Plant Hormone Salicylic Acid Produced by a Malaria Parasite Controls Host Immunity and Cerebral Malaria Outcome

PLoS One. 2015 Oct 14;10(10):e0140559. doi: 10.1371/journal.pone.0140559. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cytokines / blood
  • Cytokines / metabolism
  • Female
  • Humans
  • Immunity / drug effects*
  • Malaria, Cerebral / immunology*
  • Malaria, Cerebral / metabolism
  • Malaria, Cerebral / mortality
  • Malaria, Cerebral / parasitology*
  • Mice
  • Plant Growth Regulators / pharmacology*
  • Plasmodium berghei / metabolism*
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / immunology
  • Prostaglandins / blood
  • Prostaglandins / metabolism
  • Salicylic Acid / pharmacology*

Substances

  • Cytokines
  • Plant Growth Regulators
  • Prostaglandins
  • Salicylic Acid

Grant support

This work was financially supported by a Grant-in-Aid for JSPS Fellows (RM). This work was also supported in part by Grants-in-Aid for Scientific Research 24390103 and for Scientific Research on Innovative Areas 23117007 from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. This work was also supported by the Program for the Promotion to Improve Independent Research Environments for Young Scientists by the Japan Science and Technology Agency, a grant for research on emerging and re-emerging infectious diseases from the Ministry of Health, Labour and Welfare of Japan, a grant for research to promote the development of anti-AIDS pharmaceuticals from the Japan Health Sciences Foundation, the Naito Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Sumitomo Foundation, the Takeda Science Foundation, and the Uehara Memorial Foundation.