DMBT1 promotes SARS-CoV-2 infection and its SRCR-derived peptide inhibits SARS-CoV-2 infection

Abstract

DMBT1 is a large scavenger receptor cysteine rich (SRCR) B protein that has been reported as a tumor suppressor gene and a co-receptor for HIV-1 infection. Here we found DMBT1 is a major mucosal protein bound to SARS-CoV-2. Overexpression of DMBT1 in 293T cells enhanced infection by SARS-CoV-2 in ACE2 dependent manner. Blocking experiments using overlapping peptide library of SRCR domain of DMBT1 showed that CQGRVEVLYRGSWGTV peptide, which contains bacteria-binding VEVLXXXXW motif, could inhibit SARS-CoV-2 infection. High concentration of the peptide can significantly inhibit the replication of SARS-CoV-2 in hamsters. Single cell sequencing analysis showed the highest expression abundance of DMBT1 at airway submucosal glands. These results demonstrate that membrane DMBT1 can promote SARS-CoV-2 infection, and serve as a candidate target for antiviral development. Author SummaryWe discovered that a protein named as DMBT1, which is found in our mucous membranes, plays a significant role in SARS-CoV-2 infection. DMBT1 is a large glycoprotein that has previously reported linked to tumor suppression and HIV-1 infection. Our single-cell sequencing analysis revealed that DMBT1 is most abundant in the airway submucosal glands. In our study, we found that when DMBT1 is overexpressed in cells, it enhances SARS-CoV-2 infection. Using a peptide library from DMBT1, we pinpointed a specific peptide, CQGRVEVLYRGSWGTV, which can inhibit SARS-CoV-2 infection. At high concentrations, it significantly reduces the viruss ability to replicate in hamsters. These findings suggest that DMBT1 on the cell membrane can promote SARS-CoV-2 infection and highlight DMBT1 as a potential target for developing antiviral treatments.