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,
*
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Malaria Program, Naval Medical Research Center, Silver Spring, MD 20910;
Department of Microbiology, University of Maryland School of Medicine, Baltimore, MD 21201; and
§
Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte MG, Brazil
The protozoan parasite Toxoplasma gondii elicits
strong cell-mediated immunity against itself as well as nonspecific
resistance against other pathogens and tumors. For this reason, we
asked whether recombinant Toxoplasma could be utilized
as an effective vaccine vehicle for inducing immunity against
heterologous microbial infections. The circumsporozoite protein (PyCSP)
of Plasmodium yoelii was engineered into
a T. gondii temperature-sensitive strain (ts-4), a
mutant that induces complete protection against virulent
Toxoplasma challenge. When administered to mice in a
single dose, a recombinant ts-4 (CSC3) that both secretes and expresses
surface PyCSP induced strong anti-CSP Ab responses, with an isotype
distribution pattern similar to that stimulated by the T.
gondii carrier. When challenged with P. yoelii
sporozoites during the first month after CSC3 vaccination, these
animals displayed substantial levels of nonspecific resistance
attributable entirely to the T. gondii carrier.
Nevertheless, after the nonspecific protection had waned, high levels
(up to 79%) of specific immunity against sporozoite challenge were
achieved by boosting the animals with recombinant vaccinia virus
expressing PyCSP. These CSC3-primed PyCSP-vaccinia-boosted mice
displayed high frequencies of splenic PyCSP-specific IFN-
-producing
cells, as well as CD8+ T cell-dependent cytolytic activity.
In vivo depletion of CD8+ lymphocytes at the time of
challenge completely ablated protective immunity in the T.
gondii-primed/vaccinia-boosted animals, while neutralization of
IFN- or IL-12 caused a partial but significant reduction in
resistance. Together these findings establish the efficacy of
recombinant attenuated Toxoplasma as a vaccine vehicle
for priming CD8+-dependent cell-mediated
immunity.
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