title: Expression and function of transforming growth factor β in melioidosis.
abstract: Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an important cause of community-acquired sepsis in Southeast Asia and northern Australia. An important controller of the immune system is the pleiotropic cytokine transforming growth factor β (TGF-β), of which Smad2 and Smad3 are the major signal transducers. In this study, we aimed to characterize TGF-β expression and function in experimental melioidosis. TGF-β expression was determined in 33 patients with culture-proven infection with B. pseudomallei and 30 healthy controls. We found that plasma TGF-β concentrations were strongly elevated during melioidosis. In line with this finding, TGF-β expression in C57BL/6 mice intranasally inoculated with B. pseudomallei was enhanced as well. To assess the role of TGF-β, we inhibited TGF-β using a selective murine TGF-β antibody. Treatment of mice with anti-TGF-β antibody resulted in decreased lung Smad2 phosphorylation. TGF-β blockade appeared to be protective: mice treated with anti-TGF-β antibody and subsequently infected with B. pseudomallei showed diminished bacterial loads. Moreover, less distant organ injury was observed in anti-TGF-β treated mice as shown by reduced blood urea nitrogen (BUN) and aspartate transaminase (AST) values. However, anti-TGF-β treatment did not have an effect on survival. In conclusion, TGF-β is upregulated during B. pseudomallei infection and plays a limited but proinflammatory role during experimental melioidosis.
authors.affiliation: Center for Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, The Netherlands. t.a.weehuizen@amc.uva.nl
authors.forename: Tassili A F
authors.initials: TA
authors.lastname: Weehuizen
authors.forename: Catharina W
authors.initials: CW
authors.lastname: Wieland
authors.forename: Gerritje J W
authors.initials: GJ
authors.lastname: van der Windt
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Duitman
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Peacock
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Wiersinga
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008554:Melioidosis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D018805:Sepsis; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta