Neutrophils do not bind to or phagocytize human immune complexes formed with influenza virus

Abstract Neutrophils appear to form the first line of defense against influenza virus, yet it is unclear how these leukocytes recognize influenza- infected cells. While demonstrating that neutrophils adhere specifically to the sialic acid-binding site on the hemagglutinin molecule (HA) on the surface of influenza-infected (WSN[H1N1]) epithelial cells and not to other viral or epithelial cell antigens, it was observed that human neutrophils do not recognize immune complexes formed with influenza virus. Intact antibodies (mouse monoclonal antibodies [MoAbs] IgG1 and IgG2b, human immune heat-inactivated serum [predominantly IgG1], and IgG purified from human immune serum) that block the sialic acid-binding site on HA significantly reduced (> 80%) neutrophil adherence to influenza-infected epithelial cells. Binding and phagocytosis of free influenza virions and neutrophil agglutination by influenza virus were completely prevented by these antibodies. Intact and F(ab')2 fragments of mouse MoAbs to other viral epitopes caused increased neutrophil adherence to infected cells. This binding was eliminated by F(ab'2) fragments of MoAbs against the sialic acid- binding site on HA, but not by saturating amounts of MoAbs, which block the neutrophil Fc receptors. Thus, it appears that human neutrophils show little ability to bind via their Fc receptors to the immune complexes formed with antibody and either influenza-infected epithelial cells or the free virion. These findings are in contrast to the general dogma, and are the first example of antibody opsonization reducing, rather than enhancing, neutrophil binding and phagocytosis of a pathogen.

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Neutrophils do not bind to or phagocytize human immune complexes formed with influenza virus

Blood ◽

10.1182/blood.v82.5.1639.bloodjournal8251639 ◽

1993 ◽

Vol 82 (5) ◽

pp. 1639-1646

Author(s):

DR Ratcliffe ◽

J Michl ◽

EB Cramer

Keyword(s):

Influenza Virus ◽

Sialic Acid ◽

Epithelial Cells ◽

Binding Site ◽

Immune Complexes ◽

Human Neutrophils ◽

Sialic Acid Binding ◽

Infected Cells ◽

Neutrophil Adherence ◽

Human Immune

Neutrophils appear to form the first line of defense against influenza virus, yet it is unclear how these leukocytes recognize influenza- infected cells. While demonstrating that neutrophils adhere specifically to the sialic acid-binding site on the hemagglutinin molecule (HA) on the surface of influenza-infected (WSN[H1N1]) epithelial cells and not to other viral or epithelial cell antigens, it was observed that human neutrophils do not recognize immune complexes formed with influenza virus. Intact antibodies (mouse monoclonal antibodies [MoAbs] IgG1 and IgG2b, human immune heat-inactivated serum [predominantly IgG1], and IgG purified from human immune serum) that block the sialic acid-binding site on HA significantly reduced (> 80%) neutrophil adherence to influenza-infected epithelial cells. Binding and phagocytosis of free influenza virions and neutrophil agglutination by influenza virus were completely prevented by these antibodies. Intact and F(ab')2 fragments of mouse MoAbs to other viral epitopes caused increased neutrophil adherence to infected cells. This binding was eliminated by F(ab'2) fragments of MoAbs against the sialic acid- binding site on HA, but not by saturating amounts of MoAbs, which block the neutrophil Fc receptors. Thus, it appears that human neutrophils show little ability to bind via their Fc receptors to the immune complexes formed with antibody and either influenza-infected epithelial cells or the free virion. These findings are in contrast to the general dogma, and are the first example of antibody opsonization reducing, rather than enhancing, neutrophil binding and phagocytosis of a pathogen.

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A Secondary Sialic Acid Binding Site on Influenza Virus Neuraminidase: Fact or Fiction?

Angewandte Chemie International Edition ◽

10.1002/anie.201108245 ◽

2012 ◽

Vol 51 (9) ◽

pp. 2221-2224 ◽

Cited By ~ 23

Author(s):

Jimmy C. C. Lai ◽

Jean-Michel Garcia ◽

Jeffrey C. Dyason ◽

Raphael Böhm ◽

Paul D. Madge ◽

...

Keyword(s):

Influenza Virus ◽

Sialic Acid ◽

Binding Site ◽

Sialic Acid Binding ◽

Influenza Virus Neuraminidase

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Structural evidence for a second sialic acid binding site in avian influenza virus neuraminidases

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.94.22.11808 ◽

1997 ◽

Vol 94 (22) ◽

pp. 11808-11812 ◽

Cited By ~ 81

Author(s):

J. N. Varghese ◽

P. M. Colman ◽

A. van Donkelaar ◽

T. J. Blick ◽

A. Sahasrabudhe ◽

...

Keyword(s):

Influenza Virus ◽

Sialic Acid ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Binding Site ◽

Sialic Acid Binding

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Second Sialic Acid Binding Site in Newcastle Disease Virus Hemagglutinin-Neuraminidase: Implications for Fusion

Journal of Virology ◽

10.1128/jvi.78.7.3733-3741.2004 ◽

2004 ◽

Vol 78 (7) ◽

pp. 3733-3741 ◽

Cited By ~ 124

Author(s):

Viatcheslav Zaitsev ◽

Mark von Itzstein ◽

Darrin Groves ◽

Milton Kiefel ◽

Toru Takimoto ◽

...

Keyword(s):

Sialic Acid ◽

Newcastle Disease Virus ◽

Binding Site ◽

Disease Virus ◽

Newcastle Disease ◽

Surface Glycoprotein ◽

Crystal Forms ◽

Sialic Acid Receptors ◽

Sialic Acid Binding ◽

Infected Cells

ABSTRACT Paramyxoviruses are the leading cause of respiratory disease in children. Several paramyxoviruses possess a surface glycoprotein, the hemagglutinin-neuraminidase (HN), that is involved in attachment to sialic acid receptors, promotion of fusion, and removal of sialic acid from infected cells and progeny virions. Previously we showed that Newcastle disease virus (NDV) HN contained a pliable sialic acid recognition site that could take two states, a binding state and a catalytic state. Here we present evidence for a second sialic acid binding site at the dimer interface of HN and present a model for its involvement in cell fusion. Three different crystal forms of NDV HN now reveal identical tetrameric arrangements of HN monomers, perhaps indicative of the tetramer association found on the viral surface.

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Second sialic acid binding site of the Neuraminidase N1 of the 1918 pandemic influenza virus: An MD simulation investigation

10.1021/scimeetings.1c00251 ◽

2021 ◽

Author(s):

Elli Stefano ◽

Nicola Gambacorta ◽

Timothy Rudd ◽

Mikhail Matrosovich ◽

Marco Guerrini

Keyword(s):

Influenza Virus ◽

Sialic Acid ◽

Binding Site ◽

Pandemic Influenza ◽

Md Simulation ◽

Sialic Acid Binding

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Mapping of a Novel H3-Specific Broadly Neutralizing Monoclonal Antibody Targeting the Hemagglutinin Globular Head Isolated from an Elite Influenza Virus-Immunized Donor Exhibiting Serological Breadth

Journal of Virology ◽

10.1128/jvi.01035-19 ◽

2019 ◽

Vol 94 (6) ◽

Author(s):

Yu Qiu ◽

Svetlana Stegalkina ◽

Jianxin Zhang ◽

Ekaterina Boudanova ◽

Anna Park ◽

...

Keyword(s):

Influenza Virus ◽

Sialic Acid ◽

Neutralizing Antibodies ◽

Vaccine Design ◽

Binding Pocket ◽

Influenza Viruses ◽

Antigenic Drift ◽

Human Antibody ◽

Sialic Acid Binding ◽

Globular Head

ABSTRACT The discovery of potent and broadly protective influenza virus epitopes could lead to improved vaccines that are resistant to antigenic drift. Here, we describe human antibody C585, isolated from a vaccinee with remarkable serological breadth as measured by hemagglutinin inhibition (HAI). C585 binds and neutralizes multiple H3N2 strains isolated between 1968 and 2016, including strains that emerged up to 4 years after B cells were isolated from the vaccinated donor. The crystal structure of C585 Fab in complex with the HA from A/Switzerland/9715293/2013 (H3N2) shows that the antibody binds to a novel and well-conserved epitope on the globular head of H3 HA and that it differs from other antibodies not only in its epitope but in its binding geometry and hypermutated framework 3 region, thereby explaining its breadth and ability to mediate hemagglutination inhibition across decades of H3N2 strains. The existence of epitopes such as the one elucidated by C585 has implications for rational vaccine design. IMPORTANCE Influenza viruses escape immunity through continuous antigenic changes that occur predominantly on the viral hemagglutinin (HA). Induction of broadly neutralizing antibodies (bnAbs) targeting conserved epitopes following vaccination is a goal of universal influenza vaccines and advantageous in protecting hosts against virus evolution and antigenic drift. To date, most of the discovered bnAbs bind either to conserved sites in the stem region or to the sialic acid-binding pocket. Generally, antibodies targeting the stem region offer broader breadth with low potency, while antibodies targeting the sialic acid-binding pocket cover narrower breadth but usually have higher potency. In this study, we identified a novel neutralizing epitope in the head region recognized by a broadly neutralizing human antibody against a broad range of H3N2 with high potency. This epitope may provide insights for future universal vaccine design.

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Role of Sialic Acid Binding Specificity of the 1918 Influenza Virus Hemagglutinin Protein in Virulence and Pathogenesis for Mice

Journal of Virology ◽

10.1128/jvi.02596-08 ◽

2009 ◽

Vol 83 (8) ◽

pp. 3754-3761 ◽

Cited By ~ 50

Author(s):

Li Qi ◽

John C. Kash ◽

Vivien G. Dugan ◽

Ruixue Wang ◽

Guozhong Jin ◽

...

Keyword(s):

Influenza Virus ◽

Sialic Acid ◽

Influenza A ◽

Influenza Pandemic ◽

Binding Specificity ◽

Influenza Viruses ◽

Virulence Determinants ◽

Sialic Acid Binding ◽

1918 Influenza

ABSTRACT The 1918 influenza pandemic caused more than 40 million deaths and likely resulted from the introduction and adaptation of a novel avian-like virus. Influenza A virus hemagglutinins are important in host switching and virulence. Avian-adapted influenza virus hemagglutinins bind sialic acid receptors linked via α2-3 glycosidic bonds, while human-adapted hemagglutinins bind α2-6 receptors. Sequence analysis of 1918 isolates showed hemagglutinin genes with α2-6 or mixed α2-6/α2-3 binding. To characterize the role of the sialic acid binding specificity of the 1918 hemagglutinin, we evaluated in mice chimeric influenza viruses expressing wild-type and mutant hemagglutinin genes from avian and 1918 strains with differing receptor specificities. Viruses expressing 1918 hemagglutinin possessing either α2-6, α2-3, or α2-3/α2-6 sialic acid specificity were fatal to mice, with similar pathology and cellular tropism. Changing α2-3 to α2-6 binding specificity did not increase the lethality of an avian-adapted hemagglutinin. Thus, the 1918 hemagglutinin contains murine virulence determinants independent of receptor binding specificity.

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