RNA Sensor-Induced Type I IFN Prevents Diabetes Caused by a β Cell-Tropic Virus in Mice

J Clin Invest. 2011 Apr;121(4):1497-507. doi: 10.1172/JCI44005. Epub 2011 Mar 14.

Abstract

Viral infections have been linked to the onset of type I diabetes (T1D), with viruses postulated to induce disease directly by causing β cell injury and subsequent release of autoantigens and indirectly via the host type I interferon (IFN-I) response triggered by the virus. Consistent with this, resistance to T1D is associated with polymorphisms that impair the function of melanoma differentiation associated gene-5 (MDA5), a sensor of viral RNA that elicits IFN-I responses. In animal models, triggering of another viral sensor, TLR3, has been implicated in diabetes. Here, we found that MDA5 and TLR3 are both required to prevent diabetes in mice infected with encephalomyocarditis virus strain D (EMCV-D), which has tropism for the insulin-producing β cells of the pancreas. Infection of Tlr3-/- mice caused diabetes due to impaired IFN-I responses and virus-induced β cell damage rather than T cell-mediated autoimmunity. Mice lacking just 1 copy of Mda5 developed transient hyperglycemia when infected with EMCV-D, whereas homozygous Mda5-/- mice developed severe cardiac pathology. TLR3 and MDA5 controlled EMCV-D infection and diabetes by acting in hematopoietic and stromal cells, respectively, inducing IFN-I responses at kinetically distinct time points. We therefore conclude that optimal functioning of viral sensors and prompt IFN-I responses are required to prevent diabetes when caused by a virus that infects and damages the β cells of the pancreas.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiovirus Infections / complications
  • Cardiovirus Infections / immunology
  • Cardiovirus Infections / pathology
  • DEAD-box RNA Helicases / deficiency
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / immunology
  • Diabetes Mellitus, Type 1 / etiology
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / prevention & control*
  • Encephalomyocarditis virus / pathogenicity*
  • Insulin-Secreting Cells / virology
  • Interferon Type I / biosynthesis*
  • Interferon-Induced Helicase, IFIH1
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / pathology
  • RNA, Viral / immunology*
  • Toll-Like Receptor 3 / deficiency
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / immunology

Substances

  • Interferon Type I
  • RNA, Viral
  • TLR3 protein, mouse
  • Toll-Like Receptor 3
  • Ifih1 protein, mouse
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1