Transforming growth factor-β: activation by neuraminidase and role in highly pathogenic H5N1 influenza pathogenesis.
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.
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, United States of America.
Christina M
CM
Carlson
Elizabeth A
EA
Turpin
Lindsey A
LA
Moser
Kevin B
KB
O'Brien
Troy D
TD
Cline
Jeremy C
JC
Jones
Terrence M
TM
Tumpey
Jacqueline M
JM
Katz
Laura A
LA
Kelley
Jack
J
Gauldie
Stacey
S
Schultz-Cherry
D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D004285:Dogs; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000472:pathogenicity* / Q000502:physiology; D007251:Influenza, Human / Q000378:metabolism* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D009976:Orthomyxoviridae Infections / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000502:physiology
D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D009439:Neuraminidase