用，AIM 4将检查是否增强 NLRP10信号传导改善了肺免疫学。将使用体外和体内方法的组合。 这些目标中的发现将揭示出与与该作用的作用有关的新的先天免疫力模型 败血症中的NLRP10，并将促进增强细菌的新型治疗靶标的鉴定 清除并恢复败血症引起的全身感染中受伤器官的完整性。