Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United States.
Department of Medicine, Washington University School of Medicine, St. Louis, United States.
Elife. 2022 Feb 9;11:e74072. doi: 10.7554/eLife.74072.
Interferon-lambda (IFN-λ) protects intestinal epithelial cells (IECs) from enteric viruses by inducing expression of antiviral IFN-stimulated genes (ISGs). Here, we find that bacterial microbiota stimulate a homeostatic ISG signature in the intestine of specific pathogen-free mice. This homeostatic ISG expression is restricted to IECs, depends on IEC-intrinsic expression of IFN-λ receptor (), and is associated with IFN-λ production by leukocytes. Strikingly, imaging of these homeostatic ISGs reveals localization to pockets of the epithelium and concentration in mature IECs. Correspondingly, a minority of mature IECs express these ISGs in public single-cell RNA sequencing datasets from mice and humans. Furthermore, we assessed the ability of orally administered bacterial components to restore localized ISGs in mice lacking bacterial microbiota. Lastly, we find that IECs lacking are hyper-susceptible to initiation of murine rotavirus infection. These observations indicate that bacterial microbiota stimulate ISGs in localized regions of the intestinal epithelium at homeostasis, thereby preemptively activating antiviral defenses in vulnerable IECs to improve host defense against enteric viruses.
干扰素-λ（IFN-λ）通过诱导抗病毒干扰素刺激基因（ISGs）的表达来保护肠上皮细胞（IECs）免受肠病毒感染。在这里，我们发现细菌微生物群会刺激无特定病原体小鼠肠道中的稳态 ISG 特征。这种稳态 ISG 表达仅限于 IECs，依赖于 IEC 固有表达的干扰素-λ受体（），并与白细胞产生 IFN-λ 有关。引人注目的是，对这些稳态 ISGs 的成像显示它们定位于上皮细胞的口袋中，并集中在成熟的 IECs 中。相应地，在来自小鼠和人类的公共单细胞 RNA 测序数据集中，少数成熟的 IEC 表达这些 ISGs。此外，我们评估了口服给予细菌成分在缺乏细菌微生物群的小鼠中恢复局部 ISGs 的能力。最后，我们发现缺乏的 IECs 对启动鼠轮状病毒感染非常敏感。这些观察结果表明，细菌微生物群在肠道上皮的局部区域刺激 ISGs，从而在脆弱的 IECs 中预先激活抗病毒防御，以改善宿主对肠道病毒的防御。
