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Antimicrobial Agents and Chemotherapy, November 2007, p. 3932-3939, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00436-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Cysteine Protease Inhibitor Cures Chagas' Disease in an Immunodeficient-Mouse Model of Infection{triangledown}

Patricia S. Doyle,* Yuan M. Zhou, Juan C. Engel, and James H. McKerrow

Tropical Diseases Research Unit and Sandler Center, Department of Pathology, University of California, San Francisco, San Francisco, California 94121

Received 29 March 2007/ Returned for modification 26 June 2007/ Accepted 4 August 2007

Chagas' disease, caused by the parasite Trypanosoma cruzi, remains the leading cause of cardiopathy in Latin America with about 12 million people infected. Classic clinical manifestations derive from infection of muscle cells leading to progressive cardiomyopathy, while some patients develop megacolon or megaesophagus. A very aggressive clinical course including fulminant meningoencephalitis has been reported in patients who contract Chagas' disease in the background of immunodeficiency. This includes patients with human immunodeficiency virus infection as well as patients receiving immunosuppressive therapy for organ transplant. Currently, only two drugs are approved for the treatment of Chagas' disease, nifurtimox and benznidazole. Both have significant limitations due to common and serious side effects as well as limited availability. A promising group of new drug leads for Chagas' disease is cysteine protease inhibitors targeting cruzain, the major protease of T. cruzi. The inhibitor N-methyl-Pip-F-homoF-vinyl sulfonyl phenyl (N-methyl-Pip-F-hF-VS{phi}) is in late-stage preclinical development. Therefore, the question arose as to whether protease inhibitors targeting cruzain would have efficacy in Chagas' disease occurring in the background of immunodeficiency. To address this question, we studied the course of infection in recombinase-deficient (Rag1–/–) and normal mice infected with T. cruzi. Infections localized to heart and skeletal muscle in untreated normal animals, while untreated Rag1–/– mice showed severe infection in all organs and predominantly in liver and spleen. Treatment with the dipeptide N-methyl-Pip-F-hF-VS{phi} rescued immunodeficient animals from lethal Chagas' infection. The majority (60 to 100%) of inhibitor-treated Rag1–/– mice had increased survival, negative PCR, and normal tissues by histopathological examination.

* Corresponding author. Mailing address: UCSF, Pathology VA Medical Center, 4150 Clement Street-113B, San Francisco, CA 94121. Phone: (415) 221-4810, ext. 2631. Fax: (415) 750-6947. E-mail: patricia.doyle-engel{at}ucsf.edu

{triangledown} Published ahead of print on 13 August 2007.

Antimicrobial Agents and Chemotherapy, November 2007, p. 3932-3939, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00436-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • O'Brien, T. C., Mackey, Z. B., Fetter, R. D., Choe, Y., O'Donoghue, A. J., Zhou, M., Craik, C. S., Caffrey, C. R., McKerrow, J. H. (2008). A Parasite Cysteine Protease Is Key to Host Protein Degradation and Iron Acquisition. J. Biol. Chem. 283: 28934-28943 [Abstract] [Full Text]  


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