{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T08:53:56Z","timestamp":1790326436997,"version":"4.1.0"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T00:00:00Z","timestamp":1636070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Seemingly redundant in function, melanoma differentiation-associated protein 5 (MDA5) and toll-like receptor- 3 (TLR3) both sense RNA viruses and induce type I interferon (IFN-I). Herein, we demonstrate that changes in sensing of the same virus by MDA5 and TLR3 can lead to distinct signatures of IFN-\u03b1 and IFN-\u00df resulting in different disease outcomes. Specifically, infection with a diabetogenic islet \u03b2 cell-tropic strain of coxsackievirus (CB4) results in diabetes protection under reduced MDA5 signaling conditions while reduced TLR3 function retains diabetes susceptibility. Regulating the induction of IFN-I at the site of virus infection creates a local site of interferonopathy leading to loss of T cell regulation and induction of autoimmune diabetes. We have not demonstrated another way to prevent T1D in the NOD mouse, rather we believe this work has provided compounding evidence for a specific control of IFN-I to drive a myriad of responses ranging from virus clearance to onset of autoimmune diabetes.<\/jats:p>","DOI":"10.3389\/fimmu.2021.751341","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T06:46:09Z","timestamp":1636094769000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Changes in MDA5 and TLR3 Sensing of the Same Diabetogenic Virus Result in Different Autoimmune Disease Outcomes"],"prefix":"10.3389","volume":"12","author":[{"given":"Pamela J.","family":"Lincez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iryna","family":"Shanina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc S.","family":"Horwitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/microorganisms8070993","article-title":"Innate Viral Sensor MDA5 and Coxsackievirus Interplay in Type 1 Diabetes Development","volume":"8","author":"Blum","year":"2020","journal-title":"Microorganisms"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/db14-0510","article-title":"Is Type 1 Diabetes \u201cGoing Viral","volume":"63","author":"Richardson","year":"2014","journal-title":"Diabetes"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2017.00249","article-title":"Innate Viral Receptor Signaling Determines Type 1 Diabetes Onset","volume":"8","author":"Morse","year":"2017","journal-title":"Front Endocrinol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.coph.2018.07.006","article-title":"Enteroviral Infections in the Pathogenesis of Type 1 Diabetes: New Insights for Therapeutic Intervention","volume":"43","author":"Richardson","year":"2018","journal-title":"Curr Opin Pharmacol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11892-018-1084-3","article-title":"Pancreas Pathology During the Natural History of Type 1 Diabetes","volume":"18","author":"Rodriguez-Calvo","year":"2018","journal-title":"Curr Diabetes Rep"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.2337\/db13-1777","article-title":"A Type I Interferon Transcriptional Signature Precedes Autoimmunity in Children Genetically at Risk for Type 1 Diabetes","volume":"63","author":"Ferreira","year":"2014","journal-title":"Diabetes"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0616","article-title":"Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes","volume":"65","author":"Lundberg","year":"2016","journal-title":"Diabetes"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.12.032","article-title":"Parsing the Interferon Transcriptional Network and Its Disease Associations","volume":"164","author":"Mostafavi","year":"2016","journal-title":"Cell"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/microorganisms8071031","article-title":"Immune Transcriptome of Cells Infected With Enterovirus Strains Obtained From Cases of Type 1 Diabetes","volume":"8","author":"Poma","year":"2020","journal-title":"Microorganisms"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nm0798-781","article-title":"Diabetes Induced by Coxsackie Virus: Initiation by Bystander Damage and Not Molecular Mimicry","volume":"4","author":"Horwitz","year":"1998","journal-title":"Nat Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00631-09","article-title":"MDA5 and MAVS Mediate Type I Interferon Responses to Coxsackie B Virus","volume":"84","author":"Wang","year":"2010","journal-title":"J Virol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0004127","article-title":"Toll-Like Receptor 3 Signalling on Macrophages Is Required for Survival Following Coxsackievirus B4 Infection","volume":"4","author":"Richer","year":"2009","journal-title":"PLoS One"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2337\/db14-1223","article-title":"Reduced Expression of the MDA5 Gene IFIH1 Prevents Autoimmune Diabetes","volume":"64","author":"Lincez","year":"2015","journal-title":"Diabetes"},{"key":"B14","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1189\/jlb.0311166","article-title":"TLR7\/9 Versus TLR3\/MDA5 Signaling During Virus Infections and Diabetes","volume":"90","author":"Swiecki","year":"2011","journal-title":"J Leukoc Biol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44005","article-title":"RNA Sensor-Induced Type I IFN Prevents Diabetes Caused by A ?? 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