Bacterial flagellin can elicit production of TLR5-mediated IL-22 and NLRC4-mediated IL-18 cytokines that act in concert to cure and prevent rotavirus (RV) infection. This study investigated the mechanism by which these cytokines act to impede RV. Although IL-18 and IL-22 induce each other’s expression, we found that IL-18 and IL-22 both impeded RV independently of one another and did so by distinct mechanisms that involved activation of their cognate receptors in intestinal epithelial cells (IEC). IL-22 drove IEC proliferation and migration toward villus tips, which resulted in increased extrusion of highly differentiated IEC that serve as the site of RV replication. In contrast, IL-18 induced cell death of RV-infected IEC thus directly interrupting the RV replication cycle, resulting in spewing of incompetent virus into the intestinal lumen and causing a rapid drop in the number of RV-infected IEC. Together, these actions resulted in rapid and complete expulsion of RV, even in hosts with severely compromised immune systems. These results suggest that a cocktail of IL-18 and IL-22 might be a means of treating viral infections that preferentially target short-lived epithelial cells.

细菌鞭毛蛋白可以引发 TLR5 介导的 IL-22 和 NLRC4 介导的 IL-18 细胞因子的产生，这些细胞因子协同作用以治愈和预防轮状病毒 (RV) 感染。这项研究调查了这些细胞因子阻碍 RV 的机制。尽管 IL-18 和 IL-22 相互诱导表达，但我们发现 IL-18 和 IL-22 均彼此独立地阻碍 RV，并且通过涉及肠上皮细胞 (IEC) 中同源受体激活的不同机制来实现这一点。 IL-22 促进 IEC 增殖并向绒毛尖端迁移，从而导致高度分化的 IEC（作为 RV 复制位点）的挤出增加。相反，IL-18诱导RV感染的IEC细胞死亡，从而直接中断RV复制周期，导致无活性的病毒喷入肠腔，导致RV感染的IEC数量迅速下降。这些行动共同导致了 RV 的快速、完全排出，即使是在免疫系统严重受损的宿主中也是如此。这些结果表明，IL-18 和 IL-22 的混合物可能是治疗优先针对短寿命上皮细胞的病毒感染的一种方法。