Analysis of the Tropism of SARS-CoV-2 Based on the Host Interactome of the Spike Protein

The beta-coronavirus SARS-CoV-2 causes severe acute respiratory syndrome (COVID-19) in humans. It enters and infects epithelial airway cells upon binding of the receptor binding domain (RBD) of the virus entry protein spike to the host receptor protein Angiotensin Converting Enzyme 2 (ACE2). Here, we used coimmunoprecipitation coupled with bottom-up mass spectrometry to identify host proteins that engaged with the spike protein in human bronchial epithelial cells (16HBEo(-)). We found that the spike protein bound to extracellular laminin and thrombospondin and endoplasmatic reticulum (ER)-resident DJB11 and FBX2 proteins. The ER-resident proteins UGGT1, CALX, HSP7A, and GRP78/BiP bound preferentially to the original Wuhan D614 over the mutated G614 spike protein in the more rapidly spreading Alpha SARS-CoV-2 strain. The increase in protein binding to the D614 spike might be explained by higher accessibility of cryptic sites in RDB open and S2 only D614 spike protein conformations and may enable SARS-CoV-2 to infect additional, ACE2-negative cell types. Moreover, a novel proteome-based cell type set enrichment analysis (pCtSEA) found that host factors like laminin might render additional cell types such as macrophages and epithelial cells in the nephron permissive to SARS-CoV-2 infection.

Automated summary

In this study, the researchers identified host proteins that interacted with the spike protein of SARS-CoV-2 using coimmunoprecipitation and mass spectrometry. They found that the spike protein bound to extracellular laminin and thrombospondin, as well as endoplasmic reticulum-resident DJB11 and FBX2 proteins. They also observed that the D614 spike protein had higher binding affinity to certain ER-resident proteins in the Alpha SARS-CoV-2 strain compared to the mutated G614 spike protein. This increased binding might enable SARS-CoV-2 to infect additional cell types that do not express ACE2.