title: Plant Hormone Salicylic Acid Produced by a Malaria Parasite Controls Host Immunity and Cerebral Malaria Outcome.
abstract: The apicomplexan parasite Toxoplasma gondii produces the plant hormone abscisic acid, but it is unclear if phytohormones are produced by the malaria parasite Plasmodium spp., the most important parasite of this phylum. Here, we report detection of salicylic acid, an immune-related phytohormone of land plants, in P. berghei ANKA and T. gondii cell lysates. However, addition of salicylic acid to P. falciparum and T. gondii culture had no effect. We transfected P. falciparum 3D7 with the nahG gene, which encodes a salicylic acid-degrading enzyme isolated from plant-infecting Pseudomonas sp., and established a salicylic acid-deficient mutant. The mutant had a significantly decreased concentration of parasite-synthesized prostaglandin E2, which potentially modulates host immunity as an adaptive evolution of Plasmodium spp. To investigate the function of salicylic acid and prostaglandin E2 on host immunity, we established P. berghei ANKA mutants expressing nahG. C57BL/6 mice infected with nahG transfectants developed enhanced cerebral malaria, as assessed by Evans blue leakage and brain histological observation. The nahG-transfectant also significantly increased the mortality rate of mice. Prostaglandin E2 reduced the brain symptoms by induction of T helper-2 cytokines. As expected, T helper-1 cytokines including interferon-γ and interleukin-2 were significantly elevated by infection with the nahG transfectant. Thus, salicylic acid of Plasmodium spp. may be a new pathogenic factor of this threatening parasite and may modulate immune function via parasite-produced prostaglandin E2.
authors.affiliation: Department of Parasitology, National Institute of Infectious Diseases, Shinjyuku, Tokyo, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Ryuma
authors.initials: R
authors.lastname: Matsubara
authors.affiliation: Department of Parasitology, National Institute of Infectious Diseases, Shinjyuku, Tokyo, Japan.
authors.forename: Hiroka
authors.initials: H
authors.lastname: Aonuma
authors.affiliation: Center for Sustainable Resource Science, RIKEN, Yokohama, Kanagawa, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Kojima
authors.affiliation: Department of Parasitology, National Institute of Infectious Diseases, Shinjyuku, Tokyo, Japan.
authors.forename: Michiru
authors.initials: M
authors.lastname: Tahara
authors.affiliation: Department of Parasitology, National Institute of Infectious Diseases, Shinjyuku, Tokyo, Japan.
authors.forename: Syed Bilal Ahmad
authors.initials: SB
authors.lastname: Andrabi
authors.affiliation: Center for Sustainable Resource Science, RIKEN, Yokohama, Kanagawa, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakakibara
authors.affiliation: Department of Parasitology, National Institute of Infectious Diseases, Shinjyuku, Tokyo, Japan; Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Kisaburo
authors.initials: K
authors.lastname: Nagamune
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D005260:Female; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D016779:Malaria, Cerebral / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000469:parasitology*; D051379:Mice; D010937:Plant Growth Regulators / Q000494:pharmacology*; D010962:Plasmodium berghei / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology; D011453:Prostaglandins / Q000097:blood / Q000378:metabolism; D020156:Salicylic Acid / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D010937:Plant Growth Regulators; D011453:Prostaglandins; D020156:Salicylic Acid