Transforming growth factor-β: activation by neuraminidase and role in highly pathogenic H5N1 influenza pathogenesis.

Abstract

Transforming growth factor-beta (TGF-β), a multifunctional cytokine regulating several immunologic processes, is expressed by virtually all cells as a biologically inactive molecule termed latent TGF-β (LTGF-β). We have previously shown that TGF-β activity increases during influenza virus infection in mice and suggested that the neuraminidase (NA) protein mediates this activation. In the current study, we determined the mechanism of activation of LTGF-β by NA from the influenza virus A/Gray Teal/Australia/2/1979 by mobility shift and enzyme inhibition assays. We also investigated whether exogenous TGF-β administered via a replication-deficient adenovirus vector provides protection from H5N1 influenza pathogenesis and whether depletion of TGF-β during virus infection increases morbidity in mice. We found that both the influenza and bacterial NA activate LTGF-β by removing sialic acid motifs from LTGF-β, each NA being specific for the sialic acid linkages cleaved. Further, NA likely activates LTGF-β primarily via its enzymatic activity, but proteases might also play a role in this process. Several influenza A virus subtypes (H1N1, H1N2, H3N2, H5N9, H6N1, and H7N3) except the highly pathogenic H5N1 strains activated LTGF-β in vitro and in vivo. Addition of exogenous TGF-β to H5N1 influenza virus-infected mice delayed mortality and reduced viral titers whereas neutralization of TGF-β during H5N1 and pandemic 2009 H1N1 infection increased morbidity. Together, these data show that microbe-associated NAs can directly activate LTGF-β and that TGF-β plays a pivotal role protecting the host from influenza pathogenesis.

• Authors: Christina M Carlson, Elizabeth A Turpin, Lindsey A Moser, Kevin B O'Brien, Troy D Cline, Jeremy C Jones, Terrence M Tumpey, Jacqueline M Katz, Laura A Kelley, Jack Gauldie, Stacey Schultz-Cherry
• Journal: PLoS pathogens (PLoS Pathog) Vol. 6 Issue 10 Pg. e1001136 (Oct 07 2010) ISSN: 1553-7374 [Electronic] United States
• PMID: 20949074 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Recombinant Proteins
• Transforming Growth Factor beta
• Neuraminidase

Topics

• Animals
• Cells, Cultured
• Chick Embryo
• Dogs
• Enzyme Activation (physiology)
• Humans
• Influenza A Virus, H5N1 Subtype (pathogenicity, physiology)
• Influenza, Human (metabolism, virology)
• Mice
• Mice, Inbred BALB C
• Neuraminidase (isolation & purification, metabolism, pharmacology, physiology)
• Orthomyxoviridae Infections (metabolism)
• Recombinant Proteins (metabolism, pharmacology)
• Transforming Growth Factor beta (metabolism, physiology)