Low levels of mammalian TGF-beta1 are protective against malaria parasite infection, a paradox clarified in the mosquito host |
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Authors: | Luckhart Shirley Lieber Matthew J Singh Naresh Zamora Ruben Vodovotz Yoram |
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Institution: | University of California at Davis, Department of Medical Microbiology and Immunology, 3437 Tupper Hall, One Shields Avenue, School of Medicine, Davis, CA 95616, USA. sluckhart@ucdavis.edu |
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Abstract: | Nitric oxide (NO), derived from catalysis of inducible NO synthase (iNOS), limits malaria parasite growth in mammals. Transforming growth factor (TGF)-beta1 suppresses iNOS in cells in vitro as well as in vivo in mice, but paradoxically severe malaria in humans is associated with low levels of TGF-beta1. We hypothesized that this paradox is a universal feature of infection and occurs in the mosquito Anopheles stephensi, an invertebrate host for Plasmodium that also regulates parasite development with inducible NO synthase (AsNOS). We show that exogenous human TGF-beta1 dose-dependently regulates mosquito AsNOS expression and that parasite killing by low dose TGF-beta1 depends on AsNOS catalysis. Furthermore, induction of AsNOS expression by TGF-beta1 is regulated by NO synthesis. These results suggest that TGF-beta1 plays similar roles during parasite infection in mammals and mosquitoes and that this role is linked to the effects of TGF-beta1 on inducible NO synthesis. |
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Keywords: | Plasmodium falciparum Anopheles stephensi Malaria Protozoan Mosquito Nitric oxide synthase AsNOS Anopheles stephensi nitric oxide synthase TGF-β1 Transforming growth factor-β1 NO nitric oxide l-NAME" target="_blank">l-NAME l-arginine methyl ester" target="_blank">N-nitro-l-arginine methyl ester d-NAME" target="_blank">d-NAME d-arginine methyl ester" target="_blank">N-nitro-d-arginine methyl ester |
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