RNA sensor–induced type I IFN prevents diabetes caused by a β cell–tropic virus in mice
Stephen A. McCartney, William Vermi, Silvia Lonardi, Cristina Rossini, Karel Otero, Boris Calderon, Susan Gilfillan, Michael S. Diamond, Emil R. Unanue, Marco Colonna
Stephen A. McCartney, William Vermi, Silvia Lonardi, Cristina Rossini, Karel Otero, Boris Calderon, Susan Gilfillan, Michael S. Diamond, Emil R. Unanue, Marco Colonna
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Research Article Immunology

RNA sensor–induced type I IFN prevents diabetes caused by a β cell–tropic virus in mice

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.

Authors

Stephen A. McCartney, William Vermi, Silvia Lonardi, Cristina Rossini, Karel Otero, Boris Calderon, Susan Gilfillan, Michael S. Diamond, Emil R. Unanue, Marco Colonna

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Figure 4

Stromal MDA5 and hematopoietic cell TLR3 protect against EMCV-D infection.

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Stromal MDA5 and hematopoietic cell TLR3 protect against EMCV-D infectio...
(A and B) BM chimeras were generated between WT and Mda5–/– (n = 10 each) and WT and Tlr3–/– animals (n = 12 each) in 2 independent experiments. Chimeras were infected with 103 PFU of EMCV-D and evaluated for (A) survival and (B) blood glucose. Mda5–/–→WT and WT→Tlr3–/– chimeras survived infection, WT→Mda5–/– chimeras succumbed on day 6, and Tlr3–/–→WT chimeras succumbed on day 14 with 67% surviving infection. (C) MDA5 expression in the pancreas (original magnification, ×200; scale bars: 100 micron). Fixed tissue sections were made from Mda5–/– and WT pancreas on days 0, 2, and 4 after EMCV infection and stained with anti-MDA5 (n = 3). MDA5 is expressed in islets before infection and induced in both islets and exocrine pancreas after infection. (D) TLR3 expression in the pancreas. Frozen tissue sections were made from WT and Tlr3–/– pancreas from uninfected animals (first, second, and fourth panels) or from WT pancreas 12 hours after EMCV infection (third panel). Sections were stained with anti-TLR3 (brown) or costained with anti-TLR3 (brown) and synaptophysin (blue) to visualize expression in the islets (third panel) and are shown at different magnifications as indicated (original magnification, ×200, scale bars: 100 micron; original magnification, ×400, scale bars: 50 micron; original magnification, ×600, scale bars: 33 micron) (n = 3). TLR3 expression is found in the islets as well as in duct epithelial cells, vascular endothelial cells and interstitial stromal cells (arrowheads indicate TLR3+ interstitial cells).