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

The β-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.