A single amino acid substitution in the hemagglutinin of H3N2 subtype influenza a viruses is associated with resistance to the long pentraxin PTX3 and enhanced virulence in mice

Emma R. Job, Barbara Bottazzi, Kirsty R. Short, Yi Mo Deng, Alberto Mantovani, Andrew G. Brooks, Patrick C. Reading

Research output: Contribution to journalArticle

Abstract

The long pentraxin, pentraxin 3 (PTX3), can play beneficial or detrimental roles during infection and disease by modulating various aspects of the immune system. There is growing evidence to suggest that PTX3 can mediate antiviral activity in vitro and in vivo. Previous studies demonstrated that PTX3 and the short pentraxin serum amyloid P express sialic acids that are recognized by the hemagglutinin (HA) glycoprotein of certain influenza Aviruses (IAV), resulting in virus neutralization and anti-IAVactivity. In this study, we demonstrate that specificity of both HA and the viral neuraminidase for particular sialic acid linkages determines the susceptibility of H1N1, H3N2, and H7N9 strains to the antiviral activities of PTX3 and serum amyloid P. Selection of H3N2 virus mutants resistant to PTX3 allowed for identification of amino acid residues in the vicinity of the receptor-binding pocket of HA that are critical determinants of sensitivity to PTX3; this was supported by sequence analysis of a range of H3N2 strains that were sensitive or resistant to PTX3. In a mouse model of infection, the enhanced virulence of PTX3-resistant mutants was associated with increased virus replication and elevated levels of proinflammatory cytokines in the airways, leading to pulmonary inflammation and lung injury. Together, these studies identify determinants in the viral HA that can be associated with sensitivity to the antiviral activities of PTX3 and highlight its importance in the control of IAV infection.

Original languageEnglish
Pages (from-to)271-281
Number of pages11
JournalJournal of Immunology
Volume192
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

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Hemagglutinins
Amino Acid Substitution
Orthomyxoviridae
Virulence
Viral Hemagglutinins
Antiviral Agents
Lung Injury
Amyloid
Human Influenza
Infection
H3N2 Subtype Influenza A Virus
Sialic Acids
PTX3 protein
Neuraminidase
N-Acetylneuraminic Acid
Virus Replication
Serum
Sequence Analysis
Immune System
Pneumonia

ASJC Scopus subject areas

  • Immunology

Cite this

A single amino acid substitution in the hemagglutinin of H3N2 subtype influenza a viruses is associated with resistance to the long pentraxin PTX3 and enhanced virulence in mice. / Job, Emma R.; Bottazzi, Barbara; Short, Kirsty R.; Deng, Yi Mo; Mantovani, Alberto; Brooks, Andrew G.; Reading, Patrick C.

In: Journal of Immunology, Vol. 192, No. 1, 01.01.2014, p. 271-281.

Research output: Contribution to journalArticle

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