Enveloped RNA virus utilization of phosphatidylserine receptors: Advantages of exploiting a conserved, widely available mechanism of entry

Bohan, Dana; Maury, Wendy

doi:10.1371/journal.ppat.1009899

Cited by 11 publications

(8 citation statements)

References 58 publications

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“…The robust body of PS receptor research completed in the last decade and historical patterns of zoonotic events (Ebola virus, Zika virus, SARS-CoV) suggest that future emergent viral pathogens are likely to utilize PS receptors to enhance entry and infection [64]. The observations reported here that PS receptors are utilized by a novel pandemic coronavirus support this conclusion.…”

Section: Discussionsupporting

confidence: 63%

Phosphatidylserine receptors enhance SARS-CoV-2 infection

et al. 2021

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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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Section: Discussionsupporting

confidence: 63%

Phosphatidylserine receptors enhance SARS-CoV-2 infection

et al. 2021

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“…They found that AXL promoted SARS-CoV-2 infection in ACE2-KO cells, suggesting a role independent of ACE2 [ 101 ]. This conclusion differs from the study of Bohan et al [ 102 , 103 ] finding that AXL promoted SARS-CoV-2 infection through interactions with virion-associated-phosphatidyl serine in an ACE2-dependent manner.…”

Section: Sars-cov-2 Alternative Receptorscontrasting

confidence: 99%

“…Regarding its importance in SARS-CoV-2 infection, a study by S. Wang et al suggested that AXL is a novel candidate receptor for SARS-CoV-2 [ 101 ]. A second study by Bohan et al [ 102 , 103 ] confirmed this finding but disputed the exact role of AXL. Wang et al [ 101 ] speculated that there are additional receptors or co-receptors for SARS-CoV-2 in addition to ACE2, as it shows very low level of expression in the lungs.…”

Section: Sars-cov-2 Alternative Receptorsmentioning

confidence: 96%

Receptors and Cofactors That Contribute to SARS-CoV-2 Entry: Can Skin Be an Alternative Route of Entry?

Barthe

Hertereau

Lamghari

et al. 2023

IJMS

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To prevent the spread of SARS-CoV-2, all routes of entry of the virus into the host must be mapped. The skin is in contact with the external environment and thus may be an alternative route of entry to transmission via the upper respiratory tract. SARS-CoV-2 cell entry is primarily dependent on ACE2 and the proteases TMPRSS2 or cathepsin L but other cofactors and attachment receptors have been identified that may play a more important role in specific tissues such as the skin. The continued emergence of new variants may also alter the tropism of the virus. In this review, we summarize current knowledge on these receptors and cofactors, their expression profile, factors modulating their expression and their role in facilitating SARS-CoV-2 infection. We discuss their expression in the skin and their possible involvement in percutaneous infection since the presence of the virus has been detected in the skin.

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“…However, emerging viruses have a priori no selection pressure to evolve the capacity to recognize human receptors since virus–host co-evolution is driven mainly by long-term relationships with the reservoir hosts. Many viruses use much broader mechanisms to invade the host cells, such as binding to glycan-binding proteins via glycans on the viral glycoprotein or binding to host cell phosphatidylserine receptors via the lipids of the viral envelope [ 92 , 93 , 94 ].…”

Section: Discussionmentioning

confidence: 99%

“…These viruses acquire phosphatidylserine in their envelope during budding. The cellular phosphatidylserine receptors, which mediate their entry are molecules of the T-cell immunoglobulin and mucin (TIM) receptor family, in particular TIM-1 and TIM-4, and receptor tyrosine kinases of the Tyro3/Axl/Mer (TAM) family [ 92 , 94 ]. Thus, these viruses can exploit highly conserved clearance and immunomodulatory processes developed by the eukaryotic cells to easily cross the species barrier.…”

Section: Discussionmentioning

confidence: 99%

Designed Ankyrin Repeat Proteins: A New Class of Viral Entry Inhibitors

Walser

Mayor

Rothenberger

2022

Viruses

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Designed ankyrin repeat proteins (DARPins) are engineered proteins comprising consensus designed ankyrin repeats as scaffold. Tightly packed repeats form a continuous hydrophobic core and a large groove-like solvent-accessible surface that creates a binding surface. DARPin domains recognizing a target of interest with high specificity and affinity can be generated using a synthetic combinatorial library and in vitro selection methods. They can be linked together in a single molecule to build multispecific and multifunctional proteins without affecting expression or function. The modular architecture of DARPins offers unprecedented possibilities of design and opens avenues for innovative antiviral strategies.

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Enveloped RNA virus utilization of phosphatidylserine receptors: Advantages of exploiting a conserved, widely available mechanism of entry

Cited by 11 publications

References 58 publications

Phosphatidylserine receptors enhance SARS-CoV-2 infection

Phosphatidylserine receptors enhance SARS-CoV-2 infection

Receptors and Cofactors That Contribute to SARS-CoV-2 Entry: Can Skin Be an Alternative Route of Entry?

Designed Ankyrin Repeat Proteins: A New Class of Viral Entry Inhibitors

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