SAMHD1 promotes SARS-CoV-2 infection by enhancing HNF1-dependent ACE2 expression in lung epithelial cells

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is known to restrict viruses and suppress innate immune responses, including type-I interferon (IFN-I) production.
• Previous research indicated SAMHD1 acts as a proviral factor for SARS-CoV-2 in certain cell types by suppressing IFN responses.
• The specific role of SAMHD1 in lung epithelial cells during SARS-CoV-2 infection remained unclear.

Purpose of the Study:

• To investigate the function of SAMHD1 in SARS-CoV-2 replication within lung epithelial Calu-3 cells.
• To elucidate the mechanism by which SAMHD1 influences viral entry and replication in these cells.
• To determine if SAMHD1's role extends beyond its known IFN-suppressive functions.

Main Methods:

• Utilized SAMHD1 knockout (KO) Calu-3 cells and pseudotyped SARS-CoV-2 and lentiviral vectors.
• Assessed viral entry, ACE2 expression (mRNA and protein), and the role of hepatocyte nuclear factor 1-alpha (HNF1α) and HNF1β.
• Investigated the effect of baricitinib (JAK 1/2 inhibitor) on viral suppression in SAMHD1 KO cells.

Main Results:

• SAMHD1 facilitates SARS-CoV-2 replication in Calu-3 cells by enhancing endogenous ACE2 expression.
• SAMHD1 knockout suppressed SARS-CoV-2 entry and repressed ACE2 expression at both mRNA and protein levels.
• HNF1α and HNF1β are critical for ACE2 expression, and SAMHD1 KO reduced their expression and ACE2-promoting activity.
• Baricitinib treatment did not reverse SARS-CoV-2 suppression in SAMHD1 KO cells, indicating a mechanism independent of IFN suppression.

Conclusions:

• SAMHD1 promotes SARS-CoV-2 replication in lung epithelial cells through a novel mechanism involving HNF1-mediated ACE2 upregulation.
• This function of SAMHD1 is independent of its previously characterized role in suppressing IFN antiviral responses.
• Findings highlight a new target for antiviral strategies against SARS-CoV-2 in lung epithelial cells.