Modeling Host-Fungal Interactions in Hirschsprung-Associated Enterocolitis

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Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of Hirschsprung Disease (HSCR), a common cause of intestinal obstruction in the newborn. HAEC affects 30-60% of infants with HSCR and carries a mortality of 5-10%, with the majority of deaths occurring in newborns prior to definitive operation. A critical barrier in the field is that the etiology of HAEC is poorly defined and current treatment remains empiric (bowel rest, rectal washouts, broad-spectrum antibiotics) and directed toward alleviating acute symptoms rather than targeting underlying pathophysiology. The long-term goal of our research is to define the pathophysiology of HAEC and develop novel therapeutic approaches that reduce morbidity and mortality in HSCR patients. Our prior investigations and those of other groups, utilizing mouse models of HSCR/HAEC as well as human HSCR/HAEC patient samples, have associated a dysbiotic microbiota with the development of HAEC but have not directly tested causation or identified targetable molecular mechanisms to prevent or treat the disease. While almost exclusive focus has been placed on gut bacteria (microbiome), other microbial kingdoms contribute to the diverse intestinal community, including fungal yeast and molds (mycobiome), but these have largely been overlooked. Here, we propose a focused investigation of the mucosal barrier responses, including IgA/IgG and epithelial defense, to fungal pathogens in HSCR/HAEC patient and murine disease specific tissues. Our central hypothesis that aberrant mucosal immune responses to fungal pathobionts trigger HAEC inflammatory episodes. Our objectives are to 1) identify the disease-promoting members of the dysbiotic HAEC mycobiome and 2) define the normal and HAEC mucosal immune response to fungal pathobionts to understand etiological triggers and targets. We are approaching this problem through a synergistic and long-standing collaboration between the MPIs laboratories. The proposed research is innovative because it will utilize novel, preclinical models to establish a causative relationship between dysbiosis of the mycobiome and HAEC pathogenesis. Our group is uniquely qualified to complete the aims because of our expertise in HSCR/HAEC, host-pathogen interactions, gnotobiotic expertise, and mucosal immunology. The expected outcome of these studies will be a deeper understanding of HAEC pathophysiology and identification of novel targets for prevention or treatment of HAEC.