NLRP10 Inflamasome in Gram-positive Sepsis

摘要 脓毒症是免疫系统疾病死亡率、发病率和医疗费用的重要原因。 以及全球受免疫抑制的人群。脓毒症会导致组织损伤，最终导致 组织功能障碍和随后的衰竭。下呼吸道感染是一种重要的诱因 败血症/败血症(又名肺炎引起的败血症)。抗生素是治疗这些疾病的常用方法。 感染。然而，这些药物的使用会对细菌施加压力，使其获得抗生素。 抵抗。因此，迫切需要拓宽我们的知识，发展新的 治疗方法。在这方面，大力招募中性粒细胞来清除细菌是一个关键的先天因素。 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损伤。 失败了。除了膜结合的Toll样受体(TLRs)外，胞浆中的Nod样受体(NLRs) 在病理环境中充当先天免疫的关键分子。选择性NLR被称为 “炎症体”是先天免疫中的关键受体和/或感受器，可在体内引发炎症。 对入侵病原体的反应。在炎性小体中，NLRP3家族是一个含有3个结构域的家族 是研究最多的，并已被证明在细菌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PYD包含蛋白10(NLRP10)在 革兰氏阳性肺炎仍有待描述，因为这是最近发现的炎症性小体。 并且不具有亮氨酸富含结构域(LRR)。我们实验室的初步数据表明：(1) 肺炎患者肺中巨噬细胞、中性粒细胞和 (2)小鼠肺中髓系和结构细胞NLRP10表达上调。 (3)NLRP10基因敲除(KO)小鼠表现出肺部细菌负荷的减少和 革兰氏阳性感染后细菌向肺外器官扩散。总而言之，这是 初步数据表明，NLRP10炎症体是器官的中枢调节因子 革兰氏阳性肺炎脓毒症的损害。两个相互关联但独立的目标是 建议：(1)阐明NLRP10炎症体对病原体的调控机制 革兰氏阳性感染期间的清除；以及(2)确定消融NLRP10炎性小体是否可以 革兰氏阳性者肺泡巨噬细胞、中性粒细胞和肺泡II型上皮细胞功能的调节 感染。拟议的研究将揭示NLRP10在肺炎中的作用的机械性见解。 诱发性败血症。国家研究服务奖将使PI能够获得有指导的研究 从更有经验的教员和优秀的论文委员会进行培训，以便 获得学术地位。

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.