Pathogenicity and protective immunogenicity of cysteine proteinase-deficient mutants of Leishmania mexicana in non-murine models.
This study demonstrates that deletion of cysteine proteinase (CP) genes diminishes pathogenicity of Leishmania mexicana in non-murine experimental host models while preserving immunogenicity. Both cpb and cpa/cpb-deficient lines induced delayed disease onset, smaller lesions and lower parasite burden in hamsters. cpa/cpb-deficient L. mexicana grew more slowly as promastigotes and presented lower infectivity and growth in human mononuclear phagocytic host cells. Protection against homologous challenge comparable to that induced by infection with the virulent wild-type (WT) L. mexicana strain was achieved in the highly susceptible hamster model by immunization with 1000 cpb-deficient promastigotes. CP-deficient L. mexicana elicited significantly lower levels of Th2-associated cytokines IL-10 and TGF-beta than the WT in the primary lesion of hamsters. These findings support the feasibility of using genetically attenuated live Leishmania to achieve protective immunity.
Saravia
Nancy Gore
NG
Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Apartado Aéreo 5390, Cali, Colombia. saravian@cideim.org.co
Escorcia
Blanca
B
Osorio
Yaneth
Y
Valderrama
Liliana
L
Brooks
Darren
D
Arteaga
Lourdes
L
Coombs
Graham
G
Mottram
Jeremy
J
Travi
Bruno Luis
BL
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D017353:Gene Deletion; D017125:Genes, Protozoan; D006801:Humans; D066298:In Vitro Techniques; D007891:Leishmania / Q000276:immunology; D007894:Leishmania mexicana / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000517:prevention & control; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D008297:Male; D008647:Mesocricetus; D009154:Mutation; D016052:Protozoan Vaccines / Q000494:pharmacology; D014774:Virulence
D016207:Cytokines; D016052:Protozoan Vaccines; D003546:Cysteine Endopeptidases