University of Oulu

Bohan D, Van Ert H, Ruggio N, Rogers KJ, Badreddine M, Aguilar Briseño JA, et al. (2021) Phosphatidylserine receptors enhance SARS-CoV-2 infection. PLoS Pathog 17(11): e1009743. https://doi.org/10.1371/journal.ppat.1009743

Phosphatidylserine receptors enhance SARS-CoV-2 infection

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Author: Bohan, Dana1; Van Ert, Hanora1; Ruggio, Natalie1;
Organizations: 1Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, United States of America
2Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
3Department of Biomedicine, University of Bergen, Bergen, Norway
4BerGenBio ASA, Bergen, Norway
5Biocenter Oulu & Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.2 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022022420757
Language: English
Published: Public Library of Science, 2021
Publish Date: 2022-02-24
Description:

Abstract

Phosphatidylserine (PS) receptors enhance infection of many enveloped viruses through virion-associated PS binding that is termed apoptotic mimicry. Here we show that this broadly shared uptake mechanism is utilized by SARS-CoV-2 in cells that express low surface levels of ACE2. Expression of members of the TIM (TIM-1 and TIM-4) and TAM (AXL) families of PS receptors enhance SARS-CoV-2 binding to cells, facilitate internalization of fluorescently-labeled virions and increase ACE2-dependent infection of SARS-CoV-2; however, PS receptors alone did not mediate infection. We were unable to detect direct interactions of the PS receptor AXL with purified SARS-CoV-2 spike, contrary to a previous report. Instead, our studies indicate that the PS receptors interact with PS on the surface of SARS-CoV-2 virions. In support of this, we demonstrate that: 1) significant quantities of PS are located on the outer leaflet of SARS-CoV-2 virions, 2) PS liposomes, but not phosphatidylcholine liposomes, reduced entry of VSV/Spike pseudovirions and 3) an established mutant of TIM-1 which does not bind to PS is unable to facilitate entry of SARS-CoV-2. As AXL is an abundant PS receptor on a number of airway lines, we evaluated small molecule inhibitors of AXL signaling such as bemcentinib for their ability to inhibit SARS-CoV-2 infection. Bemcentinib robustly inhibited virus infection of Vero E6 cells as well as multiple human lung cell lines that expressed AXL. This inhibition correlated well with inhibitors that block endosomal acidification and cathepsin activity, consistent with AXL-mediated uptake of SARS-CoV-2 into the endosomal compartment. We extended our observations to the related betacoronavirus mouse hepatitis virus (MHV), showing that inhibition or ablation of AXL reduces MHV infection of murine cells. In total, our findings provide evidence that PS receptors facilitate infection of the pandemic coronavirus SARS-CoV-2 and suggest that inhibition of the PS receptor AXL has therapeutic potential against SARS-CoV-2.

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Series: PLoS pathogens
ISSN: 1553-7366
ISSN-E: 1553-7374
ISSN-L: 1553-7366
Volume: 17
Issue: 11
Article number: e1009743
DOI: 10.1371/journal.ppat.1009743
OADOI: https://oadoi.org/10.1371/journal.ppat.1009743
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
1182 Biochemistry, cell and molecular biology
Subjects:
Funding: This study was primarily supported by National Institutes of Health (NIH/NIAID grant R01 AI134733 (WM), NIH/NCI grants P50 CA070907 (JM), U54 CA260560 (JM)) and a contract from BerGenBio to WJM. DB was supported by National Institutes of Health grant T32AI007511. HVE and JME were supported by National Institutes of Health T32 GM007337. EC was supported by the Norwegian Research Council Industrial PhD Studentship 311399. Study design, data collection and analysis and preparation of the manuscript was coordinated with scientists at BerGenBio. BerGenBio was partially responsible for funding this work. A decision to publish was independent of any input from BerGenBio personnel. The funders had no role in study design, data collection, data analysis, decision to publish, or preparation of the manuscript.
Dataset Reference: RNAseq data is available at NCBI GEO under the accession number GSE178942.
Copyright information: © 2021 Bohan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
  https://creativecommons.org/licenses/by/4.0/