Vitamin D enhances type I IFN signaling in COVID-19 patients
Shirin Hafezi, Fatemeh Saheb Sharif-Askari, Narjes Saheb Sharif-Askari, Hawra Ali Hussain Alsayed, Habiba Alsafar, Fatme Al Anouti, Qutayba Hamid, Rabih Halwani
Scientific Reports, doi:10.1038/s41598-022-22307-9
The ability of Vitamin D (VitD) to modulate antiviral responses through induction of antimicrobial peptide is well established. However, the effect of VitD on host responses to SARS-CoV-2 is not well investigated. We here report the ability of VitD to enhance host IFN-alpha/beta (a/β) signaling both in vitro and among severe COVID-19 patients treated with VitD. Blood and saliva specimens were obtained from severe COVID-19 patients treated (43 patients), or not (37 patients), with vitD, during their stay in intensive care unit. Patients were followed up to 29 days following admission, and patient survival outcomes were collected. Higher activity levels of RIG-1/MDA-5 and JAK-STAT signaling pathways were observed with significantly higher gene and protein levels of antiviral interferon stimulating genes (ISGs) such as MX-1 and ISG-15; both in vitro, following treatment of PBMCs with vitD, and in whole blood and saliva specimens of VitD treated patients. Moreover, VitD treated patients had lower risk of all-cause mortality by day 29 compared to untreated patients (adjusted hazard ratio, 0.37, 95% confidence interval of 0.14-0.94; P = 0.038). The herein uncovered regulatory role of VitD on type I IFNs suggests the importance of insuring a normal level of VitD for the prevention and probably treatment of SARS-CoV-2 infection. Additional mechanistic studies, however, are needed to fully elucidate the antiviral effects of VitD particularly in the setting of COVID-19 infection. Innate immunity is critical for controlling SARS-CoV-2 infection; and patients with dysregulated innate immunity are prone to development of severe disease 1 . Type I interferons (IFN-α, and β) represent key elements of antiviral innate immunity. Several reports have shown that efficient induction of IFN-α/β signaling and the resultant interferon stimulating genes (ISGs) are essential for the control and resolution of SARS-CoV-2 infection 2 . SARS-CoV-2 is recognized in the cytosol of human epithelial cells by single-stranded (ss)RNA cytosolic sensing proteins (RIG-1 and MDA5) 3,4 . This will then lead to the downstream activation of interferon regulatory factors (IRF)3, or IRF7, and rapid production of IFN α/β cytokines, which exhibit key antiviral activity, thereby limiting viral proliferation and spreading 5 . IFN α/β cytokines bind to a dimeric receptor composed of IFNAR1 and IFNAR2 subunits; consequently, triggering the formation of transcription complex, IFN-stimulated gene factor 3 (ISGF3). ISGF3, which consists of phosphorylated signal transducer and activator of transcription STAT(1), STAT2 and IRF9, migrates to the nucleus, binds to interferon-stimulated response elements (ISREs), and activates transcription of anti-viral ISGs 6-8 . Collectively, the efficient induction of IFN-α/β signaling and ISGs in virus-infected cells is fundamental for the antiviral response of a host. As such, studies have reported that COVID-19 patients with a genetic defect in the production of..
Author contributions
Funding The authors extend their appreciation to the Deanship of Scientific Research, king Saud University for funding through Vice Deanship of Scientific Research Chairs; Research Chair of Prince Abdullah Ben Khalid Celiac Disease research chair; Riyadh, Kingdom of Saudi Arabia.
Competing interests The authors declare no competing interests.
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