Faculty Collaboration Database

Polymorphisms in STING Affect Human Innate Immune Responses to Poxviruses. Front Immunol 2020;11:567348

Date

11/07/2020

Pubmed ID

33154747

Pubmed Central ID

PMC7591719

DOI

10.3389/fimmu.2020.567348

Scopus ID

2-s2.0-85094566648 (requires institutional sign-in at Scopus site)   22 Citations

Abstract

We conducted a large genome-wide association study (GWAS) of the immune responses to primary smallpox vaccination in a combined cohort of 1,653 subjects. We did not observe any polymorphisms associated with standard vaccine response outcomes (e.g., neutralizing antibody, T cell ELISPOT response, or T cell cytokine production); however, we did identify a cluster of SNPs on chromosome 5 (5q31.2) that were significantly associated (p-value: 1.3 x 10^-12 - 1.5x10^-36) with IFNα response to in vitro poxvirus stimulation. Examination of these SNPs led to the functional testing of rs1131769, a non-synonymous SNP in TMEM173 causing an Arg-to-His change at position 232 in the STING protein-a major regulator of innate immune responses to viral infections. Our findings demonstrate differences in the ability of the two STING variants to phosphorylate the downstream intermediates TBK1 and IRF3 in response to multiple STING ligands. Further downstream in the STING pathway, we observed significantly reduced expression of type I IFNs (including IFNα) and IFN-response genes in cells carrying the H232 variant. Subsequent molecular modeling of both alleles predicted altered ligand binding characteristics between the two variants, providing a potential mechanism underlying differences in inter-individual responses to poxvirus infection. Our data indicate that possession of the H232 variant may impair STING-mediated innate immunity to poxviruses. These results clarify prior studies evaluating functional effects of genetic variants in TMEM173 and provide novel data regarding genetic control of poxvirus immunity.

Author List

Kennedy RB, Haralambieva IH, Ovsyannikova IG, Voigt EA, Larrabee BR, Schaid DJ, Zimmermann MT, Oberg AL, Poland GA

Author

Michael T. Zimmermann PhD Director, Associate Professor in the Data Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alleles
Disease Susceptibility
Founder Effect
Gene Expression
Genome-Wide Association Study
Genotype
Host-Pathogen Interactions
Humans
Immunity, Innate
Immunogenetic Phenomena
Ligands
Membrane Proteins
Models, Biological
Phosphorylation
Polymorphism, Single Nucleotide
Poxviridae
Poxviridae Infections
Promoter Regions, Genetic
Protein Binding
Protein Conformation
Structure-Activity Relationship