ORAI1 Limits SARS-CoV-2 Infection by Regulating Tonic Type I IFN Signaling

Abstract

S.S. conceptualized the study, generated KO cells, and performed imaging experiments. B.W. performed all the molecular biology and flow cytometry experiments, and A.R. performed bioinformatics analysis of the RNA sequencing data with help from S.H. G.G. and V.A. generated the severe acute respiratory syndrome coronavirus 2 virus and performed all infection experiments. S.S. wrote the manuscript with input from all authors.The RNA sequencing data have been submitted to the National Center for Biotechnology Information Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc. cgi?acc=GSE173707) under accession number GSE173707.

Calcium Signals during SARS-CoV-2 Infection: Assessing the Potential of Emerging Therapies

“…As knockout of STIM1, which results in increased STING activation, leads to enhanced IFN-I responses shown by Wu et al, the use of CCBs could possibly alter IFN-I levels and therefore also have positive effects on the resistance to SARS-CoV-2 infection. [ 84 , 85 ] Despite the observed positive effects of different CCB drugs/small molecules linked to COVID-19, none of them are currently in clinical use and only Auxora from Calcimedica completed Phase 2 clinical trials for treating acute pancreatitis ( accessed on 11 November 2021). The latter is also considered to possibly have a beneficial effect for COVID-19 patients ( (accessed on 11 November 2021)).…”

“…A recent study conducted by Wu et al supports the importance of Orai1 and STIM1 for SARS-CoV2 host cell infection and IFN-I signaling. Knockout of STIM1 led to strong resistance to SARS-CoV-2 infection as a result of enhanced IFN-I response whereas Orai1 knockout resulted in high susceptibility to SARS-CoV-2 infection via the downregulation of Ca 2+ dependent antiviral transcription factors [ 84 ]. Interestingly, STIM1-knockouts and Orai1-knockouts have opposing effects on susceptibility to SARS-CoV2 infection.…”

Potential of targeting host cell calcium dynamics to curtail SARS-CoV-2 infection and COVID-19 pathogenesis

“…Interestingly, infection of SARS-CoV-2 upon either Orai1 or STIM1 silencing showed the opposite phenotype. While Orai1 knockout cells showed high infectivity, increased viral genome copy number and enhanced cell lysis post-infection, STIM1 knockout cells showed resistance to infection [51] . The resistance to SARS-CoV-2 infection upon STIM1 silencing is attained by increased levels of baseline interferon-β (IFN-β) levels, which on the other hand, is reduced in Orai1 knockout cells.…”

“…Two main components of SOCE that regulate the entry of extracellular Ca 2+ are plasma membrane-localized pore unit (Orai1) and ER-localized sensor protein (STIM1). The role of SOCE was studied in SARS-CoV-2 infection in HEK-293-ACE-2 cells by silencing Orai1 and STIM1 [51] . Both Orai1 and STIM1 knockout cells show complete abrogation of SOCE.…”

“…Further, the expression of several antiviral signaling cascades were decreased in Orai1 knockout cells. [51] . Taken together, this study demonstrates an intriguing role of Orai1 in maintaining the basal Ca 2+ concentration required for mounting an immune response against SARS-CoV-2 infection.…”