Expression of Multiple CPB Genes Encoding Cysteine Proteases Is Required for Leishmania mexicana Virulence In Vivo

Author:

Denise Hubert1,McNeil Kathryn2,Brooks Darren R.1,Alexander James2,Coombs Graham H.3,Mottram Jeremy C.1

Affiliation:

1. Wellcome Centre for Molecular Parasitology, The Anderson College, University of Glasgow, Glasgow G11 6NU

2. Department of Immunology, University of Strathclyde, Glasgow G4 0NR

3. Division of Infection and Immunity, Institute for Biomedical and Life Science, University of Glasgow, Glasgow G12 8QQ, United Kingdom

Abstract

ABSTRACT Leishmania mexicana mutants deficient in the multicopy CPB gene array have reduced virulence, demonstrated by poor lesion growth in BALB/c mice and induction of a protective Th1 response. Reinsertion of the amastigote-specific CPB2.8 or metacyclic stage-specific CPB2 gene into a CPB -deficient mutant L. mexicana failed to restore either a Th2 response or sustained virulence. However, reexpression of multiple CPB genes from a cosmid significantly restored virulence. This was characterized by increased lesion and parasite growth and the acquisition of a Th2 response, as determined by measuring interleukin-4 production and immunoglobulin G1 (IgG1) and IgE levels. These studies confirm that L. mexicana cysteine proteases are important virulence factors and provide an explanation for the presence in L. mexicana of a multicopy tandem array of CPB genes.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Immunology,Microbiology,Parasitology

Reference26 articles.

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2. Alexander, J., G. H. Coombs, and J. C. Mottram. 1998. Leishmania mexicana cysteine proteinase-deficient mutants have attenuated virulence for mice and potentiate a T helper 1 (TH1) response. J. Immunol.161:6794-6801.

3. Alexander, J., F. Brombacher, H. A. McGachy, A. N. J. McKenzie, W. Walker, and K. C. Carter. 2002. An essential role for IL-13 in maintaining a non-healing response following Leishmania mexicana infection. Eur. J. Immunol.32:2923-2933.

4. Bart, G., G. H. Coombs, and J. C. Mottram. 1995. Isolation of lmcpc, a gene encoding a Leishmania mexicana cathepsin B-like cysteine proteinase. Mol. Biochem. Parasitol.73:271-274.

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