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Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection

Brown, Judy J. and Short, Sarah P. and Stencel-Baerenwald, Jennifer and Urbanek, Kelly and Pruijssers, Andrea J. and McAllister, Nicole and Ikizler, Mine and Taylor, Gwen and Aravamudhan, Pavithra and Khomandiak, Solomiia and Jabri, Bana and Williams, Christopher S. and Dermody, Terence S. (2018) Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection. Journal of Virology, 92 (10). Art. No. e02062-17. ISSN 0022-538X. PMCID PMC5923068.

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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.

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Additional Information:© 2018 American Society for Microbiology. Received 27 November 2017. Accepted 23 February 2018. Accepted manuscript posted online 7 March 2018. We thank members of the Dermody laboratory for helpful discussions and critical review of the manuscript and Brian Leibowitz for experimental expertise in intestinal apoptosis. We thank the Vanderbilt University and University of Pittsburgh Divisions of Animal Care for animal husbandry and Kay Washington for assistance with histological analyses. Histological slides were prepared by the Vanderbilt Translational Pathology Shared Resource, supported by Cancer Center support grant P30 CA068485 and the Vanderbilt Mouse Metabolic Phenotyping Center grant U24 DK059637. Whole-slide imaging and quantification of immunostaining were conducted in the Digital Histology Shared Resource at Vanderbilt University Medical Center ( This work was supported by United States Public Health Service awards T32 HL007751 and F31 DK108562 (J.J.B.) and R01 DK098435 (B.J. and T.S.D.). Additional support was provided by the Elizabeth B. Lamb Center for Pediatric Research.
Funding AgencyGrant Number
NIH Predoctoral FellowshipT32 HL007751
NIH Postdoctoral FellowshipF31 DK108562
NIHR01 DK098435
Elizabeth B. Lamb Center for Pediatric ResearchUNSPECIFIED
Subject Keywords:apoptosis; cell death; enteroid; gastrointestinal infection; mucosal immunity; reovirus
Issue or Number:10
PubMed Central ID:PMC5923068
Record Number:CaltechAUTHORS:20180523-132945504
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Official Citation:Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection Judy J. Brown, Sarah P. Short, Jennifer Stencel-Baerenwald, Kelly Urbanek, Andrea J. Pruijssers, Nicole McAllister, Mine Ikizler, Gwen Taylor, Pavithra Aravamudhan, Solomiia Khomandiak, Bana Jabri, Christopher S. Williams, and Terence S. Dermody J. Virol. May 2018 92:10 17 e02062-17; Accepted manuscript posted online 7 March 2018, doi:10.1128/JVI.02062-17
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:86568
Deposited By: Tony Diaz
Deposited On:24 May 2018 16:27
Last Modified:03 Oct 2019 19:45

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