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Elimination of Aicardi Goutieres Syndrome Protein SAMHD1 Activates Cellular Innate Immunity and Suppresses SARS-CoV-2 Replication.


ABSTRACT: The lack of antiviral innate immune responses during SARS-CoV-2 infections are characterized by limited production of interferon proteins (IFNs). One protein associated with Aicardi Goutières syndrome, sterile alpha motif and HD-domain-containing protein 1 (SAMHD1), has been shown to negatively regulate the IFN-1 signaling pathway. However, it is unclear whether elevated IFN signaling associated with genetic loss of SAMHD1 would affect SARS-CoV-2 replication. In this study, we established in vitro tissue culture model systems for SARS-CoV-2 and HCoV-OC43 infections in which SAMHD1 protein expression was absent as a result of CRISPR/Cas9 gene knockout (KO) or lentiviral Vpx-mediated proteosomal degradation. We show that both SARS-CoV-2 and HCoV-OC43 replication were suppressed in SAMHD1 KO 293T and differentiated THP-1 macrophage cell lines. Similarly, when SAMHD1 was degraded by virus-like particles in primary monocyte-derived macrophages, we observed lower levels of SARS-CoV-2 RNA. The loss of SAMHD1 in 293T and differentiated THP-1 cells resulted in upregulated gene expression of IFNs and innate immunity signaling proteins from several pathways, with STAT1 mRNA being the most prominently elevated. Furthermore, SARS-CoV-2 replication was significantly increased in both SAMHD1 WT and KO cells when expression and phosphorylation of STAT1 were downregulated by Jak inhibitor baricitinib, which overrode the activated antiviral innate immunity in the KO cells. This further validates baricitinib as a treatment of SARS-CoV-2 infected patients primarily at the post-viral clearance stage. Overall, our tissue culture model systems demonstrated that the elevated innate immune response and IFN activation upon genetic loss of SAMHD1 effectively suppresses SARS-CoV-2 replication.

SUBMITTER: Oo A 

PROVIDER: S-EPMC8786443 | biostudies-literature |

REPOSITORIES: biostudies-literature

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