title: Protective immunity against the protozoan Leishmania chagasi is induced by subclinical cutaneous infection with virulent but not avirulent organisms.
abstract: Protective immunity against Leishmania major is provided by s.c. immunization with a low dose of L. major promastigotes or with dihydrofolate-thymidylate synthase gene locus (DHFR-TS) gene knockout L. major organisms. Whether these vaccine strategies will protect against infection with other Leishmania species that elicit distinct immune responses and clinical syndromes is not known. Therefore, we investigated protective immunity to Leishmania chagasi, a cause of visceral leishmaniasis. In contrast to L. major, a high dose s.c. inoculum of L. chagasi promastigotes was required to elicit protective immunity. Splenocytes from mice immunized with a high dose produced significantly greater amounts of IFN-gamma and lower TGF-beta than mice immunized with a low dose of promastigotes. The development of protective immunity did not require the presence of NK cells. Protection was not afforded by s.c. immunization with either attenuated L. chagasi or with L. major promastigotes, and s.c. L. chagasi did not protect against infection with L. major. Subcutaneous immunization with DHFR-TS gene knockouts derived from L. chagasi, L. donovani, or L. major did not protect against L. chagasi infection. We conclude that s.c. inoculation of high doses of live L. chagasi causes a subclinical infection that elicits protective immune responses in susceptible mice. However, L. chagasi that have been attenuated either by long-term passage or during the raising of recombinant gene knockout organisms do not elicit protective immunity, either because they fail to establish a subclinical infection or because they no longer express critical antigenic epitopes.
authors.affiliation: Department of Internal Medicine and Microbiology, University of Iowa and the Veterans Affairs Medical Center, Iowa City, IA 52242, USA. judy-streit@uiowa.edu
authors.forename: J A
authors.initials: JA
authors.lastname: Streit
authors.forename: T J
authors.initials: TJ
authors.lastname: Recker
authors.forename: F G
authors.initials: FG
authors.lastname: Filho
authors.forename: S M
authors.initials: SM
authors.lastname: Beverley
authors.forename: M E
authors.initials: ME
authors.lastname: Wilson
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007279:Injections, Subcutaneous; D007694:Killer Cells, Natural / Q000276:immunology / Q000469:parasitology; D018314:Leishmania infantum / Q000235:genetics / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity*; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D009097:Multienzyme Complexes / Q000235:genetics; D016052:Protozoan Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D017384:Sequence Deletion; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014774:Virulence
chemical_list: D016207:Cytokines; D009097:Multienzyme Complexes; D016052:Protozoan Vaccines; D014613:Vaccines, Attenuated; D015164:Vaccines, Inactivated; C056930:thymidylate synthase-dihydrofolate reductase; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase