Transforming growth factor-ß: activation by neuraminidase and role in highly pathogenic H5N1 influenza pathogenesis.
PLoS Pathog
; 6(10): e1001136, 2010 Oct 07.
Article
em En
| MEDLINE
| ID: mdl-20949074
ABSTRACT
Transforming growth factor-beta (TGF-ß), a multifunctional cytokine regulating several immunologic processes, is expressed by virtually all cells as a biologically inactive molecule termed latent TGF-ß (LTGF-ß). We have previously shown that TGF-ß 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-ß 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-ß administered via a replication-deficient adenovirus vector provides protection from H5N1 influenza pathogenesis and whether depletion of TGF-ß during virus infection increases morbidity in mice. We found that both the influenza and bacterial NA activate LTGF-ß by removing sialic acid motifs from LTGF-ß, each NA being specific for the sialic acid linkages cleaved. Further, NA likely activates LTGF-ß 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-ß in vitro and in vivo. Addition of exogenous TGF-ß to H5N1 influenza virus-infected mice delayed mortality and reduced viral titers whereas neutralization of TGF-ß during H5N1 and pandemic 2009 H1N1 infection increased morbidity. Together, these data show that microbe-associated NAs can directly activate LTGF-ß and that TGF-ß plays a pivotal role protecting the host from influenza pathogenesis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta
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Influenza Humana
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Virus da Influenza A Subtipo H5N1
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Neuraminidase
Tipo de estudo:
Etiology_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article