Innate Viral Sensor MDA5 and Coxsackievirus Interplay in Type 1 Diabetes Development

Abstract

<jats:p>Type 1 diabetes (T1D) is a polygenic autoimmune disease characterized by immune-mediated destruction of insulin-producing β-cells. The concordance rate for T1D in monozygotic twins is ≈30–50%, indicating that environmental factors also play a role in T1D development. Previous studies have demonstrated that enterovirus infections such as coxsackievirus type B (CVB) are associated with triggering T1D. Prior to autoantibody development in T1D, viral RNA and antibodies against CVB can be detected within the blood, stool, and pancreata. An innate pathogen recognition receptor, melanoma differentiation-associated protein 5 (MDA5), which is encoded by the IFIH1 gene, has been associated with T1D onset. It is unclear how single nucleotide polymorphisms in IFIH1 alter the structure and function of MDA5 that may lead to exacerbated antiviral responses contributing to increased T1D-susceptibility. Binding of viral dsRNA via MDA5 induces synthesis of antiviral proteins such as interferon-alpha and -beta (IFN-α/β). Viral infection and subsequent IFN-α/β synthesis can lead to ER stress within insulin-producing β-cells causing neo-epitope generation, activation of β-cell-specific autoreactive T cells, and β-cell destruction. Therefore, an interplay between genetics, enteroviral infections, and antiviral responses may be critical for T1D development.</jats:p>

Viruses and Type 1 Diabetes: From Enteroviruses to the Virome

“…Molecular mimicry can occur when viral peptides exhibit high homology to islet peptides, such as similar epitopes expressed between 2C protease of EV and human islet autoantigen GAD-65, with cross reactivity leading to the presentation of viral antigens which activate antiviral or autoreactive T-lymphocytes [ 48 , 102 , 137 ]. Following entry into the host cell, EVs are recognised by pattern recognition receptors including toll-like receptors and melanoma-differentiation associated protein 5 (MDA5) [ 140 ]. This process activates downstream JAK/STAT, NF-kβ and MAPK pathways, resulting in the release of pro-inflammatory cytokines and chemokines [ 141 , 142 ].…”

Immunohistochemical detection of enteroviruses in pancreatic tissues of patients with type 1 diabetes using a polyclonal antibody against 2A protease of Coxsackievirus

“…Finally, the exact relationship between persistent EV infection and the immune-modulatory function of EV-2A pro in type 1 diabetes should be clarified. This is because EV-2A pro cleaves innate immune sensor melanoma differentiation-associated gene 5, mitochondrial antiviral signaling and eukaryotic translation initiation factor, thereby potentially allowing persistent EV infection 6,[22][23][24][25] . The present study provides a new polyclonal antiserum against EV-2A pro that is useful for the detection of EV-2A pro in human tissues stored as archive of FFPE tissue samples.…”

Viruses and Type 1 Diabetes: From Enteroviruses to the Virome

“…Molecular mimicry can occur when viral peptides exhibit high homology to islet peptides, such as similar epitopes expressed between 2C protease of EV and human islet autoantigen GAD-65, with cross reactivity leading to presentation of viral antigens which activate antiviral or autoreactive T-lymphocytes [49,101,136]. Following entry into the host cell, EVs are recognised by pattern recognition receptors (PRRs) including toll-like receptors and melanoma-differentiation associated protein 5 (MDA5) [139]. This process activates downstream JAK/STAT, NF-kβ and MAPK pathways, resulting in the release of pro-inflammatory cytokines and chemokines [140,141].…”