Elucidating astrovirus egress and the effects of infection on gut homeostasis

PROJECT SUMMARY Pediatric diarrhea is the second leading cause of infant mortality worldwide. Astroviruses are one of the most common childhood causes of diarrheal illness, with infants at risk for severe disease and hospitalization. However, astroviruses are very understudied in part due to inadequate diagnostic testing, and consequently, little is known about their pathogenesis. Recent work has shown that astrovirus targets mucus-secreting goblet cells in the small intestine. These cells generate the critical mucus layer that shields the gut epithelium from pathogens and provides a habitat for commensal microbes. However, it is unknown how astroviruses replicate inside goblet cells and how infection impacts the cell’s ability to maintain homeostasis. Therefore, the long- term objective of my research is to define how astrovirus impacts the mucosal barrier to better understand its pathogenesis. This proposal approaches this objective by utilizing infection models in mice as well as enteroids. Our murine model will allow us to better understand the viral mechanisms at play, which will then be applied to understanding human infections. The central issue that my proposal addresses is: defining how mucus secretion is linked to astrovirus release from goblet cells and how hijacking of the secretory pathway results in functional consequences for the host. Completion of the proposed studies will shed light on a critical step in the astrovirus replication cycle and define how astroviruses cause disease based on their impact on the mucosal barrier, which could have broader impacts on gut health during early childhood development. Furthermore, my proposed training will expand my knowledge of virology and cell biology and provide me with the technical tools essential to establish myself as an independent researcher and fufill my future career goals.