Introduction: Cytokine storm and critical COVID-19 pneumonia are caused in at least 10% of patients by inborn errors of or auto-Abs to type I IFNs. The pathogenesis of life-threatening COVID-19 pneumonia in other patients remains unknown. Methods: This study was conducted at Masih Daneshvari Hospital, Tehran, Iran. In the period of study, 75 confirmed cases of COVID-19 with presentations ranging from mild upper respiratory tract infection to lower respiratory tract infection, including moderate, severe, and critical disease, were recruited. Expression of STING mRNA was measured in peripheral blood mononuclear cells (PBMCs) and compared between patients with different severity and outcome. Results: There was a significant negative correlation between age and STING expression level (p value = 0.010). Patients with “severe to critical” illness had a 20-fold lower STING expression level compared to the “mild to moderate” group (p value = 0.001). Also, the results showed lower expressions of STING in the patients admitted to the ICU (p value = 0.015). Patients who finally died had lower expression of STING at the time of sampling (p value = 0.041). Conclusion: STING mRNA expression in PBMCs was significantly lower in older COVID-19 cases, the patients with more severe illness, who needed intensive care, and who eventually died.

1.
Kamel MH, Yin W, Zavaro C, Francis JM, Chitalia VC. Hyperthrombotic milieu in COVID-19 patients. Cells. 2020;9(11):E2392.
2.
Tal S, Spectre G, Kornowski R, Perl L. Venous thromboembolism complicated with COVID-19: what do we know so far? Acta haematologica. 2020;143(5):417–24.
3.
WHO. Coronavirus (COVID-19) dashboard 2022 [cited 2021 June 19]. Available from: https://covid19.who.int/.
4.
Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;324(8):782–93.
5.
Xie Y, Wang Z, Liao H, Marley G, Wu D, Tang W. Epidemiologic, clinical, and laboratory findings of the COVID-19 in the current pandemic: systematic review and meta-analysis. BMC Infect Dis. 2020;20(1):640.
6.
Zhang Q, Bastard P, Bolze A, Jouanguy E, Zhang S-Y; COVID Human Genetic Effort, et al. Life-threatening COVID-19: defective interferons unleash excessive inflammation. Med. 2020;1(1):14–20.
7.
O’Driscoll M, Ribeiro Dos Santos G, Wang L, Cummings DAT, Azman AS, Paireau J, et al. Age-specific mortality and immunity patterns of SARS-CoV-2. Nature. 2021;590(7844):140–5.
8.
Scully EP, Haverfield J, Ursin RL, Tannenbaum C, Klein SL. Considering how biological sex impacts immune responses and COVID-19 outcomes. Nat Rev Immunol. 2020;20(7):442–7.
9.
Mahmoudi S, Rezaei M, Mansouri N, Marjani M, Mansouri D. Immunologic features in coronavirus disease 2019: functional exhaustion of T cells and cytokine storm. J Clin Immunol. 2020;40(7):974–6.
10.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.
11.
Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine. 2018;104:8–13.
12.
Wong CK, Lam CWK, Wu AKL, Ip WK, Lee NLS, Chan IHS, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004;136(1):95–103.
13.
Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4585.
14.
Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4570.
15.
van der Wijst MGP, Vazquez SE, Hartoularos GC, Bastard P, Grant T, Bueno R, et al. Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19. bioRxiv. 2021;2021. Epub ahead of print.
16.
Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181(5):1036–45.e9.
17.
Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020;369(6504):718–24.
18.
McGonagle D, Sharif K, O’Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev. 2020;19(6):102537.
19.
Ye Q, Wang B, Mao J. The pathogenesis and treatment of the “cytokine storm” in COVID-19. J Infect. 2020;80(6):607–13.
20.
Carty M, Guy C, Bowie AG. Detection of viral infections by innate immunity. Biochem Pharmacol. 2021;114316.
21.
Theofilopoulos AN, Kono DH, Beutler B, Baccala R. Intracellular nucleic acid sensors and autoimmunity. J Interferon Cytokine Res. 2011;31(12):867–86.
22.
Zhang SY, Herman M, Ciancanelli MJ, Pérez de Diego R, Sancho-Shimizu V, Abel L, et al. TLR3 immunity to infection in mice and humans. Curr Opin Immunol. 2013;25(1):19–33.
23.
Thorne LG, Reuschl AK, Zuliani-Alvarez L, Whelan MVX, Turner J, Noursadeghi M, et al. SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation. EMBO J. 2021;40(15):e107826.
24.
Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455(7213):674–8.
25.
Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 2009;461(7265):788–92.
26.
Liu S, Cai X, Wu J, Cong Q, Chen X, Li T, et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science. 2015;347(6227):aaa2630.
27.
Sun W, Li Y, Chen L, Chen H, You F, Zhou X, et al. ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc Natl Acad Sci U S A. 2009;106(21):8653–8.
28.
Tanaka Y, Chen ZJ. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci Signal. 2012;5(214):ra20.
29.
Zhong B, Yang Y, Li S, Wang YY, Li Y, Diao F, et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity. 2008;29(4):538–50.
30.
Lee J, Ghonime MG, Wang R, Cassady KA. The antiviral apparatus: STING and oncolytic virus restriction. Mol Ther Oncolytics. 2019;13:7–13.
31.
Barber GN. STING: infection, inflammation and cancer. Nat Rev Immunol. 2015;15(12):760–70.
32.
Park A, Iwasaki A. Type I and type III interferons: induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe. 2020;27(6):870–8.
33.
Berthelot JM, Drouet L, Lioté F. Kawasaki-like diseases and thrombotic coagulopathy in COVID-19: delayed over-activation of the STING pathway? Emerg Microbes Infect. 2020;9(1):1514–22.
34.
Berthelot JM, Lioté F. COVID-19 as a STING disorder with delayed over-secretion of interferon-beta. EBioMedicine. 2020;56:102801.
35.
Mahmoudi S, Mehdizadeh M, Shervin Badv R, Navaeian A, Pourakbari B, Rostamyan M, et al. The Coronavirus Disease 2019 (COVID-19) in children: a study in an Iranian Children’s Referral Hospital. Infect Drug Resist. 2020;13:2649–55.
36.
NIH. Coronavirus Disease 2019 (COVID-19) treatment guidelines [updated April 21, 2021; cited 2021]. Available from: https://www.covid19treatmentguidelines.nih.gov/.
37.
Tan X, Sun L, Chen J, Chen ZJ. Detection of microbial infections through innate immune sensing of nucleic acids. Annu Rev Microbiol 2018;72:447–78.
38.
Motwani M, Pesiridis S, Fitzgerald KA. DNA sensing by the cGAS-STING pathway in health and disease. Nat Rev Genet. 2019;20(11):657–74.
39.
Sun B, Sundström KB, Chew JJ, Bist P, Gan ES, Tan HC, et al. Dengue virus activates cGAS through the release of mitochondrial DNA. Sci Rep. 2017;7(1):3594.
40.
McGuckin Wuertz K, Treuting PM, Hemann EA, Esser-Nobis K, Snyder AG, Graham JB, et al. STING is required for host defense against neuropathological West Nile virus infection. PLoS Pathog. 2019;15(8):e1007899.
41.
Zevini A, Olagnier D, Hiscott J. Crosstalk between cytoplasmic RIG-I and STING sensing pathways. Trends Immunol. 2017;38(3):194–205.
42.
Franz KM, Neidermyer WJ, Tan YJ, Whelan SPJ, Kagan JC. STING-dependent translation inhibition restricts RNA virus replication. Proc Natl Acad Sci U S A. 2018;115(9):E2058–67.
43.
Ma Z, Damania B. The cGAS-STING defense pathway and its counteraction by viruses. Cell Host Microbe. 2016;19(2):150–8.
44.
Berthelot JM, Lioté F, Maugars Y, Sibilia J. Lymphocyte changes in severe COVID-19: delayed over-activation of STING? Front Immunol. 2020;11:607069.
45.
Xie J, Li Y, Shen X, Goh G, Zhu Y, Cui J, et al. Dampened STING-dependent interferon activation in bats. Cell Host Microbe. 2018;23(3):297–301.e4.
46.
Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Sanchez GAM, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371(6):507–18.
47.
West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015;520(7548):553–7.
48.
Hamann L, Szwed M, Mossakowska M, Chudek J, Puzianowska-Kuznicka M. First evidence for STING SNP R293Q being protective regarding obesity-associated cardiovascular disease in age-advanced subjects: a cohort study. Immun Ageing. 2020;17:7.
49.
Bai J, Liu F. The cGAS-cGAMP-STING pathway: a molecular link between immunity and metabolism. Diabetes. 2019;68(6):1099–108.
50.
Mudla A, Jiang Y, Arimoto KI, Xu B, Rajesh A, Ryan AP, et al. Cell-cycle-gated feedback control mediates desensitization to interferon stimulation. eLife. 2020;9:e58825.
51.
Maekawa S, Aoki T, Wang HC. Constitutive overexpressed type I interferon induced downregulation of antiviral activity in medaka fish (Oryzias latipes). Dev Comp Immunol. 2017;68:12–20.
52.
Li Q, Lin L, Tong Y, Liu Y, Mou J, Wang X, et al. Erratum: author correction to – TRIM29 negatively controls antiviral immune response through targeting STING for degradation. Cell Discov. 2018;4:25.
53.
Wang Y, Lian Q, Yang B, Yan S, Zhou H, He L, et al. TRIM30α is a negative-feedback regulator of the intracellular DNA and DNA virus-triggered response by targeting STING. PLoS Pathog. 2015;11(6):e1005012.
54.
Helbi S, Ravanbakhsh B, Karimi M, Kooti W, Jivad N. Aligned expression of IFI16 and STING genes in RRMS patients’ blood. Endocr Metab Immune Disord Drug Targets. 2020;20(6):878–86.
55.
Ghosh A, Shao L, Sampath P, Zhao B, Patel NV, Zhu J, et al. Oligoadenylate-synthetase-family protein OASL inhibits activity of the DNA sensor cGAS during DNA virus infection to limit interferon production. Immunity. 2019;50(1):51–63.e5.
56.
Wu X, Yang J, Na T, Zhang K, Davidoff AM, Yuan BZ, et al. RIG-I and IL-6 are negative-feedback regulators of STING induced by double-stranded DNA. PLoS One. 2017;12(8):e0182961.
57.
Bastard P, Gervais A, Le Voyer T, Rosain J, Philippot Q, Manry J, et al. Autoantibodies neutralizing type I IFNs are present in ∼4% of uninfected elderly individuals and account for ∼20% of COVID-19 deaths. Sci Immunol. 2021 Aug 19;6(62):eabl4340.
58.
Asano T, Boisson B, Onodi F, Matuozzo D, Moncada-Velez M, Luxman Maglorius Renkilaraj MR, et al. Human TLR7 and plasmacytoid dendritic cells are essential for type I IFN pulmonary immunity to SARS-CoV-2. Sci immunol. Epub ahead of print.
59.
Olejnik J, Hume AJ, Mühlberger E. Toll-like receptor 4 in acute viral infection: too much of a good thing. PLoS Pathog. 2018;14(12):e1007390.
60.
Mohammadpour H, Ziai A, Sadr M, Rezaei M, Marjani M, Tabarsi P. A Novel Coronavirus Disease (COVID-19): a review of host cell signaling pathways. Tanaffos. 2020;19(2):108–11.
61.
Rezaei M, Ziai SA, Fakhri S, Pouriran R. ACE2: its potential role and regulation in severe acute respiratory syndrome and COVID-19. J Cell Physiol. 2021;236(4):2430–42.
62.
Rezaei M, Babamahmoodi A, Marjani M. Bruton’s tyrosine kinase: a promising target for the treatment of COVID-19. Tanaffos. 2020;19(2):85–8.
63.
Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71(15):762–8.
64.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–4.
65.
Copaescu A, Smibert O, Gibson A, Phillips EJ, Trubiano JA. The role of IL-6 and other mediators in the cytokine storm associated with SARS-CoV-2 infection. J Allergy Clin Immunol. 2020;146(3):518–34.e1.
66.
Luo W, Li YX, Jiang LJ, Chen Q, Wang T, Ye DW. Targeting JAK-STAT signaling to control cytokine release syndrome in COVID-19. Trends Pharmacol Sci. 2020;41(8):531–43.
67.
Walz L, Cohen AJ, Rebaza AP, Vanchieri J, Slade MD, Dela Cruz CS, et al. Janus kinase-inhibitor and type I interferon ability to produce favorable clinical outcomes in COVID-19 patients: a systematic review and meta-analysis. medRxiv. 2020. Epub ahead of print.
68.
Lee C, Lim HK, Sakong J, Lee YS, Kim JR, Baek SH. Janus kinase-signal transducer and activator of transcription mediates phosphatidic acid-induced interleukin (IL)-1beta and IL-6 production. Mol Pharmacol. 2006;69(3):1041–7.
69.
Liu D, Wu H, Wang C, Li Y, Tian H, Siraj S, et al. STING directly activates autophagy to tune the innate immune response. Cell Death Differ. 2019;26(9):1735–49.
70.
Rose KM, Elliott R, Martínez-Sobrido L, García-Sastre A, Weiss SR. Murine coronavirus delays expression of a subset of interferon-stimulated genes. J Virol. 2010;84(11):5656–69.
71.
Menachery VD, Eisfeld AJ, Schäfer A, Josset L, Sims AC, Proll S, et al. Pathogenic influenza viruses and coronaviruses utilize similar and contrasting approaches to control interferon-stimulated gene responses. mBio. 2014;5(3):e01174–14.
72.
Rui Y, Su J, Shen S, Hu Y, Huang D, Zheng W, et al. Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins. Signal Transduct Target Ther. 2021;6(1):123.
73.
Snijder EJ, van der Meer Y, Zevenhoven-Dobbe J, Onderwater JJM, van der Meulen J, Koerten HK, et al. Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex. J Virol. 2006;80(12):5927–40.
74.
Deng X, Hackbart M, Mettelman RC, O’Brien A, Mielech AM, Yi G, et al. Coronavirus nonstructural protein 15 mediates evasion of dsRNA sensors and limits apoptosis in macrophages. Proc Natl Acad Sci USA. 2017;114(21):E4251–60.
75.
Humphries F, Shmuel-Galia L, Jiang Z, Wilson R, Landis P, Ng SL, et al. A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection. Sci Immunol. 2021;6(59).
76.
Coll-Bonfill N, Cancado de Faria R, Bhoopatiraju S, Gonzalo S. Calcitriol Prevents RAD51 Loss and cGAS-STING-IFN Response Triggered by Progerin. Proteomics. 2020;20(5–6):e1800406.
77.
Newling M, Hoepel W, Vogelpoel LTC, Heineke MH, van Burgsteden JA, Taanman-Kueter EWM, et al. Fc gamma receptor IIa suppresses type I and III interferon production by human myeloid immune cells. Eur J Immunol. 2018;48(11):1796–809.
78.
Dai J, Huang YJ, He X, Zhao M, Wang X, Liu ZS, et al. Acetylation blocks cGAS activity and inhibits self-DNA-induced autoimmunity. Cell. 2019;176(6):1447–60.e14.
79.
Lopez L, Sang PC, Tian Y, Sang Y. Dysregulated interferon response underlying severe COVID-19. Viruses. 2020;12(12):E1433.
80.
Bastard P, Michailidis E, Hoffmann HH, Chbihi M, Le Voyer T, Rosain J, et al. Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine. J Exp Med. 2021;218(4):e20202486.
You do not currently have access to this content.