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: 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
• 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

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.

摘要 脓毒症仍然是一个持久和普遍的公共卫生问题和临床试验，以评估特定的 脓毒症的治疗方法并不成功。因此，迫切需要扩大我们的 能够产生更好的治疗策略的知识。多器官损伤，包括急性肺损伤 脓毒症中的损伤(ALI)和急性呼吸窘迫综合征(ARDS)是由机体调节失调引起的 对细菌感染和先天免疫的反应提供了关键的和早期的保护 感染。尽管中性粒细胞(PMN)在组织中的大量募集是一种关键的先天免疫 机制方面，过度的涌入会导致附带损害。PMN是在造血细胞中产生的 感染期间通过紧急粒细胞生成清除细菌病原体的隔室。先天免疫 细菌的识别是通过膜结合的Toll样受体(TLRs)和胞浆中的Nod样受体来实现的 受体(NLRs)。NLR的一种类型是炎性小体，这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。我们提议的工作的长期目标是 了解炎症体激活如何与有效的抗菌素耐药性相结合，以及是否如此 有可能减轻这种反应中的器官损害。在这种情况下，宿主靶向治疗是 因为出现了抗药性和超强毒力的细菌菌株，所以有理由这样做。我们主要是 以腹膜为感染部位，肺部为全身感染器官。我们使用E。 由于其在革兰氏阴性细菌败血症中的重要性，因此可用于体外实验。假说 NLRP10的激活是脓毒症诱导的全身系统中宿主防御的关键决定因素 感染。已经提出了四个目标来解决这一假设：目标1将评估 NLRP10在宿主防御中的作用，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信号增强肺免疫功能。将采用体外和体内相结合的方法。 这些研究结果将揭示一种新的天然免疫分子模型，该模型与先天免疫的作用有关。 NLRP10在脓毒症中的作用，并将促进识别新的治疗靶点，以增强细菌 清除和恢复败血症引起的全身感染中受损器官的完整性。