scholarly journals Decision letter: Influenza A virus surface proteins are organized to help penetrate host mucus

2019 ◽  
Author(s):  
Richard A Neher ◽  
Mark Zanin
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Surface Proteins ◽  
Virus Surface

scholarly journals Influenza A virus surface proteins are organized to help penetrate host mucus

2019 ◽  
Author(s):  
Michael D. Vahey ◽  
Daniel A. Fletcher
Keyword(s):  
Sialic Acid ◽  
Influenza A Virus ◽  
Influenza A ◽  
Spatial Organization ◽  
Super Resolution ◽  
Fluorescent Labeling ◽  
Viral Envelope ◽  
Surface Proteins ◽  
Virus Surface ◽  
Super Resolution Microscopy

AbstractInfluenza A virus (IAV) enters cells by binding to sialic acid on the cell surface. To accomplish this while avoiding immobilization by sialic acid in host mucus, viruses rely on a balance between the receptor-binding protein hemagglutinin (HA) and the receptor-cleaving protein neuraminidase (NA). Although genetic aspects of this balance are well-characterized, little is known about how the spatial organization of these proteins in the viral envelope may contribute. Using site-specific fluorescent labeling and super-resolution microscopy, we show that HA and NA are asymmetrically distributed on the surface of filamentous viruses, creating an organization of binding and cleaving activities that causes viruses to step consistently away from their NA-rich pole. This Brownian ratchet-like diffusion produces persistent directional mobility that resolves the virus’s conflicting needs to both penetrate mucus and stably attach to the underlying cells, and could contribute to the prevalence of the filamentous phenotype in clinical isolates of IAV.

scholarly journals Influenza A virus surface proteins are organized to help penetrate host mucus

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Michael D Vahey ◽  
Daniel A Fletcher
Keyword(s):  
Sialic Acid ◽  
Influenza A Virus ◽  
Influenza A ◽  
Spatial Organization ◽  
Super Resolution ◽  
Fluorescent Labeling ◽  
Viral Envelope ◽  
Surface Proteins ◽  
Virus Surface ◽  
Super Resolution Microscopy

Influenza A virus (IAV) enters cells by binding to sialic acid on the cell surface. To accomplish this while avoiding immobilization by sialic acid in host mucus, viruses rely on a balance between the receptor-binding protein hemagglutinin (HA) and the receptor-cleaving protein neuraminidase (NA). Although genetic aspects of this balance are well-characterized, little is known about how the spatial organization of these proteins in the viral envelope may contribute. Using site-specific fluorescent labeling and super-resolution microscopy, we show that HA and NA are asymmetrically distributed on the surface of filamentous viruses, creating a spatial organization of binding and cleaving activities that causes viruses to step consistently away from their NA-rich pole. This Brownian ratchet-like diffusion produces persistent directional mobility that resolves the virus’s conflicting needs to both penetrate mucus and stably attach to the underlying cells, potentially contributing to the prevalence of the filamentous phenotype in clinical isolates of IAV.

scholarly journals Allele-specific nonstationarity in evolution of influenza A virus surface proteins

2019 ◽  
Vol 116 (42) ◽  
pp. 21104-21112 ◽  
Author(s):  
Anfisa V. Popova ◽  
Ksenia R. Safina ◽  
Vasily V. Ptushenko ◽  
Anastasia V. Stolyarova ◽  
Alexander V. Favorov ◽  
...  
Keyword(s):  
Amino Acid ◽  
Influenza A Virus ◽  
Influenza A ◽  
Herd Immunity ◽  
Surface Proteins ◽  
Relative Fitness ◽  
Virus Surface ◽  
Antigenic Sites ◽  
Amino Acid Variant ◽  
Amino Acid Variants

Influenza A virus (IAV) is a major public health problem and a pandemic threat. Its evolution is largely driven by diversifying positive selection so that relative fitness of different amino acid variants changes with time due to changes in herd immunity or genomic context, and novel amino acid variants attain fitness advantage. Here, we hypothesize that diversifying selection also has another manifestation: the fitness associated with a particular amino acid variant should decline with time since its origin, as the herd immunity adapts to it. By tracing the evolution of antigenic sites at IAV surface proteins, we show that an amino acid variant becomes progressively more likely to become replaced by another variant with time since its origin—a phenomenon we call “senescence.” Senescence is particularly pronounced at experimentally validated antigenic sites, implying that it is largely driven by host immunity. By contrast, at internal sites, existing variants become more favorable with time, probably due to arising contingent mutations at other epistatically interacting sites. Our findings reveal a previously undescribed facet of adaptive evolution and suggest approaches for prediction of evolutionary dynamics of pathogens.

Colorimetric detection of influenza A virus using antibody-functionalized gold nanoparticles

The Analyst ◽  
2015 ◽  
Vol 140 (12) ◽  
pp. 3989-3995 ◽  
Author(s):  
Yuanjian Liu ◽  
Linqun Zhang ◽  
Wei Wei ◽  
Hongyu Zhao ◽  
Zhenxian Zhou ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Influenza A Virus ◽  
Clinical Diagnosis ◽  
Specific Antibody ◽  
Influenza A ◽  
Colorimetric Detection ◽  
Viral Pathogen ◽  
Virus Surface ◽  
Functionalized Gold Nanoparticles

A colorimetric immunosensor for IAV based on AuNPs modified with mAb is developed. This assay depends on an ordered AuNPs structure covering the virus surface and can be applied to any viral pathogen by incorporating the appropriate pathogen-specific antibody, giving the proposed method a broad prospect in clinical diagnosis applications.

scholarly journals Modified Sialic Acids on Mucus and Erythrocytes Inhibit Influenza A Virus Hemagglutinin and Neuraminidase Functions

2020 ◽  
Vol 94 (9) ◽  
Author(s):  
Karen N. Barnard ◽  
Brynn K. Alford-Lawrence ◽  
David W. Buchholz ◽  
Brian R. Wasik ◽  
Justin R. LaClair ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Protective Role ◽  
Sialic Acids ◽  
Influenza Viruses ◽  
Surface Proteins ◽  
Clear Understanding ◽  
Cellular Functions ◽  
Acetylneuraminic Acid ◽  
Mouse Tissues

ABSTRACT Sialic acids (Sia) are the primary receptors for influenza viruses and are widely displayed on cell surfaces and in secreted mucus. Sia may be present in variant forms that include O-acetyl modifications at C-4, C-7, C-8, and C-9 positions and N-acetyl or N-glycolyl at C-5. They can also vary in their linkages, including α2-3 or α2-6 linkages. Here, we analyze the distribution of modified Sia in cells and tissues of wild-type mice or in mice lacking CMP-N-acetylneuraminic acid hydroxylase (CMAH) enzyme, which synthesizes N-glycolyl (Neu5Gc) modifications. We also examined the variation of Sia forms on erythrocytes and in saliva from different animals. To determine the effect of Sia modifications on influenza A virus (IAV) infection, we tested for effects on hemagglutinin (HA) binding and neuraminidase (NA) cleavage. We confirmed that 9-O-acetyl, 7,9-O-acetyl, 4-O-acetyl, and Neu5Gc modifications are widely but variably expressed in mouse tissues, with the highest levels detected in the respiratory and gastrointestinal (GI) tracts. Secreted mucins in saliva and surface proteins of erythrocytes showed a high degree of variability in display of modified Sia between different species. IAV HAs from different virus strains showed consistently reduced binding to both Neu5Gc- and O-acetyl-modified Sia; however, while IAV NAs were inhibited by Neu5Gc and O-acetyl modifications, there was significant variability between NA types. The modifications of Sia in mucus may therefore have potent effects on the functions of IAV and may affect both pathogens and the normal flora of different mucosal sites. IMPORTANCE Sialic acids (Sia) are involved in numerous different cellular functions and are receptors for many pathogens. Sia come in chemically modified forms, but we lack a clear understanding of how they alter interactions with microbes. Here, we examine the expression of modified Sia in mouse tissues, on secreted mucus in saliva, and on erythrocytes, including those from IAV host species and animals used in IAV research. These Sia forms varied considerably among different animals, and their inhibitory effects on IAV NA and HA activities and on bacterial sialidases (neuraminidases) suggest a host-variable protective role in secreted mucus.

scholarly journals The effects of modified sialic acids on mucus and erythrocytes on influenza A virus HA and NA functions

2019 ◽  
Author(s):  
Karen N. Barnard ◽  
Brynn K. Alford-Lawrence ◽  
David W. Buchholz ◽  
Brian R. Wasik ◽  
Justin R. LaClair ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Protective Role ◽  
Sialic Acids ◽  
Influenza Viruses ◽  
Surface Proteins ◽  
Clear Understanding ◽  
Cellular Functions ◽  
Acetylneuraminic Acid ◽  
Mouse Tissues

ABSTRACTSialic acids (Sia) are the primary receptors for influenza viruses, and are widely displayed on cell surfaces and in secreted mucus. Sia may be present in variant forms that include O-acetyl modifications at C4, C7, C8, and C9 positions, and N-acetyl or N-glycolyl at C5. They can also vary in their linkages, including α2-3 or α2-6-linkages. Here, we analyzed the distribution of modified Sia in cells and tissues of wild-type mice, or in mice lacking cytidine 5’-monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) enzyme that synthesizes N-glycolyl modifications (Neu5Gc). We also examined the variation of Sia forms on erythrocytes and saliva from different animals. To determine the effect of Sia modifications on influenza A virus (IAV) infection, we tested for effects on hemagglutinin (HA) binding and neuraminidase (NA) cleavage. We confirmed that 9-O-acetyl, 7,9-O-acetyl, 4-O-acetyl, and Neu5Gc modifications are widely but variably expressed in mouse tissues, with the highest levels detected in the respiratory and gastrointestinal tracts. Secreted mucins in saliva and surface proteins of erythrocytes showed a great degree of variability in display of modified Sia between different species. IAV HA from different virus strains showed consistently reduced binding to both Neu5Gc and O-acetyl modified Sia; however, while IAV NA were inhibited by Neu5Gc and O-acetyl modifications, there was significant variability between NA types. The modifications of Sia in mucus may therefore have potent effects on the functions of IAV, and may affect both pathogens and the normal flora of different mucosal sites.IMPORTANCESialic acids (Sia) are involved in many different cellular functions and are receptors for many pathogens. Sia come in many chemically modified forms but we lack a clear understanding of how they alter the interactions with microbes. Here we examine the expression of modified Sia in mouse tissues, on secreted mucus in saliva, and on erythrocytes, including those from IAV host species and animals used in IAV research. These Sia forms varied considerably between different animals, and their inhibitory effects on IAV NA and HA activities and on bacterial sialidases (neuraminidases) suggest a host-variable protective role in secreted mucus.

scholarly journals A release-competent influenza A virus mutant lacking the coding capacity for the neuraminidase active site

2002 ◽  
Vol 83 (11) ◽  
pp. 2683-2692 ◽  
Author(s):  
Larisa V. Gubareva ◽  
Marina S. Nedyalkova ◽  
Dmitri V. Novikov ◽  
K. Gopal Murti ◽  
Erich Hoffmann ◽  
...  
Keyword(s):  
Cell Culture ◽  
Influenza A Virus ◽  
Active Site ◽  
Influenza A ◽  
Mdck Cells ◽  
Compensatory Mechanism ◽  
Receptor Binding Site ◽  
Virus Surface ◽  
Ha Gene ◽  
Coding Capacity

Both influenza A virus surface glycoproteins, the haemagglutinin (HA) and neuraminidase (NA), interact with neuraminic acid-containing receptors. The influenza virus A/Charlottesville/31/95 (H1N1) has shown a substantially reduced sensitivity to NA inhibitor compared with the A/WSN/33 (H1N1) isolate by plaque-reduction assays in Madin–Darby canine kidney (MDCK) cells. However, there was no difference in drug sensitivity in an NA inhibition assay. The replacement of the HA gene of A/WSN/33 with the HA gene of A/Charlottesville/31/95 led to a drastic reduction in sensitivity of A/WSN/33 to NA inhibitor in MDCK cells. Passage of A/Charlottesville/31/95 in cell culture in the presence of an NA inhibitor resulted in the emergence of mutant viruses (delNA) whose genomes lacked the coding capacity for the NA active site. The delNA mutants were plaque-to-plaque purified and further characterized. The delNA-31 mutant produced appreciable yields (∼106 p.f.u./ml) in MDCK cell culture supernatants in the absence of viral or bacterial NA activity. Sequence analysis of the delNA mutant genome revealed no compensatory substitutions in the HA or other genes compared with the wild-type. Our data indicate that sialylation of the oligosaccharide chains in the vicinity of the HA receptor-binding site of A/Charlottesville/31/95 virus reduces the HA binding efficiency and thus serves as a compensatory mechanism for the loss of NA activity. Hyperglycosylation of HA is common in influenza A viruses circulating in humans and has the potential to reduce virus sensitivity to NA inhibitors.

scholarly journals Identification of viral molecules recognized by influenza-specific human cytotoxic T lymphocytes.

1987 ◽  
Vol 165 (2) ◽  
pp. 408-416 ◽  
Author(s):  
F Gotch ◽  
A McMichael ◽  
G Smith ◽  
B Moss
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Cytotoxic T Cells ◽  
Viral Proteins ◽  
Target Cells ◽  
Gene Products ◽  
Virus Surface ◽  
Vaccinia Viruses ◽  
The Matrix

Human cytotoxic T cells specific for influenza A virus were tested for recognition of each of the ten influenza A virus proteins expressed in target cells using recombinant vaccinia viruses. They recognized the matrix M1, polymerase PB2, and nucleoproteins of influenza virus in association with MHC class I antigens. These internal viral proteins were seen by CTL in conjunction with one or more of the available dependent HLA gene products. There was no detectable recognition of influenza virus surface glycoproteins in target cells.

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