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.

摘要 脓毒症是免疫功能正常的人死亡率、发病率和卫生保健支出的重要原因。 和免疫抑制的人群。脓毒症可导致组织损伤，并最终导致 组织功能障碍和随后的衰竭。下呼吸道感染是一个突出的诱因， 败血症/败血症（又称肺炎源性败血症）。抗生素是治疗这些疾病的常用药物。 感染.然而，这些药物的使用将对细菌施加压力以获得抗生素 阻力因此，我们迫切需要扩大知识面，发展新的 治疗方法。在这方面，积极招募中性粒细胞清除细菌是一个关键的先天 免疫机制特别是，不受控制的中性粒细胞导致广泛的组织损伤和器官损伤。 失败除了膜结合Toll样受体（TLR），胞质NOD样受体（NLR） 在病理环境中作为先天免疫的关键分子。选择性NLR称为 “炎性体”是先天免疫中的关键受体和/或传感器，其在哺乳动物中诱导炎症。 对入侵病原体的反应。在炎性小体中，NLR家族的pyrin domain containing 3（NLRP 3） 是研究最多的，并已被证明在细菌性呼吸道感染中发挥重要作用。 然而，NACHT、富含亮氨酸的重复序列（LRR）和含PYD的蛋白10（NLRP 10）在 革兰氏阳性肺炎仍有待界定，因为这是一个最近发现的炎性小体 并且不具有富含亮氨酸的结构域（LRR）。我们的实验室初步数据表明，（1） 肺炎人肺显示巨噬细胞、嗜中性粒细胞和巨噬细胞中NLRP 10表达上调， （2）小鼠肺显示髓样和结构细胞中NLRP 10的上调， （3）NLRP 10敲除（KO）小鼠显示肺中细菌负荷降低， 革兰氏阳性菌感染后细菌播散至肺外器官。总的来说，这 初步数据导致假设NLRP 10炎性小体是器官的中枢调节因子， 革兰氏阳性肺炎引起的脓毒症中的损伤。有两个相互关联但又独立的目标， 主要研究内容如下：（1）阐明NLRP 10炎性体调控病原体的机制 革兰氏阳性感染期间的清除;和（2）确定NLRP 10炎性小体的消融是否可以 调节肺泡巨噬细胞、中性粒细胞和肺泡II型上皮细胞功能， 感染拟议的研究将揭示NLRP 10在肺炎中作用的机制见解- 诱发败血症。国家研究服务奖将使PI获得指导研究 从一个更有经验的教师沿着与优秀的论文委员会的培训，以 获得学术地位。