Investigating mammalian innate immune responses to pathogenic fungi

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

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.