Transforming Growth Factor-β: Activation by Neuraminidase and Role in Highly Pathogenic H5N1 Influenza Pathogenesis

PLoS Pathogens

Jack Gauldie¹  Terrence M. Tumpey²  Jeremy C. Jones²  Troy D. Cline²  Christina M. Carlson³  Kevin B. O'Brien³  Lindsey A. Moser³  Stacey Schultz-Cherry⁴  Jacqueline M. Katz⁵  Laura A. Kelley⁵  Elizabeth A. Turpin⁶ 

[1] Biosciences Research Laboratory, USDA Agricultural Research Station, Fargo, North Dakota, United States of America;Department of Infectious Disease, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America;Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, United States of America;Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada;Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America;Pfizer Inc., Department of Viral Vaccines, Research Triangle Park, North Carolina, United States of America

关键词: Influenza viruses;    H5N1;    Sialic acids;    Infectious disease control;    Influenza;    Proteases;    Antibodies;    Enzyme-linked immunoassays;   

DOI  :  10.1371/journal.ppat.1001136

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY