Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Virol. 2018 Apr 27;92(10). doi: 10.1128/JVI.02062-17. Print 2018 May 15.
Several viruses induce intestinal epithelial cell death during enteric infection. However, it is unclear whether proapoptotic capacity promotes or inhibits replication in this tissue. We infected mice with two reovirus strains that infect the intestine but differ in the capacity to alter immunological tolerance to new food antigen. Infection with reovirus strain T1L, which induces an inflammatory immune response to fed antigen, is prolonged in the intestine, whereas T3D-RV, which does not induce this response, is rapidly cleared from the intestine. Compared with T1L, T3D-RV infection triggered apoptosis of intestinal epithelial cells and subsequent sloughing of dead cells into the intestinal lumen. We conclude that the infection advantage of T1L derives from its capacity to subvert host restriction by epithelial cell apoptosis, providing a possible mechanism by which T1L enhances inflammatory signals during antigen feeding. Using a panel of T1L × T3D-RV reassortant viruses, we identified the viral M1 and M2 gene segments as determinants of reovirus-induced apoptosis in the intestine. Expression of the T1L M1 and M2 genes in a T3D-RV background was sufficient to limit epithelial cell apoptosis and enhance viral infection to levels displayed by T1L. These findings define additional reovirus gene segments required for enteric infection of mice and illuminate the antiviral effect of intestinal epithelial cell apoptosis in limiting enteric viral infection. Viral strain-specific differences in the capacity to infect the intestine may be useful in identifying viruses capable of ameliorating tolerance to fed antigen in autoimmune conditions like celiac disease. Acute viral infections are thought to be cleared by the host with few lasting consequences. However, there may be much broader and long-lasting effects of viruses on immune homeostasis. Infection with reovirus, a common, nonpathogenic virus, triggers inflammation against innocuous food antigens, implicating this virus in the development of celiac disease, an autoimmune intestinal disorder triggered by exposure to dietary gluten. Using two reovirus strains that differ in the capacity to abrogate oral tolerance, we found that strain-specific differences in the capacity to replicate in the intestine inversely correlate with the capacity to induce apoptotic death of intestinal epithelial cells, providing a host-mediated process to restrict intestinal infection. This work contributes new knowledge about virus-host interactions in the intestine and establishes a foundation for future studies to define mechanisms by which viruses break oral tolerance in celiac disease.
几种病毒在肠道感染过程中诱导肠上皮细胞死亡。然而，促凋亡能力是否促进或抑制该组织中的复制尚不清楚。我们用两种能感染肠道但改变对新食物抗原免疫耐受能力不同的呼肠孤病毒株感染小鼠。感染能诱导对喂养抗原产生炎症免疫反应的 T1L 病毒株的肠道感染时间延长，而不诱导这种反应的 T3D-RV 病毒株则迅速从肠道清除。与 T1L 相比，T3D-RV 感染引发肠上皮细胞凋亡，并导致死亡细胞脱落到肠腔中。我们的结论是，T1L 的感染优势源于其颠覆上皮细胞凋亡对宿主限制的能力，这为 T1L 在抗原喂养过程中增强炎症信号提供了一种可能的机制。利用一组 T1L×T3D-RV 重组病毒，我们确定了病毒 M1 和 M2 基因片段是呼肠孤病毒诱导肠道细胞凋亡的决定因素。在 T3D-RV 背景下表达 T1L 的 M1 和 M2 基因足以限制上皮细胞凋亡并增强病毒感染，使其达到 T1L 显示的水平。这些发现定义了呼肠孤病毒感染小鼠所必需的其他基因片段，并阐明了肠上皮细胞凋亡在限制肠道病毒感染中的抗病毒作用。肠道感染能力方面的病毒株特异性差异可用于鉴定在乳糜泻等自身免疫性疾病中能够改善对喂养抗原耐受的病毒。宿主通常可以清除急性病毒感染，而不会产生持久的后果。然而，病毒对免疫稳态的影响可能更广泛、更持久。一种常见的非致病性病毒呼肠孤病毒的感染会引发针对无害食物抗原的炎症，这表明该病毒与乳糜泻的发展有关，乳糜泻是一种由暴露于膳食谷蛋白引起的自身免疫性肠道疾病。我们使用两种在破坏口服耐受性能力方面存在差异的呼肠孤病毒株，发现肠道内复制能力的株间差异与诱导肠上皮细胞凋亡死亡的能力呈负相关，为限制肠道感染提供了一种宿主介导的过程。这项工作为肠道中病毒-宿主相互作用提供了新知识，并为未来研究确定病毒在乳糜泻中破坏口服耐受性的机制奠定了基础。
