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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结