Abstract
We tested the hypothesis that cathepsins and specifically toxopain-1, a cathepsin B, play a critical role in the pathogenesis of toxoplasmosis. We found that inhibiting the expression of toxopain-1-specific mRNA and protein by >60% significantly decreased the capacity of the parasites to multiply and invade in vitro. To relate these in vitro results to the role of toxopain-1 in pathogenesis in vivo, we developed a novel chicken embryo model of congenital toxoplasmosis. Inhibiting either toxopain-1 expression or specific cysteine proteinase activity significantly reduced congenital infection of chicken embryos, as determined by histopathology and by the number of parasites quantified by real-time PCR. Our new model provides key in vivo validation for the hypothesis that toxopain-1 is a potential drug target in Toxoplasma gondii and also provides a new animal model for rapid, inexpensive screening of antiparasitic compounds.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Base Sequence
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Chick Embryo
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / physiology*
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DNA, Protozoan / genetics
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Disease Models, Animal
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Gene Expression / drug effects
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Genes, Protozoan
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Humans
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In Vitro Techniques
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RNA, Antisense / genetics
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RNA, Antisense / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Protozoan / genetics
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RNA, Protozoan / metabolism
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Species Specificity
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Toxoplasma / genetics
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Toxoplasma / pathogenicity*
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Toxoplasma / physiology*
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Toxoplasmosis, Animal / etiology*
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Toxoplasmosis, Animal / pathology
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Toxoplasmosis, Cerebral / etiology
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Toxoplasmosis, Cerebral / pathology
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Toxoplasmosis, Congenital / etiology*
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Toxoplasmosis, Congenital / pathology
Substances
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DNA, Protozoan
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RNA, Antisense
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RNA, Messenger
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RNA, Protozoan
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Cysteine Endopeptidases
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toxopain-1, Toxoplasma gondii