Low levels of mammalian TGF-beta1 are protective against malaria parasite infection, a paradox clarified in the mosquito host.
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.
Luckhart
Shirley
S
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
Lieber
Matthew J
MJ
Singh
Naresh
N
Zamora
Ruben
R
Vodovotz
Yoram
Y
D000818:Animals; D000852:Anopheles / Q000201:enzymology / Q000469:parasitology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007303:Insect Vectors / Q000201:enzymology / Q000469:parasitology*; D008288:Malaria / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D010961:Plasmodium / Q000276:immunology*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester