Investigating mammalian innate immune responses to pathogenic fungi

哺乳动物的屏障组织（肠道、皮肤、肺）被大量的微生物物种定殖，这些微生物物种在形成宿主免疫和生理学方面发挥重要作用。虽然迄今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植物植物群的重要组成部分。除真菌外，真菌病原体还造成人类高疾病负担，导致全球每年3亿例感染和多达150万例死亡。由于缺乏有效的药物和耐药病原体的增加，这些感染很难治疗。我们的实验室在微生物学和免疫学的交叉点运作，以了解决定屏障组织真菌暴露结果的因素。我们的工作采取跨学科的方法，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。我们的研究项目探讨了对真菌病原体的异常免疫与保护性免疫的机制。在过去的一个财政年度里，我们已经确定了在肺部对吸入性真菌感染做出反应时扩增的关键骨髓细胞亚群，并使用遗传小鼠命运映射工具来跟踪它们的个体发育。我们的实验已经发现，交替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来鉴定肺中离散巨噬细胞类型表达的候选分子，我们现在正在使用条件性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由真菌产生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遗传筛选，以了解肠道真菌污染食物的宿主检测机制。

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.