MAPK ERK Signaling Regulates the TGF-β1-Dependent Mosquito Response to Plasmodium falciparum

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.

ERK signaling couples nutrient status to antiviral defense in the insect gut

“…2E and SI Appendix, Fig. S11) (30). We found that cell number was not affected by U0126 treatment of Aag2 cells (SI Appendix, Fig.…”

“…Using an orthogonal approach, we took advantage of the ERK pathway inhibitor U0126 that blocks MEK activation across diverse species (29,30), including Drosophila (31,32). Using an antibody that recognizes activated Drosophila Erk, we found that vertebrate insulin induces Erk activation within 15 min (SI Appendix, Fig.…”

“…Because ERK signaling can be activated in the mosquito digestive tract by nutrients and insulin in the blood meal (30,34), we reasoned that the ERK pathway may couple signals in the meal with antiviral defense to protect insects from orally acquired viral infections, including arboviruses. To determine whether ERK activity in the gut impacts local viral susceptibility, we took advantage of U0126 to inhibit ERK signaling in the gut.…”

The role of Vitamin D in malaria

“…P. falciparum histones extracted from merozoites directly stimulate the production of IL-8 and other inflammatory mediators by primary human dermal micro-vascular endothelial cells through a signaling pathway that involves the Src family kinases and p38 MAPK [131]. Malaria parasite development in the mosquito is regulated by a conserved MAPK signaling pathway that mediates the effects of an ingested cytokine [132]. ERK and p38 pathway regulate TNF-α and IL-12 production in macrophage-stimulated with purified P. falciparum GPI [133].…”

Immunological consequences of arthropod vector‐derived salivary factors

“…The arthropod injects salivary factors into the vertebrate host skin and, at the same time, the vector ingests cytokines [1], growth factors [2], complement components, antibodies and other blood-derived molecules with the blood meal. In both hosts -mammal and arthropod -these molecules can affect the survival and thus infectivity of vectorborne pathogens [3]. Various bioactive molecules in the saliva of blood-feeding arthropods have evolved to facilitate feeding.…”