scholarly journals Phosphatidylserine Receptors Enhance SARS-CoV-2 Infection: AXL as a Therapeutic Target for COVID-19

2021 ◽  
Author(s):  
Dana Bohan ◽  
Hanora Van Ert ◽  
Natalie Ruggio ◽  
Kai J. Rogers ◽  
Mohammad Baddredine ◽  
...  
Keyword(s):  
Virus Infection ◽  
Human Lung ◽  
Virus Entry ◽  
Endosomal Escape ◽  
Apoptotic Bodies ◽  
Enveloped Viruses ◽  
Surface Receptors ◽  
Cognate Receptor ◽  
Low Concentrations ◽  
Important Host

Phosphatidylserine (PS) receptors are PS binding proteins that mediate uptake of apoptotic bodies. Many enveloped viruses utilize this PS/PS receptor mechanism to adhere to and internalize into the endosomal compartment of cells and this is termed apoptotic mimicry. For viruses that have a mechanism(s) of endosomal escape, apoptotic mimicry is a productive route of virus entry. We evaluated if PS receptors serve as cell surface receptors for SARS-CoV-2 and found that the PS receptors, AXL, TIM-1 and TIM-4, facilitated virus infection when low concentrations of the SARS-CoV-2 cognate receptor, ACE2, was present. Consistent with the established mechanism of PS receptor utilization by other viruses, PS liposomes competed with SARS-CoV-2 for binding and entry. We demonstrated that this PS receptor enhances SARS-CoV-2 binding to and infection of an array of human lung cell lines and is an under-appreciated but potentially important host factor facilitating SARS-CoV-2 entry.

scholarly journals Phosphatidylethanolamine and Phosphatidylserine Synergize To Enhance GAS6/AXL-Mediated Virus Infection and Efferocytosis

2020 ◽  
Vol 95 (2) ◽  
pp. e02079-20
Author(s):  
Lizhou Zhang ◽  
Audrey S. Richard ◽  
Cody B. Jackson ◽  
Amrita Ojha ◽  
Hyeryun Choe
Keyword(s):  
Plasma Membrane ◽  
Virus Infection ◽  
Zika Virus ◽  
Virus Entry ◽  
Eukaryotic Cells ◽  
Target Cells ◽  
Apoptotic Cells ◽  
Biological Processes ◽  
Enveloped Viruses ◽  
Outer Leaflet

ABSTRACTPhosphatidylserine (PS) receptors mediate clearance of apoptotic cells—efferocytosis—by recognizing the PS exposed on those cells. They also mediate the entry of enveloped viruses by binding PS in the virion membrane. Here, we show that phosphatidylethanolamine (PE) synergizes with PS to enhance PS receptor-mediated efferocytosis and virus entry. The presence of PE on the same surface as PS dramatically enhances recognition of PS by PS-binding proteins such as GAS6, PROS, and TIM1. Liposomes containing both PE and PS bound to GAS6 and were engulfed by AXL-expressing cells much more efficiently than those containing PS alone. Further, infection of AXL-expressing cells by infectious Zika virus or Ebola, Chikungunya, or eastern equine encephalitis pseudoviruses was inhibited with greater efficiency by the liposomes containing both PS and PE compared to a mixture of liposomes separately composed of PS and PE. These data demonstrate that simultaneous recognition of PE and PS maximizes PS receptor-mediated virus entry and efferocytosis and underscore the important contribution of PE in these major biological processes.IMPORTANCE Phosphatidylserine (PS) and phosphatidylethanolamine (PE) are usually sequestered to the inner leaflet of the plasma membrane of the healthy eukaryotic cells. During apoptosis, these phospholipids move to the cell’s outer leaflet where they are recognized by so-called PS receptors on surveilling phagocytes. Several pathogenic families of enveloped viruses hijack these PS receptors to gain entry into their target cells. Here, we show that efficiency of these processes is enhanced, namely, PE synergizes with PS to promote PS receptor-mediated virus infection and clearance of apoptotic cells. These findings deepen our understanding of how these fundamental biological processes are executed.

scholarly journals Effects of Basic Amino Acids and Their Derivatives on SARS-CoV-2 and Influenza-A Virus Infection

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1301
Author(s):  
Ivonne Melano ◽  
Li-Lan Kuo ◽  
Yan-Chung Lo ◽  
Po-Wei Sung ◽  
Ni Tien ◽  
...  
Keyword(s):  
Amino Acids ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Enveloped Viruses ◽  
Virus Attachment ◽  
Basic Amino Acids ◽  
Ester Derivative ◽  
Endosomal Acidification

Amino acids have been implicated with virus infection and replication. Here, we demonstrate the effects of two basic amino acids, arginine and lysine, and their ester derivatives on infection of two enveloped viruses, SARS-CoV-2, and influenza A virus. We found that lysine and its ester derivative can efficiently block infection of both viruses in vitro. Furthermore, the arginine ester derivative caused a significant boost in virus infection. Studies on their mechanism of action revealed that the compounds potentially disturb virus uncoating rather than virus attachment and endosomal acidification. Our findings suggest that lysine supplementation and the reduction of arginine-rich food intake can be considered as prophylactic and therapeutic regimens against these viruses while also providing a paradigm for the development of broad-spectrum antivirals.

scholarly journals Authentic Modeling of Human Respiratory Virus Infection in Human Pluripotent Stem Cell-Derived Lung Organoids

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
M. Porotto ◽  
M. Ferren ◽  
Y.-W. Chen ◽  
Y. Siu ◽  
N. Makhsous ◽  
...  
Keyword(s):  
Virus Infection ◽  
Viral Infection ◽  
Pluripotent Stem Cells ◽  
Respiratory Virus ◽  
Human Lung ◽  
Cultured Cells ◽  
Virus Infections ◽  
Distal Lung ◽  
Syncytial Virus ◽  
Respiratory Virus Infections

ABSTRACTInfectious viruses so precisely fit their hosts that the study of natural viral infection depends on host-specific mechanisms that affect viral infection. For human parainfluenza virus 3, a prevalent cause of lower respiratory tract disease in infants, circulating human viruses are genetically different from viruses grown in standard laboratory conditions; the surface glycoproteins that mediate host cell entry on circulating viruses are suited to the environment of the human lung and differ from those of viruses grown in cultured cells. Polarized human airway epithelium cultures have been used to represent the large, proximal airways of mature adult airways. Here we modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids derived from human pluripotent stem cells contain mesoderm and pulmonary endoderm and develop into branching airway and alveolar structures. Whole-genome sequencing analysis of parainfluenza viruses replicating in the organoids showed maintenance of nucleotide identity, suggesting that no selective pressure is exerted on the virus in this tissue. Infection with parainfluenza virus led to viral shedding without morphological changes, while respiratory syncytial virus infection induced detachment and shedding of infected cells into the lung organoid lumens, reminiscent of parainfluenza and respiratory syncytial virus in human infant lungs. Measles virus infection, in contrast, induced syncytium formation. These human stem cell-derived lung organoids may serve as an authentic model for respiratory viral pathogenesis in the developing or infant lung, recapitulating respiratory viral infection in the host.IMPORTANCERespiratory viruses are among the first pathogens encountered by young children, and the significant impact of these viral infections on the developing lung is poorly understood. Circulating viruses are suited to the environment of the human lung and are different from those of viruses grown in cultured cells. We modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids, derived from human pluripotent stem cells, develop into branching airway and alveolar structures and provide a tissue environment that maintains the authentic viral genome. The lung organoids can be genetically engineered prior to differentiation, thereby generating tissues bearing or lacking specific features that may be relevant to viral infection, a feature that may have utility for the study of host-pathogen interaction for a range of lung pathogens.

scholarly journals Murine Polyomavirus Cell Surface Receptors Activate Distinct Signaling Pathways Required for Infection

mBio ◽  
2016 ◽  
Vol 7 (6) ◽  
Author(s):  
Samantha D. O’Hara ◽  
Robert L. Garcea
Keyword(s):  
Cell Surface ◽  
Cell Signaling ◽  
Signaling Pathways ◽  
Mapk Pathway ◽  
Virus Entry ◽  
Pi3k Pathway ◽  
Cell Surface Receptors ◽  
Virus Binding ◽  
Surface Receptors ◽  
Host Signaling

ABSTRACTVirus binding to the cell surface triggers an array of host responses, including activation of specific signaling pathways that facilitate steps in virus entry. Using mouse polyomavirus (MuPyV), we identified host signaling pathways activated upon virus binding to mouse embryonic fibroblasts (MEFs). Pathways activated by MuPyV included the phosphatidylinositol 3-kinase (PI3K), FAK/SRC, and mitogen-activated protein kinase (MAPK) pathways. Gangliosides and α4-integrin are required receptors for MuPyV infection. MuPyV binding to both gangliosides and the α4-integrin receptors was required for activation of the PI3K pathway; however, either receptor interaction alone was sufficient for activation of the MAPK pathway. Using small-molecule inhibitors, we confirmed that the PI3K and FAK/SRC pathways were required for MuPyV infection, while the MAPK pathway was dispensable. Mechanistically, the PI3K pathway was required for MuPyV endocytosis, while the FAK/SRC pathway enabled trafficking of MuPyV along microtubules. Thus, MuPyV interactions with specific cell surface receptors facilitate activation of signaling pathways required for virus entry and trafficking. Understanding how different viruses manipulate cell signaling pathways through interactions with host receptors could lead to the identification of new therapeutic targets for viral infection.IMPORTANCEVirus binding to cell surface receptors initiates outside-in signaling that leads to virus endocytosis and subsequent virus trafficking. How different viruses manipulate cell signaling through interactions with host receptors remains unclear, and elucidation of the specific receptors and signaling pathways required for virus infection may lead to new therapeutic targets. In this study, we determined that gangliosides and α4-integrin mediate mouse polyomavirus (MuPyV) activation of host signaling pathways. Of these pathways, the PI3K and FAK/SRC pathways were required for MuPyV infection. Both the PI3K and FAK/SRC pathways have been implicated in human diseases, such as heart disease and cancer, and inhibitors directed against these pathways are currently being investigated as therapies. It is possible that these pathways play a role in human PyV infections and could be targeted to inhibit PyV infection in immunosuppressed patients.

scholarly journals Lipidomics Issues on Human Positive ssRNA Virus Infection: An Update

Metabolites ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 356 ◽  
Author(s):  
David Balgoma ◽  
Luis Gil-de-Gómez ◽  
Olimpio Montero
Keyword(s):  
Lipid Metabolism ◽  
Virus Infection ◽  
Host Cell ◽  
Viral Infections ◽  
Virus Entry ◽  
Pathogenic Mechanisms ◽  
Cell Lipid ◽  
Ssrna Virus ◽  
Infected Cells

The pathogenic mechanisms underlying the Biology and Biochemistry of viral infections are known to depend on the lipid metabolism of infected cells. From a lipidomics viewpoint, there are a variety of mechanisms involving virus infection that encompass virus entry, the disturbance of host cell lipid metabolism, and the role played by diverse lipids in regard to the infection effectiveness. All these aspects have currently been tackled separately as independent issues and focused on the function of proteins. Here, we review the role of cholesterol and other lipids in ssRNA+ infection.

scholarly journals Enhancement of Enveloped Virus Entry by Phosphatidylserine

2005 ◽  
Vol 79 (17) ◽  
pp. 11496-11500 ◽  
Author(s):  
David A. Coil ◽  
A. Dusty Miller
Keyword(s):  
Cultured Cells ◽  
Virus Entry ◽  
Cell Types ◽  
Virus Vector ◽  
Virus Binding ◽  
Virus Receptor ◽  
Enveloped Viruses ◽  
Virus Vectors ◽  
Enveloped Virus ◽  
Virus Fusion

ABSTRACT Enveloped virus vectors are used in a wide variety of applications. We have discovered that treatment of cultured cells with phosphatidylserine (PS) liposomes can increase virus vector infection by up to 20-fold. This effect does not abrogate virus receptor requirements, is specific to PS compared to other phospholipids, and is limited to enveloped viruses. Furthermore, the enhancement of infection does not occur through increases in virus receptor levels or virus binding, indicating that virus fusion is enhanced. The liposomes are easily generated, store well, and allow enhanced infection with a variety of virus vectors and cell types.

scholarly journals A Conserved Sequence within the H2 Subunit of the Vaccinia Virus Entry/Fusion Complex Is Important for Interaction with the A28 Subunit and Infectivity

2008 ◽  
Vol 82 (13) ◽  
pp. 6244-6250 ◽  
Author(s):  
Gretchen E. Nelson ◽  
Timothy R. Wagenaar ◽  
Bernard Moss
Keyword(s):  
Amino Acid ◽  
Virus Infection ◽  
Glutamic Acid ◽  
Vaccinia Virus ◽  
Virus Entry ◽  
Amino Acid Substitutions ◽  
Null Mutant ◽  
Negative Effects ◽  
Conserved Sequence ◽  
Amino Acid Segment

ABSTRACT The recently described vaccinia virus entry/fusion complex (EFC) comprises at least eight polypeptides that are conserved in all poxviruses. Neither the structure of the complex nor the roles of individual subunits are known. Here we provide evidence for an interaction between the H2 and A28 subunits in the context of a virus infection as well as in uninfected cells transfected with plasmids expressing the corresponding genes. We focused on a highly conserved 21-amino acid-segment in H2 that is flanked by cysteine residues. The effect of amino acid substitutions within the 21-amino-acid segment was determined by an infectivity complementation assay using a conditional H2-null mutant of vaccinia virus. Mutations that had no, moderate, or large negative effects on complementation were found. The latter group included glutamic acid substitutions of leucine and individual glycines and alanine substitution of both glycines within a LGYSG sequence. Mutations with the most pronounced effect on infectivity disrupted the interaction of H2 with A28 to the greatest extent in both infected and uninfected cells. These data indicate that the LGYSG sequence is important for the interaction of H2 with A28 and suggest that this sequence is buried within the EFC complex.

scholarly journals Antibody Binding in Proximity to the Receptor/Glycoprotein Complex Leads to a Basal Level of Virus Neutralization

2007 ◽  
Vol 81 (16) ◽  
pp. 8809-8813 ◽  
Author(s):  
Xinzhen Yang ◽  
Inna Lipchina ◽  
Michelle Lifton ◽  
Liping Wang ◽  
Joseph Sodroski
Keyword(s):  
Conformational Changes ◽  
Steric Hindrance ◽  
Virus Entry ◽  
Receptor Protein ◽  
Receptor Complex ◽  
Retroviral Infection ◽  
Enveloped Viruses ◽  
Glycoprotein Complex ◽  
Additional Support ◽  
Avian Sarcoma

ABSTRACT Hypothetically, antibodies may neutralize enveloped viruses by diverse mechanisms, such as disruption of receptor binding, interference with conformational changes required for virus entry, steric hindrance, or virus aggregation. Here, we demonstrate that retroviral infection mediated by the avian sarcoma-leukosis virus (ASLV-A) envelope glycoproteins can be neutralized by an antibody directed against a functionally unimportant component of a chimeric receptor protein. Thus, the binding of an antibody in proximity to the retroviral envelope glycoprotein-receptor complex, without binding to the entry machinery itself, results in neutralization. This finding provides additional support for the hypothesis that steric hindrance is sufficient for antibody-mediated neutralization of retroviruses.

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