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Activation of plasminogen activator inhibitor implicates protease InhA in the acute-phase response to Bacillus anthracis infection

Myung-Chul Chung, Shelley C. Jorgensen, Taissia G. Popova, Jessica H. Tonry, Charles L. Bailey and Serguei G. Popov

National Center for Biodefense and Infectious Diseases, George Mason University, 10900 University Blvd, Manassas, VA 20110, USA

Correspondence
Serguei G. Popov
spopov{at}gmu.edu

Received October 17, 2008
Accepted February 14, 2009

Anthrax is a zoonotic disease caused by Bacillus anthracis. The infection is associated with inflammation and sepsis, but little is known about the acute-phase response during disease and the nature of the bacterial factors causing it. In this study, we examined the levels of the acute-phase proteins (APPs) in comparative experiments using mice challenged with spores and a purified B. anthracis protease InhA as a possible factor mediating the response. A strong increase in the plasma levels of APPs such as haptoglobin and serum amyloid A was observed during infection. Protein and mRNA levels of plasminogen activator inhibitor (PAI)-1 in the liver were also increased concurrently with bacterial dissemination at 72 h post-infection. Similar effects were observed at 6 h post injection with InhA. Induction of hepatic transforming growth factor-β1, a PAI-1 inducer, was also found in the liver of InhA-injected mice. PAI-1 elevation by InhA resulted in an increased level of urokinase-type plasminogen activator complex with PAI-1 and a decreased level of D-dimers indicating inhibition of blood fibrinolysis. These results reveal an acute liver response to anthrax infection and provide a plausible pathophysiological link between the host inflammatory response and the pro-thrombotic haemostatic imbalance in the course of disease through PAI-1 induction in the liver.

Abbreviations: APP, acute-phase protein; CRP, C-reactive protein; HPG, haptoglobin; HPX, haemopexin; InhA, neutral metalloprotease immune inhibitor A; PAI-1, plasminogen activator inhibitor-1; SAA, serum amyloid A; TGF, transforming growth factor; uPA, urokinase-type plasminogen activator.

Present address: Clinical Laboratory, US Army Medical Research Institute for Infectious Diseases (USAMRIID), 1425 Porter Street, Fort Detrick, MD 21702, USA.

Supplementary tables are available with the online version of this paper.