Abstract
Malaria is caused by infection with intraerythrocytic protozoa of the genus Plasmodium that are transmitted by Anopheles mosquitoes. Although a variety of anti-parasite effector genes have been identified in anopheline mosquitoes, little is known about the signaling pathways that regulate these responses during parasite development. Here we demonstrate that the MEK-ERK signaling pathway in Anopheles is controlled by ingested human TGF-β1 and finely tunes mosquito innate immunity to parasite infection. Specifically, MEK-ERK signaling was dose-dependently induced in response to TGF-β1 in immortalized cells in vitro and in the A. stephensi midgut epithelium in vivo. At the highest treatment dose of TGF-β1, inhibition of ERK phosphorylation increased TGF-β1-induced expression of the anti-parasite effector gene nitric oxide synthase (NOS), suggesting that increasing levels of ERK activation negatively feed back on induced NOS expression. At infection levels similar to those found in nature, inhibition of ERK activation reduced P. falciparum oocyst loads and infection prevalence in A. stephensi and enhanced TGF-β1-mediated control of P. falciparum development. Taken together, our data demonstrate that malaria parasite development in the mosquito is regulated by a conserved MAPK signaling pathway that mediates the effects of an ingested cytokine.
Highlights
300 to 500 million malaria cases and 1 to 3 million deaths are reported annually, with the greatest numbers of deaths occurring in sub-Saharan Africa following infection with Plasmodium falciparum [1]
We reveal the role of MEK-extracellular signal regulated kinase (ERK) signaling in the regulation of malaria parasite development by an ingested blood-derived, mammalian cytokine in the mosquito host
Our results provide new insights into the host–parasite–vector relationship that could be utilized as a foundation for new strategies to reduce malaria transmission
Summary
300 to 500 million malaria cases and 1 to 3 million deaths are reported annually, with the greatest numbers of deaths occurring in sub-Saharan Africa following infection with Plasmodium falciparum [1]. Inducible expression of nitric oxide synthase (NOS) and production of toxic nitrogen oxides as well as a variety of other anti-parasite effectors in the mosquito midgut [4,7,8,9] – a critical tissue for early parasite development – suggest that the midgut response could be targeted to enhance antiparasite resistance In support of this concept, published data have confirmed that genetic manipulation of the NF-kB-dependent Toll and Imd signaling pathways can alter development of the murine parasite Plasmodium berghei in the African malaria vector Anopheles gambiae [10,11]. Manipulation of cell signaling pathways in this way can facilitate the regulation of a large number of anti-parasite effectors in concert, minimizing the likelihood that the parasite could adapt to an altered host [12]
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