Type I Interferon and the Spectrum of Susceptibility to Viral Infection and Autoimmune Disease: A Shared Genomic Signature

Abstract

Type I interferons (IFN-I) and their cognate receptor, the IFNAR1/2 heterodimer, are critical components of the innate immune system in humans. They have been widely explored in the context of viral infection and autoimmune disease where they play key roles in protection against infection or shaping disease pathogenesis. A false dichotomy has emerged in the study of IFN-I where interferons are thought of as either beneficial or pathogenic. This ‘good or bad’ viewpoint excludes more nuanced interpretations of IFN-I biology - for example, it is known that IFN-I is associated with the development of systemic lupus erythematosus, yet is also protective in the context of infectious diseases and contributes to resistance to viral infection. Studies have suggested that a shared transcriptomic signature underpins both potential resistance to viral infection and susceptibility to autoimmune disease. This seems to be particularly evident in females, who exhibit increased viral resistance and increased susceptibility to autoimmune disease. The molecular mechanisms behind such a signature and the role of sex in its determination have yet to be precisely defined. From a genomic perspective, several single nucleotide polymorphisms (SNPs) in the IFN-I pathway have been associated with both infectious and autoimmune disease. While overlap between infection and autoimmunity has been described in the incidence of these SNPs, it has been overlooked in work and discussion to date. Here, we discuss the possible contributions of IFN-Is to the pathogenesis of infectious and autoimmune diseases. We comment on genetic associations between common SNPs in IFN-I or their signalling molecules that point towards roles in protection against viral infection and susceptibility to autoimmunity and propose that a shared transcriptomic and genomic immunological signature may underlie resistance to viral infection and susceptibility to autoimmunity in humans. We believe that defining shared transcriptomic and genomic immunological signatures underlying resistance to viral infection and autoimmunity in humans will reveal new therapeutic targets and improved vaccine strategies, particularly in females.

Transcriptome Sequencing Reveals Salmonella Flagellin Activation of Interferon-β-Related Immune Responses in Macrophages

“…In particular, the expression of type I IFN (IFN-β) was significantly upregulated by flagellin stimulation of RAW264.7 cells, which was verified by qRT-PCR. Type I IFN binds to the interferon α/β receptor and induces the expression of more than 300 ISGs through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway [ 43 ]. Our RNA-Seq analysis revealed that various ISGs were significantly upregulated in expression in FliC-treated RAW264.7 cells, including those encoding the myxovirus resistance proteins (Mx1 and Mx2), the IFIT family (IFIT1, IFIT2, and IFIT3b), and IRF3-dependent ISGs (ISG15, ISG20, OAS1b, etc).…”

Uncovering Resistance to Hepatitis C Virus Infection: Scientific Contributions and Unanswered Questions in the Irish Anti-D Cohort

“…The nature of this outbreak, wherein all HCV-exposed individuals were pregnant females, potentially limits the extrapolation of findings from the cohort to other less homogenous groups. Several sex differences in the immune systems of males and females were described, including in Toll-like receptor (TLR) expression, the type I IFN system, and the ability to spontaneously resolve HCV infection [ 71 , 72 , 73 , 74 ]. Given the Irish anti-D cohort are all female, phenotypes described using data from these donors may not apply directly to HCV-exposed males.…”

A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes

“…Other pathway regulators have also been shown to have variants causing IEI such as JAK1, TYK2, IFNAR1, and IFNAR2 [63][64][65]. While IEI have been thought to be rare, common single nucleotide polymorphisms (SNPs) have also been found in TYK2 and IFNAR1 and are associated with improved protection from infection as well as increased risk of autoimmunity [66]. The prevalence of such SNPs may account for a wide range of IFN pathway responses among individuals [67,68].…”