abscisic-acid and Malaria

The ancient stress signaling molecule abscisic acid (ABA) is ubiquitous in animals and plants but is perhaps most well-known from its early discovery as a plant hormone. ABA can be released into water by plants and is found in nectar, but is also present in mammalian blood, three key contexts for mosquito biology. We previously established that addition of ABA to

Topics: Abscisic Acid; Animals; Anopheles; Disease Resistance; Female; Gene Expression; Larva; Malaria; Mice; Parasitic Diseases; Signal Transduction

Artemisinin is biosynthesized in Artemisia annua and widely used for the treatment of malaria. Abscisic acid (ABA)-responsive kinase 1 (AaAPK1), a member of the SnRK2 family, is involved in the regulation of artemisinin biosynthesis through the phosphorylation of AabZIP1, which directly transactivates genes involved in artemisinin biosynthesis. Through diverse assays - including yeast two-hybrid and bimolecular fluorescence complementation assays - we report that the ABA-responsive protein phosphatase AaPP2C1 physically interacts with AaAPK1. In addition, phos-tag mobility shift assays indicate that AaPP2C1 dephosphorylates AaAPK1. Moreover, dual-luciferase assays demonstrate that the presence of AaPP2C1 reduces the transactivation of artemisinin biosynthesis genes by AabZIP1. These results further refine the post-translational regulatory network of artemisinin biosynthesis, showing that AaPP2C1 is negatively involved through dephosphorylation of AaAPK1.

Topics: Abscisic Acid; Arabidopsis Proteins; Artemisia annua; Artemisinins; Gene Expression Regulation, Plant; Humans; Malaria; Phosphorylation; Phosphotransferases; Plant Leaves; Plants, Genetically Modified; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Transcription Factors

Abscisic acid (ABA) is an ancient stress hormone and is detectable in a wide variety of organisms where it regulates innate immunity and inflammation. Previously, we showed that oral supplementation with ABA decreased parasitemia in a mouse model of malaria, decreased liver and spleen pathology and reduced parasite transmission to mosquitoes. Here, we report that higher circulating ABA levels were associated with a reduced risk of symptomatic malaria in a cohort of Plasmodium falciparum-infected Ugandan children. To understand possible mechanisms of ABA protection in malaria, we returned to our mouse model to show that ABA effects on Plasmodium yoelii 17XNL infection were accompanied by minimal effects on complete blood count and blood chemistry analytes, suggesting a benefit to host health. In addition, orally delivered ABA induced patterns of gene expression in mouse liver and spleen that suggested enhancement of host anti-parasite defenses. To test these inferences, we utilized passive immunization and knockout mice to demonstrate that ABA supplementation increases circulating levels of protective, parasite-specific IgG and requires caspase-1 to reduce parasitemia. Collectively, ABA induces host responses that ameliorate infection and disease in an animal model and suggest that further studies of ABA in the context of human malaria are warranted.

Topics: Abscisic Acid; Acids; Animals; Asymptomatic Diseases; Caspase 1; Child; Child, Preschool; Disease Models, Animal; Humans; Immunoglobulin G; Malaria; Mice; Mice, Knockout; Plant Growth Regulators; Plasmodium falciparum; Plasmodium yoelii; Uganda

Nearly half of the world's population is at risk for malaria. Increasing drug resistance has intensified the need for novel therapeutics, including treatments with intrinsic transmission-blocking properties. In this study, we demonstrate that the isoprenoid abscisic acid (ABA) modulates signaling in the mammalian host to reduce parasitemia and the formation of transmissible gametocytes and in the mosquito host to reduce parasite infection. Oral ABA supplementation in a mouse model of malaria was well tolerated and led to reduced pathology and enhanced gene expression in the liver and spleen consistent with infection recovery. Oral ABA supplementation also increased mouse plasma ABA to levels that can signal in the mosquito midgut upon blood ingestion. Accordingly, we showed that supplementation of a Plasmodium falciparum-infected blood meal with ABA increased expression of mosquito nitric oxide synthase and reduced infection prevalence in a nitric oxide-dependent manner. Identification of the mechanisms whereby ABA reduces parasite growth in mammals and mosquitoes could shed light on the balance of immunity and metabolism across eukaryotes and provide a strong foundation for clinical translation.

Topics: Abscisic Acid; Animals; Anopheles; Antimalarials; Dietary Supplements; Female; Malaria; Mice; Parasitemia; Plasmodium yoelii