scholarly journals The Mechanism of Poly-Galloyl-Glucoses Preventing Influenza A Virus Entry into Host Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e94392 ◽  
Author(s):  
Hu Ge ◽  
Ge Liu ◽  
Yang-Fei Xiang ◽  
Yu Wang ◽  
Chao-Wan Guo ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Virus Entry ◽  
Host Cells

scholarly journals The immunomodulatory CEA cell adhesion molecule 6 (CEACAM6/CD66c) is a candidate receptor for the influenza A virus

2017 ◽  
Author(s):  
Shah Kamranur Rahman ◽  
Mairaj Ahmed Ansari ◽  
Pratibha Gaur ◽  
Imtiyaz Ahmad ◽  
Chandrani Chakravarty ◽  
...  
Keyword(s):  
Cell Surface ◽  
Influenza A Virus ◽  
Influenza A ◽  
Virus Entry ◽  
Semipermeable Membrane ◽  
Host Cells ◽  
Lung Cells ◽  
Membrane Glycoprotein ◽  
Virus Binding ◽  
Host Membrane

AbstractTo establish a productive infection in host cells, viruses often use one or multiple host membrane glycoprotein as their receptors. For Influenza A virus (IAV) such a glycoprotein receptor has not been described, to date. Here we show that IAV is using the host membrane glycoprotein CD66c as a receptor for entry into human epithelial lung cells. Neuraminidase (NA), a viral spike protein binds to CD66c on the cell surface during IAV entry into the host cells. Lung cells overexpressing CD66c showed an increase in virus binding and subsequent entry into the cell. Upon comparison, CD66c demonstrated higher binding capacity than other membrane glycoproteins (EGFR and DC-SIGN) reported earlier to facilitate IAV entry into host cells. siRNA mediated knockdown of CD66c from lung cells inhibited virus binding on cell surface and entry into cells. Blocking CD66c by antibody on the cell surface resulted in decreased virus entry. We found CD66c is a specific glycoprotein receptor for influenza A virus that did not affect entry of non-IAV RNA virus (Hepatitis C virus). Finally, IAV pre-incubated with recombinant CD66c protein when administered intranasally in mice showed decreased cytopathic effects in mice lungs. This publication is the first to report CD66c (CEACAM6) as a glycoprotein receptor for Influenza A virus.Significance StatementCells are enclosed by a semipermeable membrane that allows selective exchange of biomolecules between cells and their surroundings. A set of specialized proteins in this semipermeable membrane, work like gatekeepers to the cell and regulate entry of these biomolecules. One class of such surface proteins is termed as receptors. Viruses bind to one or more of these receptors and manipulate gatekeepers for their own successful entry into host-cells. A membrane protein that influenza A virus (Flu virus) uses for entry into the cells was not discovered till date. This study reports for the first time, a receptor for influenza A virus, that was sought after by researchers for decades. The viral receptor is a promising target that can be used to inhibit virus entry into host cells.

scholarly journals Suppression of influenza A virus replication in human lung epithelial cells by noncytotoxic concentrations bafilomycin A1

2015 ◽  
Vol 308 (3) ◽  
pp. L270-L286 ◽  
Author(s):  
Behzad Yeganeh ◽  
Saeid Ghavami ◽  
Andrea L. Kroeker ◽  
Thomas H. Mahood ◽  
Gerald L. Stelmack ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Host Cell ◽  
Influenza A Virus ◽  
Influenza A ◽  
Life Cycles ◽  
Host Cells ◽  
Nuclear Accumulation ◽  
Low Concentration ◽  
High Concentrations ◽  
The Impact

Subcellular trafficking within host cells plays a critical role in viral life cycles, including influenza A virus (IAV). Thus targeting relevant subcellular compartments holds promise for effective intervention to control the impact of influenza infection. Bafilomycin A1(Baf-A1), when used at relative high concentrations (≥10 nM), inhibits vacuolar ATPase (V-ATPase) and reduces endosome acidification and lysosome number, thus inhibiting IAV replication but promoting host cell cytotoxicity. We tested the hypothesis that much lower doses of Baf-A1also have anti-IAV activity, but without toxic effects. Thus we assessed the antiviral activity of Baf-A1at different concentrations (0.1–100 nM) in human alveolar epithelial cells (A549) infected with IAV strain A/PR/8/34 virus (H1N1). Infected and mock-infected cells pre- and cotreated with Baf-A1were harvested 0–24 h postinfection and analyzed by immunoblotting, immunofluorescence, and confocal and electron microscopy. We found that Baf-A1had disparate concentration-dependent effects on subcellular organelles and suppressed affected IAV replication. At concentrations ≥10 nM Baf-A1inhibited acid lysosome formation, which resulted in greatly reduced IAV replication and release. Notably, at a very low concentration of 0.1 nM that is insufficient to reduce lysosome number, Baf-A1retained the capacity to significantly impair IAV nuclear accumulation as well as IAV replication and release. In contrast to the effects of high concentrations of Baf-A1, very low concentrations did not exhibit cytotoxic effects or induce apoptotic cell death, based on morphological and FACS analyses. In conclusion, our results reveal that low-concentration Baf-A1is an effective inhibitor of IAV replication, without impacting host cell viability.

scholarly journals Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

2016 ◽  
Vol 113 (42) ◽  
pp. 11931-11936 ◽  
Author(s):  
Wenqian He ◽  
Gene S. Tan ◽  
Caitlin E. Mullarkey ◽  
Amanda J. Lee ◽  
Mannie Man Wai Lam ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Critical Role ◽  
Host Cells ◽  
Viral Glycoprotein ◽  
Effector Functions ◽  
Dependent Cell

The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections. The majority of these antibodies bind to the hemagglutinin (HA) head domain and function by blocking the receptor binding site, preventing infection of host cells. Recently, elicitation of broadly neutralizing antibodies which target the conserved HA stalk domain has become a promising “universal” influenza virus vaccine strategy. The ability of these antibodies to elicit Fc-dependent effector functions has emerged as an important mechanism through which protection is achieved in vivo. However, the way in which Fc-dependent effector functions are regulated by polyclonal influenza virus-binding antibody mixtures in vivo has never been defined. Here, we demonstrate that interactions among viral glycoprotein-binding antibodies of varying specificities regulate the magnitude of antibody-dependent cell-mediated cytotoxicity induction. We show that the mechanism responsible for this phenotype relies upon competition for binding to HA on the surface of infected cells and virus particles. Nonneutralizing antibodies were poor inducers and did not inhibit antibody-dependent cell-mediated cytotoxicity. Interestingly, anti-neuraminidase antibodies weakly induced antibody-dependent cell-mediated cytotoxicity and enhanced induction in the presence of HA stalk-binding antibodies in an additive manner. Our data demonstrate that antibody specificity plays an important role in the regulation of ADCC, and that cross-talk among antibodies of varying specificities determines the magnitude of Fc receptor-mediated effector functions.

scholarly journals LY6E Restricts Entry of Human Coronaviruses, Including Currently Pandemic SARS-CoV-2

2020 ◽  
Vol 94 (18) ◽  
Author(s):  
Xuesen Zhao ◽  
Shuangli Zheng ◽  
Danying Chen ◽  
Mei Zheng ◽  
Xinglin Li ◽  
...  
Keyword(s):  
Influenza A ◽  
Yellow Fever Virus ◽  
Virus Entry ◽  
Ectopic Expression ◽  
A549 Cells ◽  
Cellular Protein ◽  
Host Cells ◽  
Cellular Proteins ◽  
Human Coronavirus ◽  
Human Coronaviruses

ABSTRACT C3A is a subclone of the human hepatoblastoma HepG2 cell line with strong contact inhibition of growth. We fortuitously found that C3A was more susceptible to human coronavirus HCoV-OC43 infection than HepG2, which was attributed to the increased efficiency of virus entry into C3A cells. In an effort to search for the host cellular protein(s) mediating the differential susceptibility of the two cell lines to HCoV-OC43 infection, we found that ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2), gamma-interferon-inducible lysosome/endosome-localized thiolreductase (GILT), and lymphocyte antigen 6 family member E (LY6E), the three cellular proteins identified to function in interference with virus entry, were expressed at significantly higher levels in HepG2 cells. Functional analyses revealed that ectopic expression of LY6E, but not GILT or ADAP2, in HEK 293 cells inhibited the entry of HCoV-O43. While overexpression of LY6E in C3A and A549 cells efficiently inhibited the infection of HCoV-OC43, knockdown of LY6E expression in HepG2 significantly increased its susceptibility to HCoV-OC43 infection. Moreover, we found that LY6E also efficiently restricted the entry mediated by the envelope spike proteins of other human coronaviruses, including the currently pandemic SARS-CoV-2. Interestingly, overexpression of serine protease TMPRSS2 or amphotericin treatment significantly neutralized the IFN-inducible transmembrane 3 (IFITM3) restriction of human coronavirus (CoV) entry, but did not compromise the effect of LY6E on the entry of human coronaviruses. The work reported herein thus demonstrates that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis via a mechanism distinct from other factors that modulate CoV entry. IMPORTANCE Virus entry into host cells is one of the key determinants of host range and cell tropism and is subjected to the control of host innate and adaptive immune responses. In the last decade, several interferon-inducible cellular proteins, including IFITMs, GILT, ADAP2, 25CH, and LY6E, had been identified to modulate the infectious entry of a variety of viruses. Particularly, LY6E was recently identified as a host factor that facilitates the entry of several human-pathogenic viruses, including human immunodeficiency virus, influenza A virus, and yellow fever virus. Identification of LY6E as a potent restriction factor of coronaviruses expands the biological function of LY6E and sheds new light on the immunopathogenesis of human coronavirus infection.

scholarly journals Low-Fidelity Assembly of Influenza A Virus Promotes Escape from Host Cells

Cell ◽  
2020 ◽  
Vol 180 (1) ◽  
pp. 205
Author(s):  
Michael D. Vahey ◽  
Daniel A. Fletcher
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Host Cells

scholarly journals Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

2015 ◽  
Vol 90 (5) ◽  
pp. 2403-2417 ◽  
Author(s):  
Chuan Xia ◽  
Madhuvanthi Vijayan ◽  
Curtis J. Pritzl ◽  
Serge Y. Fuchs ◽  
Adrian B. McDermott ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Influenza A Virus ◽  
Influenza A ◽  
Type I Interferon ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Ha Protein

ABSTRACTInfluenza A virus (IAV) employs diverse strategies to circumvent type I interferon (IFN) responses, particularly by inhibiting the synthesis of type I IFNs. However, it is poorly understood if and how IAV regulates the type I IFN receptor (IFNAR)-mediated signaling mode. In this study, we demonstrate that IAV induces the degradation of IFNAR subunit 1 (IFNAR1) to attenuate the type I IFN-induced antiviral signaling pathway. Following infection, the level of IFNAR1 protein, but not mRNA, decreased. Indeed, IFNAR1 was phosphorylated and ubiquitinated by IAV infection, which resulted in IFNAR1 elimination. The transiently overexpressed IFNAR1 displayed antiviral activity by inhibiting virus replication. Importantly, the hemagglutinin (HA) protein of IAV was proved to trigger the ubiquitination of IFNAR1, diminishing the levels of IFNAR1. Further, influenza A viral HA1 subunit, but not HA2 subunit, downregulated IFNAR1. However, viral HA-mediated degradation of IFNAR1 was not caused by the endoplasmic reticulum (ER) stress response. IAV HA robustly reduced cellular sensitivity to type I IFNs, suppressing the activation of STAT1/STAT2 and induction of IFN-stimulated antiviral proteins. Taken together, our findings suggest that IAV HA causes IFNAR1 degradation, which in turn helps the virus escape the powerful innate immune system. Thus, the research elucidated an influenza viral mechanism for eluding the IFNAR signaling pathway, which could provide new insights into the interplay between influenza virus and host innate immunity.IMPORTANCEInfluenza A virus (IAV) infection causes significant morbidity and mortality worldwide and remains a major health concern. When triggered by influenza viral infection, host cells produce type I interferon (IFN) to block viral replication. Although IAV was shown to have diverse strategies to evade this powerful, IFN-mediated antiviral response, it is not well-defined if IAV manipulates the IFN receptor-mediated signaling pathway. Here, we uncovered that influenza viral hemagglutinin (HA) protein causes the degradation of type I IFN receptor subunit 1 (IFNAR1). HA promoted phosphorylation and polyubiquitination of IFNAR1, which facilitated the degradation of this receptor. The HA-mediated elimination of IFNAR1 notably decreased the cells' sensitivities to type I IFNs, as demonstrated by the diminished expression of IFN-induced antiviral genes. This discovery could help us understand how IAV regulates the host innate immune response to create an environment optimized for viral survival in host cells.

scholarly journals A “building block” approach to the new influenza A virus entry inhibitors with reduced cellular toxicities

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Dongguo Lin ◽  
Fangfang Li ◽  
Qiuyi Wu ◽  
Xiangkun Xie ◽  
Wenjiao Wu ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Building Block ◽  
Influenza A ◽  
Virus Entry ◽  
Entry Inhibitors ◽  
Virus Entry Inhibitors ◽  
Block Approach

scholarly journals The Influenza A Virus M2 Cytoplasmic Tail Is Required for Infectious Virus Production and Efficient Genome Packaging

2005 ◽  
Vol 79 (6) ◽  
pp. 3595-3605 ◽  
Author(s):  
Matthew F. McCown ◽  
Andrew Pekosz
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Infectious Virus ◽  
Virus Production ◽  
Cytoplasmic Tail ◽  
Host Cells ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Virus Particles

ABSTRACT The M2 integral membrane protein encoded by influenza A virus possesses an ion channel activity that is required for efficient virus entry into host cells. The role of the M2 protein cytoplasmic tail in virus replication was examined by generating influenza A viruses encoding M2 proteins with truncated C termini. Deletion of 28 amino acids (M2Stop70) resulted in a virus that produced fourfold-fewer particles but >1,000-fold-fewer infectious particles than wild-type virus. Expression of the full-length M2 protein in trans restored the replication of the M2 truncated virus. Although the M2Stop70 virus particles were similar to wild-type virus in morphology, the M2Stop70 virions contained reduced amounts of viral nucleoprotein and genomic RNA, indicating a defect in vRNP packaging. The data presented indicate the M2 cytoplasmic tail plays a role in infectious virus production by coordinating the efficient packaging of genome segments into influenza virus particles.

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