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* Department of Pathobiology, School of Veterinary Medicine, and
Department of Medicine, Division of Infectious Diseases, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Wellcome Centre for Molecular Parasitology, and
Division of Infection and Immunity, Institute for Biomedical and Life Science, University of Glasgow, Glasgow, United Kingdom; and
¶ Department of Immunology, University of Strathclyde, Glasgow, United Kingdom
C3H mice infected with Leishmania mexicana fail to develop a protective Th1 response, and are unable to cure. In this study, we show that L. mexicana cysteine proteases suppress the antileishmanial immune response. Previous studies demonstrated that deletion of the entire multicopy cysteine protease B (CPB) gene array in L. mexicana is associated with decreased parasite virulence, potentially attributable to factors related to parasite fitness rather than to direct effects on the host immune response. We now show that C3H mice infected with the L. mexicana deletion mutant (
cpb) initially develop lesions that grow at rates comparable to those of wild-type L. mexicana-infected mice. However, in contrast to controls, cpb-induced lesions heal with an accompanying Th1 immune response. Lesion resolution was Th1 dependent, as cpb-infected IL-12p40-/- and STAT4-/- mice developed high parasite burdens and progressive disease. Moreover, when L. major was transfected with a cosmid expressing multiple L. mexicana CPB genes, this parasite induced a significantly lower IFN-
response compared with wild-type L. major. These data indicate that cysteine proteases of L. mexicana are critical in suppressing protective immune responses and that inhibition of CPB may prove to be a valuable immunomodulatory strategy for chronic forms of leishmaniasis.
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