Phosphatidylserine Receptor Enhancement of SARS-CoV-2 Entry: AXL as a Therapeutic Target for COVID-19
Author(s): ,
Dana Bohan
Affiliations:
Department of Microbiology and Immunology, University of Iowa
,
Wendy Maury
Affiliations:
Department of Microbiology and Immunology, University of Iowa
,
Hanora Van Ert
Affiliations:
Department of Microbiology and Immunology, University of Iowa
,
James Lorens
Affiliations:
University of Bergen
,
Hillel Haim
Affiliations:
Department of Microbiology and Immunology, University of Iowa
,
Natalie Ruggio
Affiliations:
Department of Microbiology and Immunology, University of Iowa
,
Kai Rogers
Affiliations:
Department of Microbiology and Immunology, University of Iowa
,
Tomasz Stokowy
Affiliations:
University of Bergen
,
Roberth Anthony Rojas Chávez
Affiliations:
Department of Microbiology and Immunology, University of Iowa
,
David Micklem
Affiliations:
BerGenBio Ltd
,
Boning Gao
Affiliations:
University of Texas Southwestern Medical Center
John Minna
Affiliations:
University of Texas Southwestern Medical Center
AAI VIRTUAL. Bohan D. 05/10/21; 318196; 1377 Disclosure(s): Nothing to disclose
Mr. Dana Bohan
Mr. Dana Bohan
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Abstract
Discussion Forum (1)
Engage with the presenter here during: Poster Session: Innate immunity to viruses
On Monday May 10, 2021 from 6:30 PM to 8:00 PM (ET)

Phosphatidylserine Receptor Enhancement of SARS-CoV-2 Entry: AXL as a Therapeutic Target for COVID-19

Author(s): Dana Bohan, Hanora Van Ert, Kai Rogers, Natalie Ruggio, Roberth Anthony Rojas Chávez, Tomasz Stokowy, Hillel Haim, Boning Gao, John Minna, David Micklem, James Lorens, Wendy Maury

Author Institution(s): Department of Microbiology and Immunology, University of Iowa; Department of Microbiology and Immunology, University of Iowa; Department of Microbiology and Immunology, University of Iowa; Department of Microbiology and Immunology, University of Iowa; Department of Microbiology and Immunology, University of Iowa; University of Bergen; Department of Microbiology and Immunology, University of Iowa; University of Texas Southwestern Medical Center; University of Texas Southwestern Medical Center; BerGenBio Ltd; University of Bergen; Department of Microbiology and Immunology, University of Iowa

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.
Engage with the presenter here during: Poster Session: Innate immunity to viruses
On Monday May 10, 2021 from 6:30 PM to 8:00 PM (ET)

Phosphatidylserine Receptor Enhancement of SARS-CoV-2 Entry: AXL as a Therapeutic Target for COVID-19

Author(s): Dana Bohan, Hanora Van Ert, Kai Rogers, Natalie Ruggio, Roberth Anthony Rojas Chávez, Tomasz Stokowy, Hillel Haim, Boning Gao, John Minna, David Micklem, James Lorens, Wendy Maury

Author Institution(s): Department of Microbiology and Immunology, University of Iowa; Department of Microbiology and Immunology, University of Iowa; Department of Microbiology and Immunology, University of Iowa; Department of Microbiology and Immunology, University of Iowa; Department of Microbiology and Immunology, University of Iowa; University of Bergen; Department of Microbiology and Immunology, University of Iowa; University of Texas Southwestern Medical Center; University of Texas Southwestern Medical Center; BerGenBio Ltd; University of Bergen; Department of Microbiology and Immunology, University of Iowa

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.
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