Phosphatidylserine receptors enhance SARS-CoV-2 infection

作者：Dana Bohan, Hanora Van Ert, Natalie Ruggio, Kai J. Rogers, Mohammad Badreddine, José A. Aguilar-Briseño, Jonah Elliff, Roberth Anthony Rojas Chávez, Boning Gao, Tomasz Stokowy, Eleni Christakou, Petri Kursula, David Micklem, Gro Gausdal, Hillel Haim, John D. Minna, James B. Lorens, Wendy Maury · 发表于：PLoS Pathogens · 年份：2021 · DOI：10.1371/journal.ppat.1009743 · 被引用次数：134 · 研究领域：Phagocytosis and Immune Regulation、SARS-CoV-2 and COVID-19 Research、COVID-19 Clinical Research Studies

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...