NLRP10 Inflamasome in Gram-positive Sepsis

革兰氏阳性脓毒症中的 NLRP10 炎性体

• 批准号: 10680214
• 负责人: John Le
• 金额: $ 4.21万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680214
• 关键词: Ablation; Adult; Alveolar; Alveolar Macrophages; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Binding; CXC Chemokines; Candida albicans; Cause of Death; Cell physiology; Cells; Chemotaxis; Child; Clinical Trials; Cytokinesis; Data; Development; Drug usage; Epithelial Cells; Faculty; Failure; Family; Foundations; Functional disorder; Goals; Gram-Positive Bacteria; Health Expenditures; High Prevalence; Host Defense; Human; Immune response; Immunocompetent; Immunologic Receptors; Immunotherapy; In Vitro; Infection; Inflammasome; Inflammation; Innate Immune Response; Invaded; Knock-out; Knockout Mice; Knowledge; Leucine; Leucine-Rich Repeat; Leukocytes; Ligands; Lower Respiratory Tract Infection; Lung; Lung infections; Macrophage; Mediating; Mediator; Membrane; Mentors; Methods; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; National Research Service Awards; Natural Immunity; Neutrophil Infiltration; Organ; Organ failure; Pathogenesis; Pathologic; Phagocytosis; Play; Pneumonia; Population; Positioning Attribute; Predisposition; Production; Proteins; Public Health; Reporting; Research Training; Respiratory Tract Infections; Role; Sepsis; Septicemia; Spleen; Staphylococcus aureus infection; Stromal Cells; System; Testing; Tissues; Toll-like receptors; Up-Regulation; Vaccines; common treatment; experience; experimental study; extracellular; human pathogen; immunosuppressed; in vivo; innate immune mechanisms; insight; marenostrin; methicillin resistant Staphylococcus aureus; mortality; mouse model; neutrophil; novel therapeutic intervention; novel therapeutics; pathogen; pressure; receptor; recruit; response; sensor; septic; tissue injury

ABSTRACT Sepsis is an important cause of mortality, morbidity, and health care expenditures in immunocompetent and immunosuppressed populations globally. Sepsis can lead to tissue injury, and eventually results in tissue dysfunction and subsequent failure. Lower respiratory tract infections are a prominent inducer of septicemia/sepsis (aka pneumonia-derived sepsis). Antibiotics are common treatments for these infections. However, the use of these drugs will apply pressure on the bacterium to gain antibiotic resistance. Therefore, there is a strong need for to broaden our knowledge and the development of new methods of treatment. In this regard, vigorous recruitment of neutrophils to clear bacteria is a key innate immune mechanism. Paradoxically, uncontrolled neutrophil leads to extensive tissue damage and organ failure. In addition to membrane bound Toll-Like Receptors (TLRs), cytosolic NOD-like receptors (NLRs) serve as critical molecules of innate immunity in pathological settings. Selective NLRs termed “Inflammasomes” which are key receptors and/or sensors in innate immunity that induce inflammation in response to invading pathogens. Among inflammasomes, NLR family pyrin domain containing 3 (NLRP3) is the most studied and has been shown to play an important role during bacterial respiratory infections. However, the role of NACHT, leucine-rich repeat (LRR), and PYD containing protein 10 (NLRP10) in Gram-positive pneumonia remains to be delineated because this is a recently identified inflammasome and does not have a leucine rich domain (LRR). Our lab preliminary data demonstrated that (1) pneumonic human lungs show upregulated NLRP10 expression in macrophages, neutrophils, and epithelial cells; (2) mouse lungs display upregulation of NLRP10 in myeloid and structural cells following sepsis; and (3) NLRP10 knockout (KO) mice show reduced bacterial burden in the lungs and decreased bacterial dissemination to extrapulmonary organs following Gram-positive infection. Taken together, this preliminary data led to the hypothesis that the NLRP10 inflammasome is a central regulator of organ damage in Gram-positive pneumonia-induced sepsis. Two related but independent aims have been proposed: (1) To delineate the mechanisms by which NLRP10 inflammasome regulates pathogen clearance during Gram-positive infection; and (2) To determine if ablation of NLRP10 inflammasome can modulate alveolar macrophage, neutrophil, and alveolar type II epithelial cell function in Gram-positive infection. The proposed studies will uncover mechanistic insights into the role of NLRP10 on pneumonia- induced sepsis. The National Research Service Award will enable the PI to gain mentored research training from a more experienced faculty along with an outstanding dissertation committee in order to obtain an academic position.

抽象的 败血症是免疫能力的死亡率，发病率和医疗支出的重要原因 和全球免疫抑制人群。败血症会导致组织损伤，并最终导致 组织功能障碍和随后的失败。下呼吸道感染是 败血症/败血症（又称肺炎衍生的败血症）。抗生素是这些的常见治疗方法 感染。但是，这些药物的使用将对细菌施加压力以获得抗生素 反抗。因此，强烈需要扩大我们的知识和新的发展 治疗方法。在这方面，中性粒细胞迅速募集以清除细菌是一个关键的先天性 免疫机制。矛盾的是，不受控制的中性粒细胞会导致广泛的组织损伤和器官 失败。除了膜结合的收费受体（TLR）外，胞质点头样受体（NLR） 作为病理环境中先天免疫的关键分子。选择性NLR被称为 “炎症”是诱导炎症的智力接收器和/或传感器的关键接收器和/或传感器 对入侵病原体的反应。在炎症中，NLR家族pyrin结构域包含3（NLRP3） 是研究最多的，并且已被证明在细菌呼吸道感染中起着重要作用。 然而，NACHT，富含亮氨酸的重复（LRR）和含有蛋白10（NLRP10）的PYD的作用 革兰氏阳性肺炎仍有待描述，因为这是最近确定的炎症体 并且没有富含亮氨酸的域（LRR）。我们的实验室初步数据表明（1） 肺炎人肺在巨噬细胞，中性粒细胞和 上皮细胞； （2）小鼠肺在随后在髓样和结构细胞中表现出NLRP10的上调 败血症； （3）NLRP10敲除（KO）小鼠显示肺部细菌燃烧减少并改善 革兰氏阳性感染后，细菌传播到肺外器官。总的来说，这个 初步数据导致了以下假设：NLRP10炎症体是器官的中心调节剂 革兰氏阳性肺炎诱导的败血症的损伤。两个相关但独立的目标是 提议：（1）描述NLRP10炎症体调节病原体的机制 革兰氏阳性感染期间的间隙； （2）确定nlrp10炎症体的消融是否可以 在革兰氏阳性中调节肺泡巨噬细胞，中性粒细胞和牙槽 感染。拟议的研究将发现机械洞察NLRP10对肺炎的作用 诱发败血症。国家研究服务奖将使PI能够获得指导的研究 经验丰富的教职员工以及一个杰出的论文委员会培训 获得学术职位。