Regulation of neutrophil death by GSDMD in Candida albicans infection

GSDMD 对白色念珠菌感染中性粒细胞死亡的调节

• 批准号: 10687091
• 负责人: Hongbo R Luo
• 金额: $ 30.87万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687091
• 关键词: Acute; Agreement; Animal Experiments; Animal Model; Animals; Antifungal Agents; Antifungal Therapy; Binding; Biology; Blood Circulation; Boston; CASP1 gene; Candida; Candida albicans; Candidiasis; Cell Membrane Permeability; Cells; Cessation of life; Chemicals; Clinical; Clinical Trials; Collaborations; Complement; Data; Disease; Disseminated candidiasis; Effectiveness; Fungal Drug Resistance; Fungemia; Future; Goals; Homeostasis; Host Defense; Human; Hyphae; Immune; Immunity; Immunocompromised Host; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Intervention; Kidney; Knockout Mice; Knowledge; Letters; Life; Liver; Lung; Lytic; Macrophage; Mediating; Modeling; Mus; Natural Immunity; Nature; Neutropenia; Pathway interactions; Patients; Pediatric Hospitals; Phagocytosis; Pharmaceutical Preparations; Physicians; Play; Positioning Attribute; Regulation; Reporting; Resistance; Resolution; Risk Factors; Role; Scientist; Sepsis; Spleen; Testing; Therapeutic; Translational Research; clinically relevant; design; experimental study; fungicide; in vitro Model; in vivo; inhibitor; insight; mouse model; neutrophil; new therapeutic target; novel; novel therapeutic intervention; personalized medicine; pharmacologic; protective effect; treatment strategy

Project Summary Candida albicans (C. albicans) is a leading cause of bloodstream infection in immunocompromised patients. Neutrophils play a key role in C. albicans host defense and neutropenia is a major risk factor for developing severe disseminated candidiasis. In current study, we propose to alleviate neutropenia-related disseminated C. albicans infection by inhibiting C. albicans-induced neutrophil death and thus enhancing neutrophil- mediated fungal killing in neutropenic patients. We will do so by targeting Gasdermin D (GSDMD) which has been implicated in the regulation of neutrophil death. GSDMD was originally identified as a key factor responsible for the inflammatory form of lytic pyroptotic death (pyroptosis) in macrophages. We recently reported that GSDMD is also highly expressed in neutrophils and mediates neutrophil death which plays essential roles in neutrophil homeostasis and resolution of inflammation. Our preliminary data show that C. albicans can hijack GSDMD-mediated neutrophil death mechanism to eliminate neutrophils and therefore suppress neutrophil-mediated host defense again C. albicans infection. GSDMD deficiency drastically inhibited C. albicans-induced neutrophil death and conferred resistance to disseminated C. albicans infection. Together, these results present a novel pathophysiological role for GSDMD in regulation of neutrophil death, leading us to hypothesize that inhibition of GSDMD will lead to elevated neutrophil-mediated host defense and should be a legitimate therapeutic strategy for the treatment of neutropenia-related C. albicans infection. To further understand the role GSDMD in regulating C. albicans-induced neutrophil death and host fungicidal activity, we will first reveal the mechanism by which C. albicans activates GSDMD in neutrophils. The contribution of lysosomal membrane permeabilization (LMP), phagocytosis, ROS, candida hyphae formation, and candidalysin to GSDMD cleavage will be examined in both human and mouse neutrophils (Aim 1). Next, we will elucidate the role of GSDMD in regulating neutrophil death in vivo during C. albicans infection in both normal and neutropenic mice (Aim 2). We will also directly assess the contribution of neutrophil GSDMD to host defense against C. albicans using a newly developed neutrophil-specific conditional GSDMD KO mouse (Aim 3). Finally, we will examine whether the host defense against C. albicans can be enhanced by pharmacologically targeting GSDMD (Aim 4). Together, experiments proposed in these four specific aims will provide a better understanding of the role and regulation of GSDMD-mediated neutrophil death in disseminated C. albicans infection. This study will solidify GSDMD and related pathways as novel therapeutic targets for treatment of neutropenia-related severe candidiasis.

项目摘要 白色念珠菌（白色念珠菌）是免疫功能低下患者血流感染的主要原因。 中性粒细胞在白色念珠菌宿主防御和中性粒细胞减少症中起关键作用，是发展的主要危险因素 严重传播念珠菌病。在当前的研究中，我们建议减轻中性粒细胞减少相关的传播 白色念珠菌通过抑制白色念珠菌诱导的中性粒细胞死亡，从而增强中性粒细胞 中性粒细胞减少患者介导的真菌杀伤。我们将通过针对具有的Gasdermin D（GSDMD）来做到这一点 与中性粒细胞死亡的调节有关。 GSDMD最初被确定为关键因素 负责巨噬细胞中裂解凋亡死亡（凋亡）的炎症形式。我们最近 据报道，GSDMD在中性粒细胞中也高度表达，并介导嗜中性粒细胞死亡 在中性粒细胞稳态和炎症解决方案中的重要作用。我们的初步数据表明C. 白色唱片可以劫持GSDMD介导的中性粒细胞死亡机制以消除中性粒细胞，因此 抑制中性粒细胞介导的宿主防御再次抑制白色念珠菌感染。 GSDMD缺乏症极大地抑制 白色念珠菌诱导的中性粒细胞死亡，并赋予对白色念珠菌感染的耐药性。一起， 这些结果表现出GSDMD在调节中性粒细胞死亡中的新型病理生理作用，导致美国 假设抑制GSDMD将导致中性粒细胞介导的宿主防御升高，应该是 一种合法的治疗策略，用于治疗中性粒细胞减少相关的白色念珠菌感染。进一步 了解GSDMD在调节白色念珠菌诱导的中性粒细胞死亡和宿主杀真菌活性中的作用，我们 将首先揭示白色念珠菌在中性粒细胞中激活GSDMD的机制。的贡献 溶酶体膜通透性（LMP），吞噬作用，ROS，念珠菌形成和 在人和小鼠中性粒细胞中将检查念珠菌素至GSDMD裂解（AIM 1）。接下来，我们 将阐明GSDMD在白色念珠菌感染期间体内调节中性粒细胞死亡中的作用 正常和中性粒细胞减少小鼠（AIM 2）。我们还将直接评估中性粒细胞GSDMD对 使用新开发的中性粒细胞特异性有条件GSDMD KO小鼠对白色念珠菌的宿主防御 （目标3）。最后，我们将研究是否可以通过 药理学靶向GSDMD（AIM 4）。一起，在这四个特定目标中提出的实验将 更好地了解GSDMD介导的中性粒细胞死亡的作用和调节 传播白色念珠菌感染。这项研究将巩固GSDMD和相关途径作为新的治疗 治疗中性粒细胞相关的严重念珠菌病的靶标。