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The Journal of Immunology, 1998, 161: 6794-6801.
Copyright © 1998 by The American Association of Immunologists

Leishmania mexicana Cysteine Proteinase-Deficient Mutants Have Attenuated Virulence for Mice and Potentiate a Th1 Response1

James Alexander*, Graham H. Coombs2,{dagger} and Jeremy C. Mottram{ddagger}

* Department of Immunology, University of Strathclyde, Glasgow, United Kingdom; and {dagger} Division of Infection and Immunity and {ddagger} Wellcome Unit of Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom

Leishmania mexicana mutants lacking cysteine proteinase genes cpa ({Delta}cpa), cpb ({Delta}cpb), or both cpa and cpb ({Delta}cpa/cpb) have been generated by targeted gene disruption. {Delta}cpa mutants produce a disease phenotype in BALB/c mice close to that of wild-type L. mexicana, but {Delta}cpb mutants are much less infective, producing very slowly growing small lesions, and {Delta}cpa/cpb double mutants do not induce lesion growth. Immunologic analysis of Ab isotype during infection and splenocyte IFN-{gamma}, IL-2, and IL-4 production following stimulation with Leishmania Ag or Con A indicates that there was a significant shift from a predominantly Th2-associated immune response in mice infected with wild-type L. mexicana to a Th1-associated response in mice inoculated with {Delta}cpb or {Delta}cpa/cpb. Significantly, {Delta}cpa altered the balance of the immunologic response to a lesser extent than did the other mutants. Similar disease outcomes and switches in the Th1/Th2 balance were also observed when other L. mexicana-susceptible mouse strains were infected with the mutants. BALB/c and C57BL/6 mice vaccinated with {Delta}cpa/cpb and CBA/Ca mice vaccinated with {Delta}cpb or {Delta}cpa/cpb were subsequently more resistant, to varying degrees, than were untreated mice to infection with wild-type parasites, as measured by development of lesions and parasite burden. These data implicate leishmanial cysteine proteinases not only as parasite virulence factors but also in modulation of the immune response and provide strong encouragement that cysteine proteinase-deficient L. mexicana mutants are candidate attenuated live vaccines.




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