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Influenza viral neuraminidase primes bacterial coinfection through TGF-β–mediated expression of host cell receptors
Edited by Emil C. Gotschlich, The Rockefeller University, New York, NY, and approved November 21, 2014 (received for review July 29, 2014)

Significance
Pneumonia caused by bacterial coinfection with influenza virus is the leading cause of mortality in influenza pandemics. TGF-β is known to be activated by influenza virus. In this study we demonstrated that cellular adhesins for bacteria, such as fibronectin and α5 integrin, are up-regulated in influenza viral infection. Inhibition of TGF-β impeded the up-regulation of these cellular adhesins and also influenza viral-enhanced bacterial adherence. In addition, we found that influenza viral-promoted bacterial adherence was dependent on bacterial fibronectin-binding protein. The results indicate that up-regulated expression of cellular adhesins by TGF-β, which is activated in influenza viral infection, increases host susceptibility to bacterial coinfection and suggest that TGF-β and host adhesion molecules are potential pharmaceutical targets for prevention of coinfection.
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.
Footnotes
- ↵1To whom correspondence should be addressed. Email: wangbn{at}im.ac.cn.
Author contributions: B.W. designed research; N.L., A.R., X.W., and X.F. performed research; Y.Z., G.F.G., and P.C. contributed new reagents/analytic tools; N.L. and B.W. analyzed data; and B.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1414422112/-/DCSupplemental.