Abstract
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-α and IFN-ß resulting in different disease outcomes. Specifically, infection with a diabetogenic islet β 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.
Highlights
As is commonly described for most autoimmune diseases, type 1 diabetes (T1D) is a disease that results from changes in specific genes, disruption in the balance of immune responses, and exposure to environmental agents like viruses [1,2,3]
To better understand how immune pathologies like IFN-I responses that result from melanoma differentiation-associated protein 5 (MDA5) and toll-like receptor- 3 (TLR3) signaling influence T1D development, we challenged heterozygous NOD mice that retained MDA5 and TLR3 function with known diabetes and IFN-I inducers like coxsackievirus B4 (CB4)
With our MDA5+/- and TLR3+/- CB4-infection models, we have identified, using a virus clinically linked to T1D, how changes in MDA5 and not TLR3 signaling are critical in producing an IFN-I response and subsequent adaptive responses that protect from T1D
Summary
As is commonly described for most autoimmune diseases, type 1 diabetes (T1D) is a disease that results from changes in specific genes, disruption in the balance of immune responses, and exposure to environmental agents like viruses [1,2,3]. Not included as type 1 interferonopathies, organ-specific autoimmune diseases such as T1D have been strongly associated with upregulation of the type 1 interferon (IFN-I) response. Patients with insulitis-affected islets have an overexpression of interferonstimulated genes (ISGs), comparable to responses seen in islets infected with virus or treated with inflammatory agents like IFN-a or IFN-g [7, 8]. Included in the overexpressed ISGs identified in MDA5, TLR3, Virus and Diabetes
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