Polymorphisms in STING Affect Human Innate Immune Responses to Poxviruses

Area of Science:

• Immunology
• Genetics
• Virology

Background:

• Smallpox vaccination elicits immune responses, but individual variability exists.
• Genome-wide association studies (GWAS) are crucial for identifying genetic factors influencing immune responses.
• Understanding genetic control of poxvirus immunity is vital for public health.

Purpose of the Study:

• To identify genetic polymorphisms associated with immune responses to smallpox vaccination.
• To investigate the functional impact of identified genetic variants on poxvirus-induced innate immunity.
• To elucidate the role of STING protein variants in antiviral responses.

Main Methods:

• Conducted a large GWAS of 1,653 subjects for immune responses to smallpox vaccination.
• Performed functional testing of a specific single nucleotide polymorphism (SNP) in TMEM173 (rs1131769).
• Utilized molecular modeling to predict the effect of STING variants on ligand binding.

Main Results:

• No polymorphisms correlated with standard vaccine responses, but SNPs on chromosome 5q31.2 associated with IFNα response to poxvirus stimulation.
• The rs1131769 SNP in TMEM173, resulting in an Arg232His change in STING, showed impaired phosphorylation of TBK1 and IRF3.
• Cells with the H232 variant exhibited reduced type I IFN and IFN-response gene expression, suggesting impaired innate immunity.

Conclusions:

• Genetic variation in TMEM173 (STING) significantly influences IFNα response to poxviruses.
• The H232 STING variant may impair STING-mediated innate immunity, potentially affecting individual susceptibility to poxvirus infections.
• These findings clarify the functional effects of TMEM173 variants and offer insights into genetic control of poxvirus immunity.