Trained Immunity of Intestinal Tuft Cells Enhances Host Defense against Enteroviral Infections

Intestinal tuft cells are recognized for their crucial roles in the host defense against pathogens, there remains uncertainty regarding their trainability. Enterovirus 71 (EV71), primarily infects children but rarely infects adults. At present, there is a significant expansion of tuft cells in EV71-infected mouse, which is associated with EV71-induced interleukin-25 (IL-25) production. We further found IL-25 pre-treatment at 2 weeks old mouse enabled tuft cells to acquire immune memory. This was evidenced by the rapid expansion and stronger response of IL-25-trained tuft cells in response to EV71 at 6 weeks old, surpassing the reactivity of naïve tuft cells in mice without IL-25-trained progress. Interestingly, IL-25-trained tuft cells exhibit anti-enteroviral effect via producing a higher level of IL-25. Mechanically, IL-25 treatment upregulates spermidine/spermine acetyl-transferase enzyme (SAT1) expression, mediates intracellular polyamine deficiency, further inhibits enterovirus replication. Thus, tuft cells can be trained by IL-25,which supports faster and higher level IL-25 production in response to EV71 and exhibits anti-EV71 effect via SAT1-mediated intracellular polyamine deficiency.It may partially explain the different susceptibility to EV71 between adults and children.