Anopheles gambiae eicosanoids modulate Plasmodium berghei survival from oocyst to salivary gland invasion

Abstract

Eicosanoids affect the immunity of several pathogen/insect models, but their role on the Anopheles gambiae response to Plasmodium is still unknown. Plasmodium berghei-infected mosquitoes were injected with an eicosanoid biosynthesis inhibitor, indomethacin (IN), or a substrate, arachidonic acid (AA), at day 7 or day 12 post-infection (p.i.). Salivary gland invasion was evaluated by sporozoite counts at day 21 p.i. IN promoted infection upon sporozoite release from oocysts, but inhibited infection when sporozoites were still maturing within the oocysts, as observed by a reduction in the number of sporozoites reaching the salivary glands. AA treatment had the opposite effect. We show for the first time that An. gambiae can modulate parasite survival through eicosanoids by exerting an antagonistic or agonistic effect on the parasite, depending on its stage of development.

Mosquito Midgut Prostaglandin Release Establishes Systemic Immune Priming

“…Direct contact between bacteria and midgut cells is necessary to establish immune priming (Rodrigues et al., 2010), suggesting that midgut PG release might be involved in this response. Therefore, we investigated whether systemic injection of PGs previously detected in insects (PGE1, PGE2, and PGF2) (Garcia Gil de Muñoz et al., 2008, Stanley-Samuelson and Ogg, 1994, Ramos et al., 2014) could recapitulate the priming response. Injection of PGE1, PGE2, or PGF2 significantly increased the proportion of circulating granulocytes (Figure 3A, p = 0.0015, <0.0001, and <0.0001, respectively, Mann-Whitney U test , Table S10), with PGE2 having the strongest effect.…”

“…Additional studies indicate that indomethacin inhibits vertebrate thyroid peroxidase and lactoperoxidase (Van Zyl and Louw, 1979) in addition to cyclooxygenase, suggesting that peroxidases may be the targets of this drug in insects. This could explain the pharmacological effect of indomethacin on antibacterial response in lepidoptera (Downer et al., 1997) and Plasmodium sporozoite infection in mosquitoes (Ramos et al., 2014). Furthermore, there are reports that vertebrate peroxidases can catalyze PG synthesis in vitro using arachidonic acid as a substrate (Zilletti et al., 1989, Panganamala et al., 1974, Egan et al., 1979).…”

Identification of a prostaglandin E2 receptor that regulates mosquito oenocytoid immune cell function in limiting bacteria and parasite infection

“…Eicosanoids are lipid-derived signaling molecules that include prostaglandins (PGs), leukotrienes (LTs), lipoxins (LXAs), and epoxyeicosatrienoic acid (EETs), that serve important roles in immune regulation (1)(2)(3). Evidence suggests that these responses are evolutionally conserved across metazoa, where eicosanoids significantly influence insect cellular immunity (4)(5)(6)(7)(8)(9)(10). In the mosquito, Anopheles gambiae, eicosanoids such as prostaglandin E2 (PGE2) and lipoxins have integral roles in mediating immune priming and mosquito susceptibility to malaria parasite infection (11,12).…”

Inhibitors of Eicosanoid Biosynthesis Reveal that Multiple Lipid Signaling Pathways Influence Malaria Parasite Survival in Anopheles gambiae

“…However, the significance of eicosanoids in mosquito physiology and immune function has only recently been addressed [23,25,33,36,37,38,41], leaving several fundamental questions of eicosanoid function in the mosquito host unanswered. This includes the potential role of eicosanoids in mediating the vectorial capacity of Anopheles to malaria parasites [23,25,41], which, due to the complexity of eicosanoid pathways and the limited knowledge of the enzymes responsible for its biosynthesis, has not been fully addressed. Using a pharmaceutical approach with known eicosanoid inhibitors, we examined the potential roles of each major eicosanoid biosynthesis pathway on Plasmodium oocyst numbers.…”

“…One possible explanation is that indomethacin, a COX inhibitor, may not inhibit the heme peroxidases HPX7 and HPX8 which were recently implicated in PGE2 synthesis [25]. Alternatively, since indomethacin can impair vertebrate peroxidase activity [46], and the injection of indomethacin can influence Plasmodium sporozoite salivary gland numbers [41], it is plausible that indomethacin can similarly inhibit mosquito HPX activity. Further experiments are therefore required to delineate the potential inhibitory effects of indomethacin on prostaglandin signaling in mosquitoes.…”