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: 9894354
• 负责人: Hongbo R Luo
• 金额: $ 44.25万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894354
• 关键词: Acute; Address; Animal Experiments; Animal Model; Animals; Antifungal Agents; Antifungal Therapy; Biology; Blood Circulation; Boston; CASP1 gene; Candida; Candida albicans; Candidiasis; 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; Industrial fungicide; Infection; Inflammasome; Inflammation; Inflammatory; Intervention; Kidney; Knockout Mice; Knowledge; Letters; Life; Liver; Lung; Lytic; Mediating; Membrane; Modeling; Mus; Natural Immunity; Nature; Neutropenia; Pathway interactions; Patients; Pediatric Hospitals; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Physicians; Play; Positioning Attribute; Regulation; Reporting; Resistance; Resolution; Risk Factors; Role; Scientist; Sepsis; Spleen; Testing; Therapeutic; Translational Research; base; clinically relevant; design; experimental study; in vitro Model; in vivo; inhibitor/antagonist; insight; macrophage; mouse model; neutrophil; new therapeutic target; novel; novel therapeutics; personalized medicine; 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（C.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C.白念珠菌宿主防御和中性粒细胞减少症是发展中国家的主要危险因素， 严重的播散性念珠菌病。在目前的研究中，我们建议减轻与疟疾有关的传播性疾病， C.白念珠菌感染。白色念珠菌诱导的中性粒细胞死亡，从而增强中性粒细胞- 介导的真菌杀伤作用。我们将通过针对Gasdermin D（GSDMD）来实现这一目标， 参与调节中性粒细胞死亡。GSDMD最初被确定为一个关键因素 导致巨噬细胞中炎性形式的裂解性热死（焦亡）。我们最近 报道GSDMD在中性粒细胞中也高度表达，并介导中性粒细胞死亡， 在中性粒细胞稳态和炎症消退中起重要作用。初步数据表明，C. 白色念珠菌可以劫持GSDMD介导的中性粒细胞死亡机制来消除中性粒细胞，因此 再次抑制嗜中性粒细胞介导的宿主防御C.白色念珠菌感染GSDMD缺乏症显著抑制 C.白念珠菌诱导的中性粒细胞死亡，并赋予耐药播散性念珠菌。白色念珠菌感染在一起， 这些结果表明GSDMD在调节中性粒细胞死亡中具有新的病理生理学作用， 假设GSDMD的抑制将导致嗜中性粒细胞介导的宿主防御增强， 一个合法的治疗策略，用于治疗与阴茎海绵体相关的C。白色念珠菌感染进一步 了解GSDMD在调节C.白念珠菌诱导的中性粒细胞死亡和宿主杀真菌活性，我们 将首先揭示C.白色念珠菌激活中性粒细胞中的GSDMD。的贡献 溶酶体膜透化（LMP）、吞噬作用、ROS、念珠菌菌丝形成，以及 将在人和小鼠嗜中性粒细胞中检测念珠菌溶素对GSDMD裂解的作用（目的1）。接下来我们 将阐明GSDMD在调节体内嗜中性粒细胞死亡过程中的作用。白色念珠菌感染 正常小鼠和血小板减少小鼠（Aim 2）。我们还将直接评估中性粒细胞GSDMD对 宿主对C.使用新开发的嗜中性粒细胞特异性条件性GSDMD KO小鼠 (Aim 3）。最后，我们将研究宿主对C.白色念珠菌可通过以下方式增强 以GSDMD为目标（目标4）。在这四个具体目标中提出的实验将共同 更好地理解GSDMD介导的中性粒细胞死亡在 散布C.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方法 治疗与阴茎海绵体病相关的严重念珠菌病的靶点。