title: Influenza viral neuraminidase primes bacterial coinfection through TGF-β-mediated expression of host cell receptors.
abstract: Influenza infection predisposes the host to secondary bacterial pneumonia, which is a major cause of mortality during influenza epidemics. The molecular mechanisms underlying the bacterial coinfection remain elusive. Neuraminidase (NA) of influenza A virus (IAV) enhances bacterial adherence and also activates TGF-β. Because TGF-β can up-regulate host adhesion molecules such as fibronectin and integrins for bacterial binding, we hypothesized that activated TGF-β during IAV infection contributes to secondary bacterial infection by up-regulating these host adhesion molecules. Flow cytometric analyses of a human lung epithelial cell line indicated that the expression of fibronectin and α5 integrin was up-regulated after IAV infection or treatment with recombinant NA and was reversed through the inhibition of TGF-β signaling. IAV-promoted adherence of group A Streptococcus (GAS) and other coinfective pathogens that require fibronectin for binding was prevented significantly by the inhibition of TGF-β. However, IAV did not promote the adherence of Lactococcus lactis unless this bacterium expressed the fibronectin-binding protein of GAS. Mouse experiments showed that IAV infection enhanced GAS colonization in the lungs of wild-type animals but not in the lungs of mice deficient in TGF-β signaling. Taken together, these results reveal a previously unrecognized mechanism: IAV NA enhances the expression of cellular adhesins through the activation of TGF-β, leading to increased bacterial loading in the lungs. Our results suggest that TGF-β and cellular adhesins may be potential pharmaceutical targets for the prevention of coinfection.
authors.affiliation: Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, and.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, and.
authors.forename: Aihui
authors.initials: A
authors.lastname: Ren
authors.affiliation: Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, and.
authors.forename: Xiaoshuang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, and.
authors.forename: Xin
authors.initials: X
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, and.
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.affiliation: Department of Microbiology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cleary
authors.affiliation: Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, and wangbn@im.ac.cn.
authors.forename: Beinan
authors.identifier: http://orcid.org/0000-0002-9260-7197
authors.initials: B
authors.lastname: Wang
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D060085:Coinfection / Q000382:microbiology* / Q000821:virology*; D015169:Colony Count, Microbial; D004847:Epithelial Cells / Q000382:microbiology / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D009980:Influenza A virus / Q000201:enzymology*; D007251:Influenza, Human / Q000473:pathology / Q000821:virology; D008168:Lung / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000821:virology; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013290:Streptococcal Infections / Q000150:complications* / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; D005353:Fibronectins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D009439:Neuraminidase
keywords: TGF-beta; bacterial adherence; coinfection; fibronectin binding protein; influenza A virus