Hou Gaopeng, Son Juhee, Gomez Castro Maria Florencia, Kawagishi Takahiro, Ren Xingxing, Roth Alexa N, Antia Avan, Zeng Qiru, DeVeaux Anna L, Feng Ningguo, Kohio Hinissan P, Baldridge Megan T, Dermody Terence S, Zhu Shu, Ding Siyuan
Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Cell Host Microbe. 2025 Mar 12;33(3):408-419.e8. doi: 10.1016/j.chom.2025.02.005. Epub 2025 Mar 3.
Diarrhea is the predominant symptom of acute gastroenteritis resulting from enteric infections and a leading cause of death in infants and young children. However, the role of the host response in diarrhea pathogenesis is unclear. Using rotavirus and neonatal mice as a model, we found that oral inoculation of UV-inactivated replication-defective rotavirus consistently induced watery diarrhea by robust activation of cytosolic double-stranded RNA sensing pathways and type III interferon (IFN-λ) secretion. Diarrhea was significantly diminished in mice lacking the IFN-λ receptor. Mechanistically, IFN-λ signaling downregulates the expression of Dra, a chloride and bicarbonate exchanger, which contributes to reduced water absorption. We confirmed these findings in mice inoculated with reovirus, as well as in donor-derived human intestinal organoids and human biopsy samples. Our data highlight a mechanism of rapid diarrhea induction by host innate immune sensing in the gastrointestinal tract and suggest that diarrhea induction is an active host defense strategy to eliminate the pathogen.
腹泻是由肠道感染引起的急性肠胃炎的主要症状，也是婴幼儿死亡的主要原因。然而，宿主反应在腹泻发病机制中的作用尚不清楚。我们以轮状病毒和新生小鼠为模型，发现口服紫外线灭活的复制缺陷型轮状病毒通过强烈激活胞质双链RNA传感途径和III型干扰素（IFN-λ）分泌，持续诱发水样腹泻。在缺乏IFN-λ受体的小鼠中，腹泻明显减轻。从机制上讲，IFN-λ信号下调了Dra（一种氯化物和碳酸氢盐交换体）的表达，这导致水吸收减少。我们在用呼肠孤病毒接种的小鼠以及供体来源的人肠道类器官和人活检样本中证实了这些发现。我们的数据突出了胃肠道中宿主先天免疫感应快速诱发腹泻的机制，并表明腹泻诱发是一种消除病原体的主动宿主防御策略。
