Polymorphisms in STING affect human innate immune responses to poxviruses

Kennedy, Richard B.; Haralambieva, Iana H.; Ovsyannikova, Inna G.; Voigt, Emily A.; Larrabee, Beth R.; Schaid, Daniel J.; Zimmermann, Michael T.; Oberg, Ann L.

doi:10.1101/2020.05.28.121657

Cited by 2 publications

(3 citation statements)

References 55 publications

(81 reference statements)

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“…Single nucleotide polymorphisms (SNPs) of STING/Tmem173 in human are common in the population and affects the immune response against viral infection (29). Here, we identified that the STING gain-offunction mutation increased SLE risk in humans, while STING loss-of-function reduced the risk.…”

Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 96%

Role ofSTING/TMEM173mutation in systemic lupus erythematosus: from animal model to intrinsic human genetics

Vejvisithsakul

Wanachate

Ngamjanyaporn

et al. 2022

Preprint

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Objective: We aim to confirm the function of Sting/Tmem173 in pristane-induced lupus and identify the role of STING/TMEM173 variants in SLE susceptibility. Methods: Pristane-induced lupus model was introduced in the Sting-deficient mice (ENU-induced Goldenticket mutant mice). Autoantibody, histopathology, and immunophenotypes were analyzed after pristane injection for six months. Isolated DNA from 302 SLE patients and 173 healthy donors were tested for STING genotyping. We calculated the Odd Ratios of each STING variant and the inheritance patterns that significantly increased SLE susceptibility. Then, we analyzed the associations between STING genotypes and lupus phenotypes. Results: The absence of STING signaling in the Goldenticket mutant mice reduced the autoantibody production and severity of glomerulonephritis in pristane-induced lupus. The human STING mutation at p.R284S (gain-of-function) significantly increased the SLE risk in autosomal dominant pattern [OR = 64.0860 (95%CI = 22.8605-179.6555), p < 0.0001], while the mutation at p.R232H (loss of function) reduced the SLE risk in autosomal recessive pattern [OR = 0.2515 (95%CI = 0.1648-0.3836), p < 0.0001]. The combination of STING variants in a specific inheritance pattern increased the higher OR than a single variant. The patient who had p.R284S with p.R232H showed milder disease activity than those who had p.R284S alone at the time of diagnosis. Conclusion: The inhibition of STING rescued autoimmune phenotypes in pristane-induced lupus. Gain-of-function STING mutation increased SLE susceptibility and severity of the disease. These data suggested the critical function via STING-mediated signaling in SLE. Targeted at STING may provide a favorable outcome in SLE patients.

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Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 96%

Role ofSTING/TMEM173mutation in systemic lupus erythematosus: from animal model to intrinsic human genetics

Vejvisithsakul

Wanachate

Ngamjanyaporn

et al. 2022

Preprint

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“…The result is in line with the previous data from a HAQ knock-in mouse mode [ 51 ]. Lastly, Kennedy R. B. et al demonstrated that PBMC from H232/H232 individuals had an impaired STING-mediated innate immunity (~90% decrease of IFNα induction) to poxviruses [ 91 ]. A large human population carries these STING alleles [ 51 ].…”

Section: Confounding Factors In Cdn Adjuvanticity In Humansmentioning

confidence: 99%

“…Accumulating evidence in humans [ 90 , 91 , 100 , 101 ] and mouse models [ 50 , 51 , 102 ] indicated that the HAQ and H232 alleles are impaired in the STING function. CDN-adjuvanted vaccines aim to protect the general public from the pandemic and endemic.…”

Section: Future Of Cdn Vaccine Adjuvantsmentioning

confidence: 99%

The Age of Cyclic Dinucleotide Vaccine Adjuvants

2020

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As prophylactic vaccine adjuvants for infectious diseases, cyclic dinucleotides (CDNs) induce safe, potent, long-lasting humoral and cellular memory responses in the systemic and mucosal compartments. As therapeutic cancer vaccine adjuvants, CDNs induce potent anti-tumor immunity, including cytotoxic T cells and NK cells activation that achieve durable regression in multiple mouse models of tumors. Clinical trials are ongoing to fulfill the promise of CDNs (ClinicalTrials.gov: NCT02675439, NCT03010176, NCT03172936, and NCT03937141). However, in October 2018, the first clinical data with Merck’s CDN MK-1454 showed zero activity as a monotherapy in patients with solid tumors or lymphomas (NCT03010176). Lately, the clinical trial from Aduro’s CDN ADU-S100 monotherapy was also disappointing (NCT03172936). The emerging hurdle in CDN vaccine development calls for a timely re-evaluation of our understanding on CDN vaccine adjuvants. Here, we review the status of CDN vaccine adjuvant research, including their superior adjuvant activities, in vivo mode of action, and confounding factors that affect their efficacy in humans. Lastly, we discuss the strategies to overcome the hurdle and advance promising CDN adjuvants in humans.

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Polymorphisms in STING affect human innate immune responses to poxviruses

Cited by 2 publications

References 55 publications

Role ofSTING/TMEM173mutation in systemic lupus erythematosus: from animal model to intrinsic human genetics

Role ofSTING/TMEM173mutation in systemic lupus erythematosus: from animal model to intrinsic human genetics

The Age of Cyclic Dinucleotide Vaccine Adjuvants

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