Interaction network of SARS-CoV-2 with host receptome through spike protein

Abstract

Host cellular receptors are key determinants of virus tropism and pathogenesis. Virus utilizes multiple receptors for attachment, entry, or specific host responses. However, other than ACE2, little is known about SARS-CoV-2 receptors. Furthermore, ACE2 cannot easily interpret the multi-organ tropisms of SARS-CoV-2 nor the clinical differences between SARS-CoV-2 and SARS-CoV. To identify host cell receptors involved in SARS-CoV-2 interactions, we performed genomic receptor profiling to screen almost all human membrane proteins, with SARS-CoV-2 capsid spike (S) protein as the target. Twelve receptors were identified, including ACE2. Most receptors bind at least two domains on S protein, the receptor-binding-domain (RBD) and the N-terminal-domain (NTD), suggesting both are critical for virus-host interaction. Ectopic expression of ASGR1 or KREMEN1 is sufficient to enable entry of SARS-CoV-2, but not SARS-CoV and MERS-CoV. Analyzing single-cell transcriptome profiles from COVID-19 patients revealed that virus susceptibility in airway epithelial ciliated and secretory cells and immune macrophages highly correlates with expression of ACE2, KREMEN1 and ASGR1 respectively, and ACE2/ASGR1/KREMEN1 (ASK) together displayed a much better correlation than any individual receptor. Based on modeling of systemic SARS-CoV-2 host interactions through S receptors, we revealed ASK correlation with SARS-CoV-2 multi-organ tropism and provided potential explanations for various COVID-19 symptoms. Our study identified a panel of SARS-CoV-2 receptors with diverse binding properties, biological functions, and clinical correlations or implications, including ASGR1 and KREMEN1 as the alternative entry receptors, providing insights into critical interactions of SARS-CoV-2 with host, as well as a useful resource and potential drug targets for COVID-19 investigation.

Genome-Scale Identification of SARS-CoV-2 and Pan-coronavirus Host Factor Networks

“…As expected, the screens identified the SARS-CoV-2 receptor ACE2 and the well-known host factor cathepsin L ( CTSL ) ( Hoffmann et al., 2020 ; Letko et al., 2020 ; Yeager et al., 1992 ; Figure S2 A). The MERS-CoV receptor DPP4 ( Earnest et al., 2017 ; Wang et al., 2013 ) and the putative SARS-CoV-2 receptors KREMEN1 and ASGR1 did not score in any screen ( Gu et al., 2020 ). Our analysis identified 146 and 171 genes that significantly influenced SARS-CoV-2-induced cell death at 37°C and 33°C, respectively (false discovery rate [FDR] < 0.05) (summarized in Figures 1 B–1E, Figures S2 B and S2C, and Tables S1 A and S1B).…”

AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells

“…Several proteins have been recently identified to interact with SARS-CoV-2 S, including lectin receptors and multiple innate immune receptors, 40,41 heparan sulfate, 42,43 neuropilins, 44,45 asialoglycoprotein receptor 1 and Kremen protein 1. 46 However, most of them lack virology-related evidence to support their roles as SARS-CoV-2 entry factors. Further investigations are needed to establish their roles in mediating SARS-CoV-2 viral entry.…”

Functional interrogation of a SARS-CoV-2 host protein interactome identifies unique and shared coronavirus host factors

“…Moreover, the temperature-specific differences we observed among the same virus (SARS-CoV-2) raises the intriguing hypothesis that there might be differences in the infection process across the temperature gradient spanning the upper and lower airway. Recent studies have nominated additional SARS-CoV-2 entry factors, including kringle containing transmembrane protein 1 (KREMEN1) and asialoglycoprotein receptor 1 (ASGR1) ( Gu et al., 2020 ). One potential explanation for the temperature-specific differences we observed in entry pathways could be differential use of entry factors at 33°C and 37°C.…”