Journal article
Phosphatidylserine receptors enhance SARS-CoV-2 infection
PLoS pathogens, Vol.17(11), pp.e1009743-e1009743
11/2021
DOI: 10.1371/journal.ppat.1009743
PMCID: PMC8641883
PMID: 34797899
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.
Details
- Title: Subtitle
- Phosphatidylserine receptors enhance SARS-CoV-2 infection
- Creators
- Dana Bohan - University of IowaHanora Van Ert - University of IowaNatalie Ruggio - University of IowaKai J Rogers - University of IowaMohammad Badreddine - University of IowaJosé A Aguilar-Briseño - University of IowaJonah M Elliff - University of IowaRoberth Anthony Rojas Chavez - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, United States of AmericaBoning Gao - The University of Texas Southwestern Medical CenterTomasz Stokowy - University of BergenEleni Christakou - University of BergenPetri Kursula - University of BergenDavid Micklem - BerGenBio (Norway)Gro Gausdal - BerGenBio (Norway)Hillel Haim - University of IowaJohn Minna - The University of Texas Southwestern Medical CenterJames B Lorens - University of BergenWendy Maury - University of Iowa
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.17(11), pp.e1009743-e1009743
- DOI
- 10.1371/journal.ppat.1009743
- PMID
- 34797899
- PMCID
- PMC8641883
- NLM abbreviation
- PLoS Pathog
- ISSN
- 1553-7366
- eISSN
- 1553-7374
- Publisher
- Public Library of Science
- Grant note
- T32 AI007511 / NIAID NIH HHS P50 CA070907 / NCI NIH HHS U54 CA260560 / NCI NIH HHS T32 GM007337 / NIGMS NIH HHS T32 GM139776 / NIGMS NIH HHS R01 AI134733 / NIAID NIH HHS
- Language
- English
- Date published
- 11/2021
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984230422602771
Metrics
5 Record Views