Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

TLDR

Coronaviruses have repeatedly crossed species barriers, causing severe respiratory outbreaks, yet few functional tools exist to assess their human infectivity. The study aimed to develop a rapid screening method for lineage B betacoronaviruses to determine receptor usage and cross‑species cell infectivity. The authors constructed an assay that evaluates receptor usage and cell entry across species for viruses such as SARS‑CoV and SARS‑CoV‑2. They found that host protease processing limits entry for several lineage B viruses, that bypassing this barrier enables entry via an unknown receptor, and that SARS‑CoV‑2 uses human ACE2, with recombination allowing other lineage B viruses to gain human cell entry.

Abstract

Over the past 20 years, several coronaviruses have crossed the species barrier into humans, causing outbreaks of severe, and often fatal, respiratory illness. Since SARS-CoV was first identified in animal markets, global viromics projects have discovered thousands of coronavirus sequences in diverse animals and geographic regions. Unfortunately, there are few tools available to functionally test these viruses for their ability to infect humans, which has severely hampered efforts to predict the next zoonotic viral outbreak. Here, we developed an approach to rapidly screen lineage B betacoronaviruses, such as SARS-CoV and the recent SARS-CoV-2, for receptor usage and their ability to infect cell types from different species. We show that host protease processing during viral entry is a significant barrier for several lineage B viruses and that bypassing this barrier allows several lineage B viruses to enter human cells through an unknown receptor. We also demonstrate how different lineage B viruses can recombine to gain entry into human cells, and confirm that human ACE2 is the receptor for the recently emerging SARS-CoV-2.