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

Figures

• 

  Figure 1. Model of coxsackievirus type B (CVB)-induced type 1 diabetes (T1D). (A) Coxsackievirus binds to the Coxsackievirus and Adenovirus Receptor (CAR) on the β-cell leading to β-cell infection, cellular dysregulation, interferon-alpha and -beta (IFN-α/β) synthesis, and generation of neo-epitopes. Phagocytosis and presentation of neo-epitopes by antigen-presenting cells (APCs) leads to the activation of autoreactive CD4 and CD8 T cells. (B) CVB dissemination leads to the generation and differentiation of CVB-specific CD4 and CD8 T cells. Both CD4 and CD8 T cells will gain effector responses, CD4 T cells will produce ROS and IFN-γ. Whereas, CD8 T cells will produce ROS, perforin, and granzyme B targeting infected β-cells and acinar cells, while APCs will concomitantly produce ROS, IFN-α/β, and TNF to promote viral clearance and immune cell activation. (C) The proinflammatory response to CVB infection and generation of IFN-α/β and IFN-γ leads to the loss of Treg peripheral tolerance. Subsequent activation of proinflammatory APCs and autoreactive CD4 and CD8 T cells further propagate CVB-induced T1D.

• 

  Figure 2. Diagram of melanoma differentiation-associated protein 5 (MDA5) functional domains and IFIH1 single nucleotide polymorphisms (SNPs). ↑↑ indicates increased functionality, whereas ↓↓ indicates decreased functionality. The N-terminal CARD domains of MDA5 are located between amino acid residues 8–201, with no known SNPs in MDA5 associated with T1D. The helicase domains in MDA5 are located between residues 305–873, containing helicase sub-domains Hel1, Hel2i, Hel2, and a pincer domain. The Hel1 subdomain comprises of amino acid residues 305–491, Hel2i subdomain contains amino acids 548–694, and the Hel2 subdomain is located at amino acid positions 698–823. The T1D protective E627x SNP is located within the Hel2i subdomain. The pincer domain is located within the main helicase domain of residues 824–873 and contains the R843H SNP associated with T1D susceptibility. Finally, the C-terminal domain (CTD) located between residues 900–1015 contains both SNPS I923V and A946T associated with both T1D protection and risk, respectively.