Expression and function of transforming growth factor ß 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 ß (TGF-ß), of which Smad2 and Smad3 are the major signal transducers. In this study, we aimed to characterize TGF-ß expression and function in experimental melioidosis. TGF-ß expression was determined in 33 patients with culture-proven infection with B. pseudomallei and 30 healthy controls. We found that plasma TGF-ß concentrations were strongly elevated during melioidosis. In line with this finding, TGF-ß expression in C57BL/6 mice intranasally inoculated with B. pseudomallei was enhanced as well. To assess the role of TGF-ß, we inhibited TGF-ß using a selective murine TGF-ß antibody. Treatment of mice with anti-TGF-ß antibody resulted in decreased lung Smad2 phosphorylation. TGF-ß blockade appeared to be protective mice treated with anti-TGF-ß antibody and subsequently infected with B. pseudomallei showed diminished bacterial loads. Moreover, less distant organ injury was observed in anti-TGF-ß treated mice as shown by reduced blood urea nitrogen (BUN) and aspartate transaminase (AST) values. However, anti-TGF-ß treatment did not have an effect on survival. In conclusion, TGF-ß is upregulated during B. pseudomallei infection and plays a limited but proinflammatory role during experimental melioidosis.