Effects of Type 1 Diabetes-Associated IFIH1 Polymorphisms on MDA5 Function and Expression

Abstract

Recent evidence has highlighted the role of the innate immune system in type 1 diabetes (T1D) pathogenesis. Specifically, aberrant activation of the interferon response prior to seroconversion of T1D-associated autoantibodies supports a role for the interferon response as a precipitating event toward activation of autoimmunity. Melanoma differentiation-associated protein 5 (MDA5), encoded by IFIH1, mediates the innate immune system's interferon response to certain viral species that form double-stranded RNA (dsRNA), the MDA5 ligand, during their life cycle. Extensive research has associated single nucleotide polymorphisms (SNPs) within the coding region of IFIH1 with T1D. This review discusses the different risk and protective IFIH1 alleles in the context of recent structural and functional analysis that relate to MDA5 regulation of interferon responses. These studies have provided a functional hypothesis for IFIH1 T1D-associated SNPs' effects on MDA5-mediated interferon responses as well as supporting the genome-wide association (GWA) studies that first associated IFIH1 with T1D.

Predicting Intra- and Intertypic Recombination in Enterovirus 71

“…We have developed a cell-based assay to study recombination of EV-A71 based upon previously reported assays for poliovirus recombination. Our results show that: (1) EV-A71 strain-type and RNA sequence diversity impacts recombination frequency in a predictable manner that mimics the observations found in nature; (2) recombination is primarily a replicative process mediated by the RNA-dependent RNA polymerase (RdRp); (3) a mutation shown to reduce recombination in PV (L420A) similarly reduces EV-A71 recombination suggesting conservation in mechanism(s); and (4) sequencing of intertypic recombinant genomes indicates that template-switching is by a mechanism that requires some sequence homology at the recombination junction and that the triggers for template-switching may be sequence independent. The development of this recombination assay will permit further investigation on the interplay between replication, recombination and disease.…”

“…This group of viruses, typified by poliovirus, has a 7.5 kb positive-sense RNA genome that encodes a single polyprotein that is flanked by non-coding regions (NCR). The polyprotein is co- and post-translationally processed by virus-encoded proteases to generate the structural proteins (VP4, VP2, VP3 and VP1), which assemble to form the icosahedral capsid and the non-structural proteins (2A pro , 2B, 2C, 3A, 3B VPg , 3C pro and 3D pol ) that mediate replication of the virus genome (2, 3).…”

Coxsackievirus B Tailors the Unfolded Protein Response to Favour Viral Amplification in Pancreatic β Cells

“…Polymorphisms in IFIH1 are associated with T1D. [10, 11]. Enterovirus, especially coxsackievirus B (CVB) [12], have a tropism for pancreatic β cells, and persistent CVB infection of β cells is detected in 60–70% of pancreases from T1D individuals compared to only 6% in non-diabetic individuals [13].…”

Association between interferon-induced helicase (IFIH1 ) rs1990760 polymorphism and seasonal variation in the onset of type 1 diabetes mellitus

“…Previously, we described that this relatively common polymorphism is associated with T1DM both in the high‐incidence Finnish and medium‐incidence Hungarian populations (G allele [vs A allele] was significantly associated with the decreasing risk of T1DM [odds ratio 0.81 with 95% confidence interval CI of 0.71‐0.92]) . Other investigations and meta‐analyses also indicated that an association between IFIH1 rs1990760 polymorphism and T1DM exists and carriers of the minor G allele might truly have a modest protection for T1DM, primarily in the Caucasian population . The exact mechanism of the observed association has remained to be determined so far …”

“…9 Other investigations and meta-analyses also indicated that an association between IFIH1 rs1990760 polymorphism and T1DM exists and carriers of the minor G allele might truly have a modest protection for T1DM, primarily in the Caucasian population. [10][11][12][13][14] The exact mechanism of the observed association has remained to be determined so far. 15,16 Undoubtedly, the genetic architecture of T1DM is complex and, besides IFIH1 polymorphisms, other gene variants may contribute to diabetes manifestation.…”