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Infection and Immunity, August 2005, p. 5101-5105, Vol. 73, No. 8
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.8.5101-5105.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inter-Alpha-Inhibitor Proteins Are Endogenous Furin Inhibitors and Provide Protection against Experimental Anthrax Intoxication

Steven M. Opal,1* Andrew W. Artenstein,1 Patricia A. Cristofaro,1 Jhung W. Jhung,2 John E. Palardy,1 Nicholas A. Parejo,1 and Yow-Pin Lim3

Center for Biodefense and Emerging Pathogens,1 Department of Pathology, Memorial Hospital of Rhode Island, Brown Medical School,2 ProThera Biologics, East Providence, Rhode Island3

Received 2 December 2004/ Returned for modification 26 December 2004/ Accepted 18 March 2005

Inter-alpha-inhibitor protein (I{alpha}Ip) functions as an endogenous serine protease inhibitor in human plasma, and I{alpha}Ip levels diminish rapidly during acute inflammatory states. One potential target for I{alpha}Ip is furin, a cell-associated serine endopeptidase essential for the activation of protective antigen and the formation of anthrax lethal toxin (LT). I{alpha}Ip blocks furin activity in vitro and provides significant protection against cytotoxicity for murine peritoneal macrophages exposed to up to 500 ng/ml LT. A monoclonal antibody (MAb), 69.31, that specifically blocks the enzymatic activity of I{alpha}Ip eliminates its protective effect against LT-induced cytotoxicity. I{alpha}Ip (30 mg/kg of body weight) administered to BALB/c mice 1 hour prior to an intravenous LT challenge resulted in 71% survival after 7 days compared with no survivors among the control animals (P < 0.001). We conclude that human I{alpha}Ip may be an effective preventative or therapeutic agent against anthrax intoxication.

* Corresponding author. Mailing address: Center for Biodefense and Emerging Pathogens, Memorial Hospital of RI, 111 Brewster Street, Pawtucket, RI 02860. Phone: (401) 729-2545. Fax: (401) 729-2795. E-mail: Steven_Opal{at}brown.edu.

Editor: D. L. Burns

Infection and Immunity, August 2005, p. 5101-5105, Vol. 73, No. 8
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.8.5101-5105.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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