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Single-cell sequencing of rotavirus-infected intestinal epithelium reveals cell-type specific epithelial repair and tuft cell infection

Significance Rotavirus infects enterocytes at the tips of intestinal villi, leading to damage. Single-cell RNA sequencing of the infected murine intestinal epithelium reveals broad responses, including expansion of the stem cell and immature enterocyte populations. Subsets of stem cells enter the cell cycle more frequently, resulting in production of more enterocytes to compensate for damaged enterocytes at the villus tip. The presence of viral transcripts in tuft cells and evidence of tuft cell transcriptional activation suggests that tuft cells contribute important signals to the epithelial response following damage. Until now the mechanism of repair following viral damage in the intestinal epithelium has remained uncharacterized. We find that intestinal regeneration and repair require cooperation of several specialized epithelial cells. Intestinal epithelial damage is associated with most digestive diseases and results in detrimental effects on nutrient absorption and production of hormones and antimicrobial defense molecules. Thus, understanding epithelial repair and regeneration following damage is essential in developing therapeutics that assist in rapid healing and restoration of normal intestinal function. Here we used a well-characterized enteric virus (rotavirus) that damages the epithelium at the villus tip but does not directly damage the intestinal stem cell, to explore the regenerative transcriptional response of the intestinal epithelium at the single-cell level. We found that there are specific Lgr5+ cell subsets that exhibit increased cycling frequency associated with significant expansion of the epithelial crypt. This was accompanied by an increase in the number of immature enterocytes. Unexpectedly, we found rotavirus infects tuft cells. Transcriptional profiling indicates tuft cells respond to viral infection through interferon-related pathways. Together these data provide insights as to how the intestinal epithelium responds to insults by providing evidence of stimulation of a repair program driven by stem cells with involvement of tuft cells that results in the production of immature enterocytes that repair the damaged epithelium.