Investigating mammalian innate immune responses to pathogenic fungi

研究哺乳动物对病原真菌的先天免疫反应

• 批准号: 10927999
• 负责人: Eric Dang
• 金额: $ 124.82万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10927999
• 关键词: Address; Bacteria; Biochemistry; CRISPR screen; Cells; Cellular Immunology; Cessation of life; Cytokine Signaling; Detection; Food Contamination; Genetic; Genetic Screening; Genomics; Goals; Growth; Immunity; Immunology; Immunosuppression; Infection; Inflammation; Inhalation; Innate Immune Response; Intestines; Knockout Mice; Laboratories; Lung; Macrophage; Maps; Microbiology; Molecular Immunology; Mus; Mycoses; Myeloid Cells; Outcome; Pathway interactions; Pharmaceutical Preparations; Physiological; Physiology; Play; Research; Role; Shapes; Skin; Tissues; Virus; Work; burden of illness; candidate identification; cell type; chemical genetics; commensal microbes; conditional knockout; drug resistant pathogen; experimental study; forward genetics; fungal genetics; fungus; genome-wide; human disease; insight; interdisciplinary approach; interest; microbial; mouse genetics; pathogenic fungus; programs; receptor; response; single-cell RNA sequencing; tool

Mammalian barrier tissues (gut, skin, lungs) are colonized by a plethora of microbial species that play important roles in shaping host immunity and physiology. While most research has thus far focused on bacteria and viruses, fungi are increasingly recognized as important components of our commensal flora. In addition to commensals, fungal pathogens cause a high human disease burden, leading to 300 million infections and up to 1.5 million deaths per year globally. These infections are difficult to treat, due to a lack of effective drugs and the increased emergence of drug-resistant pathogens. Our laboratory operates at the intersection of microbiology and immunology to understand the factors that dictate the outcome of fungal exposure at barrier tissues. Our work takes an interdisciplinary approach combining cellular and molecular immunology, forward genetics, chemical-genetics, genomics, and microbiology. Our research program explores the mechanisms underlying aberrant versus protective immunity to fungal pathogens. Over the past fiscal year, we have identified key myeloid cell subsets that expand in the lungs in response to inhaled fungal infection, and used genetic mouse fate mapping tools to track their ontogeny. Our experiments have found that alternatively activated macrophages play a detrimental role in fungal infection through cell-extrinsic immunosuppressive mechanisms. To gain deeper insights into the mechanisms underlying macrophage immunosuppression during fungal infection, we used single cell RNA-seq to identify candidate molecules expressed by discrete macrophage cell types in the lung, which we are now mechanistically probing using conditional knockout mice and genome-wide CRISPR-Cas9 screens. Our work also uncovered key secreted molecules made by commensal fungi that activate physiological host receptor pathways. We are now following up on these chemical-genetic screens to understand mechanisms of host detection of fungal contamination of food by the intestine.

哺乳动物的屏障组织(肠道、皮肤、肺)被过多的微生物物种定植，这些微生物在塑造宿主免疫和生理方面发挥着重要作用。虽然到目前为止大多数研究都集中在细菌和病毒上，但真菌越来越被认为是我们共生菌群的重要组成部分。除了共生性，真菌病原体还会给人类带来沉重的疾病负担，导致全球每年3亿人感染和多达150万人死亡。这些感染很难治疗，因为缺乏有效的药物，耐药病原体的出现增加。我们的实验室在微生物学和免疫学的交叉中运作，以了解决定屏障组织中真菌暴露结果的因素。我们的工作采取了结合细胞和分子免疫学、正向遗传学、化学遗传学、基因组学和微生物学的跨学科方法。我们的研究项目探索了对真菌病原体的异常免疫和保护性免疫的潜在机制。在过去的一年里，我们已经确定了在肺部扩张的关键髓系细胞亚群，以应对吸入性真菌感染，并使用遗传小鼠命运图谱工具来跟踪它们的个体发育。我们的实验发现，另一种激活的巨噬细胞通过细胞-外源性免疫抑制机制在真菌感染中发挥有害作用。为了更深入地了解真菌感染期间巨噬细胞免疫抑制的机制，我们使用单细胞RNA-SEQ来识别由肺中离散的巨噬细胞类型表达的候选分子，我们现在正在使用条件基因敲除小鼠和全基因组CRISPR-Cas9筛选进行机械探测。我们的工作还发现了共生真菌制造的激活生理宿主受体途径的关键分泌分子。我们现在正在跟进这些化学基因筛查，以了解宿主检测肠道真菌污染食物的机制。