Abstract
Phosphatidylserine Receptor Enhancement of SARS-CoV-2 Entry: AXL as a Therapeutic Target for COVID-19
The Journal of immunology (1950), Vol.206(1_Supplement), pp.20-20.38
05/01/2021
DOI: 10.4049/jimmunol.206.Supp.20.38
Abstract
Abstract Phosphatidylserine (PS) receptors enhance infection of a wide range of enveloped RNA 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. Under ACE2lo conditions, expression of members of the TIM and TAM families of PS receptors synergized with ACE2 to enhance SARS-CoV-2 infection; however, PS receptors alone did not mediate infection. PS receptors enhanced SARS-CoV-2 binding to the surface of cells. While PS receptors did not interact directly with purified SARS-CoV-2 spike, addition of PS liposomes reduced entry of VSV-SARS-CoV-2 spike pseudovirions, providing evidence that PS/PS receptor interactions are mediating the effect. AXL being abundant on airway cell 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 some lung cell lines that expressed AXL. This inhibition correlated well with inhibitors that block cathepsin activity, consistent with AXL-mediated uptake of SARS-CoV-2 into the endosomal compartment. RNAseq studies in Vero E6 and A549-hACE2 cells demonstrated that bemcentinib reduced SARS-CoV-2 transcripts dramatically. The ability of bemcentinib to decrease coronavirus infection in vivo was assessed using the betacoronavirus mouse hepatitis virus (MHV). Liver titers and virus load of MHV were significantly inhibited by bemcentinib at day 5 of infection. In total, our findings provide evidence that PS receptors facilitate infection of the pandemic coronavirus SARS-CoV-2 and that inhibition of signaling of the PS receptor AXL has therapeutic potential against SARS-CoV-2.
Details
- Title: Subtitle
- Phosphatidylserine Receptor Enhancement of SARS-CoV-2 Entry: AXL as a Therapeutic Target for COVID-19
- Creators
- Dana Bohan - University of IowaHanora Van Ert - University of IowaKai Rogers - University of IowaNatalie Ruggio - University of IowaRoberth Anthony Rojas Chávez - University of IowaTomasz Stokowy - University of BergenHillel Haim - University of IowaBoning Gao - The University of Texas Southwestern Medical CenterJohn Minna - The University of Texas Southwestern Medical CenterDavid Micklem - 4BerGenBio Ltd, United KingdomJames Lorens - University of BergenWendy Maury - University of Iowa
- Resource Type
- Abstract
- Publication Details
- The Journal of immunology (1950), Vol.206(1_Supplement), pp.20-20.38
- DOI
- 10.4049/jimmunol.206.Supp.20.38
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Language
- English
- Date published
- 05/01/2021
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984413079102771
Metrics
1 Record Views