Cytosolic D‐type CpG‐oligonucleotides induce a type i interferon response by activating the cGAS‐STING signaling pathway

Abstract Background Inflammation is a key contributor of neuronal death and dysfunction following traumatic brain injury (TBI). Recent evidence suggests that interferons may be a key regulator of this response. Our studies evaluated the role of the Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes (cGAS-STING) signaling pathway a murine model of TBI. Methods Male, eight-week old wildtype, STING knockout ( -/- ), cGAS -/- , and NLRX1 -/- mice were subjected to controlled cortical impact (CCI) or sham injury. Histopathological evaluation of tissue damage was assessed using non-biased stereology, which was complemented by analysis at the mRNA and protein level using qPCR and western blot analysis, respectively. Results We found that STING and Type I interferon-stimulated genes were upregulated after CCI injury in a bi-phasic manner and that loss of cGAS or STING conferred neuroprotection concomitant with a blunted inflammatory response at 24 hours post-injury. cGAS -/- animals showed reduced motor deficit 4 days after injury (dpi), and amelioration of tissue damage was seen in both groups of mice up to 14 dpi. Given that cGAS requires a cytosolic damage- or pathogen- associated molecular pattern (DAMP/PAMP) to prompt downstream STING signaling, we further show that mitochondrial DNA is present in the cytosol after TBI. Finally, our findings demonstrate that NLRX1 may be an additional regulator that functions upstream to regulate cGASSTING pathway. Conclusions These findings suggest that the canonical cGAS-STING-mediated Type I interferon signaling axis is a critical component of neural tissue damage following TBI and that mtDNA may be a possible trigger in this response.

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Faculty Opinions recommendation of Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1104493.560531 ◽

2008 ◽

Author(s):

Ann Hill

Keyword(s):

B Cells ◽

Type I Interferon ◽

Interferon Response ◽

Type I

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Faculty Opinions recommendation of USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726829800.793527398 ◽

2017 ◽

Author(s):

Benedict Michael ◽

Mark Ellul

Keyword(s):

Type I Interferon ◽

Interferon Response ◽

Type I

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Viral Invasion and Type I Interferon Response Characterize the Immunophenotypes during COVID-19 Infection

SSRN Electronic Journal ◽

10.2139/ssrn.3555695 ◽

2020 ◽

Cited By ~ 8

Author(s):

Lai Wei ◽

Siqi Ming ◽

Bin Zou ◽

Yongjian Wu ◽

Zhongsi Hong ◽

...

Keyword(s):

Type I Interferon ◽

Interferon Response ◽

Type I

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Positive natural selection in primate genes of the type I interferon response

BMC Ecology and Evolution ◽

10.1186/s12862-021-01783-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Elena N. Judd ◽

Alison R. Gilchrist ◽

Nicholas R. Meyerson ◽

Sara L. Sawyer

Keyword(s):

Natural Selection ◽

Positive Selection ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Sequence Alignments ◽

Multiple Sequence ◽

Multiple Sequence Alignments ◽

Interferon Stimulated Genes ◽

Interferon Induction

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

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