title: Receptor specificity of the influenza virus hemagglutinin modulates sensitivity to soluble collectins of the innate immune system and virulence in mice.
abstract: The hemagglutinin (HA) glycoprotein of influenza virus binds to cell surface sialic acid (SA) to initiate infection. In this study, a mutant of influenza A virus strain BJx109 (H3N2) was plaque-purified from the lungs of virus-infected mice that had been depleted of airway macrophages. Sequence analysis identified a single amino acid substitution (S186I) in the vicinity of the receptor-binding site of HA. This substitution was associated with enhanced binding to α(2,3)-Gal-linked SA and an increased ability to infect murine airway epithelial cells. Mutant viruses were less sensitive to neutralization by mouse airway fluids and less efficient in their ability to infect murine macrophages. Moreover, infection of mice with viruses bearing the S186I substitution led to severe disease, characterized by enhanced virus replication, lung pathology and pulmonary edema. Together, these studies confirm that residue 186 of H3 subtype viruses is a critical determinant of virulence in a mouse model of influenza infection.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Tate
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Brooks
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Reading
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D037222:Collectins / Q000276:immunology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007107:Immune System / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D007251:Influenza, Human / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008168:Lung / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D011485:Protein Binding; D011991:Receptors, Virus / Q000378:metabolism*; D013045:Species Specificity; D014774:Virulence
chemical_list: D037222:Collectins; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus; D019158:N-Acetylneuraminic Acid