Abstract
Despite efficient vector transmission, Plasmodium parasites suffer great bottlenecks during their developmental stages within Anopheles mosquitoes. The outcome depends on a complex three-way interaction between host, parasite and gut bacteria. Although considerable progress has been made recently in deciphering Anopheles effector responses, little is currently known regarding the underlying microbial immune elicitors. An interesting candidate in this sense is the pathogen-derived prenyl pyrophosphate and designated phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), found in Plasmodium and most eubacteria but not in higher eukaryotes. HMBPP is the most potent stimulant known of human Vγ9Vδ2 T cells, a unique lymphocyte subset that expands during several infections including malaria. In this study, we show that Vγ9Vδ2 T cells proliferate when stimulated with supernatants from intraerythrocytic stages of Plasmodium falciparum cultures, suggesting that biologically relevant doses of phosphoantigens are excreted by the parasite. Next, we used Anopheles gambiae to investigate the immune- and redox- stimulating effects of HMBPP. We demonstrate a potent activation in vitro of all but one of the signaling pathways earlier implicated in the human Vγ9Vδ2 T cell response, as p38, JNK and PI3K/Akt but not ERK were activated in the A. gambiae 4a3B cell line. Additionally, both HMBPP and the downstream endogenous metabolite isopentenyl pyrophosphate displayed antioxidant effects by promoting cellular tolerance to hydrogen peroxide challenge. When provided in the mosquito blood meal, HMBPP induced temporal changes in the expression of several immune genes. In contrast to meso-diaminopimelic acid containing peptidoglycan, HMBPP induced expression of dual oxidase and nitric oxide synthase, two key determinants of Plasmodium infection. Furthermore, temporal fluctuations in midgut bacterial numbers were observed. The multifaceted effects observed in this study indicates that HMBPP is an important elicitor in common for both Plasmodium and gut bacteria in the mosquito.
Highlights
Human malaria is caused by Plasmodium parasites transmitted via Anopheles mosquitoes and results in more than 600,000 deaths annually [1]
Vγ9Vδ2 T cells are stimulated by phosphoantigens that are produced in Plasmodium falciparum [28]
When the Peripheral blood mononuclear cells (PBMCs) were stimulated with four times diluted supernatants, the fraction of Vγ9Vδ2 T cells increased to around 80% for both donors with two different extracts (Figure 1 B-C, E-F)
Summary
Human malaria is caused by Plasmodium parasites transmitted via Anopheles mosquitoes and results in more than 600,000 deaths annually [1]. To enable transmission in the mosquito, parasites ingested along with the blood meal must quickly undertake a complex series of developmental and invasive events (reviewed in 2) Several of these stages are associated with severe parasite population bottlenecks, mainly due to host immune responses triggered by both the parasite [3,4,5] and the growing midgut bacterial flora [6,7]. We have previously shown that provision of PfGPI in the blood meal induces the expression of antimicrobial peptides in A. gambiae [12] Both elicitors activate Akt and ERK signaling in cell lines and expression of the antiplasmodial factor nitric oxide synthase (NOS) in the midgut of Anopheles mosquitoes [10,11]
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