Research Article: The JNK Pathway Is a Key Mediator of Anopheles gambiae Antiplasmodial Immunity

Date Published: September 5, 2013

Publisher: Public Library of Science

Author(s): Lindsey S. Garver, Giselle de Almeida Oliveira, Carolina Barillas-Mury, Kirk Deitsch.

http://doi.org/10.1371/journal.ppat.1003622

Abstract

The innate immune system of Anopheles gambiae mosquitoes limits Plasmodium infection through multiple molecular mechanisms. For example, midgut invasion by the parasite triggers an epithelial nitration response that promotes activation of the complement-like system. We found that suppression of the JNK pathway, by silencing either Hep, JNK, Jun or Fos expression, greatly enhanced Plasmodium infection; while overactivating this cascade, by silencing the suppressor Puckered, had the opposite effect. The JNK pathway limits infection via two coordinated responses. It induces the expression of two enzymes (HPx2 and NOX5) that potentiate midgut epithelial nitration in response to Plasmodium infection and regulates expression of two key hemocyte-derived immune effectors (TEP1 and FBN9). Furthermore, the An. gambiae L3–5 strain that has been genetically selected to be refractory (R) to Plasmodium infection exhibits constitutive overexpression of genes from the JNK pathway, as well as midgut and hemocyte effector genes. Silencing experiments confirmed that this cascade mediates, to a large extent, the drastic parasite elimination phenotype characteristic of this mosquito strain. In sum, these studies revealed the JNK pathway as a key regulator of the ability of An. gambiae mosquitoes to limit Plasmodium infection and identified several effector genes mediating these responses.

Partial Text

Malaria is a worldwide disease that is highly endemic in Sub-Saharan Africa and causes over half a million deaths annually. The mosquito Anopheles gambiae is a major vector of Plasmodium falciparum, the parasite responsible for most cases of human malaria in Africa. An. gambiae can mount effective antiplasmodial responses by activating several signaling cascades involved in immune regulation, such as the Imd, Toll, and STAT pathways [1]–[4]. Pathway activation leads to the transcription of effector genes that mediate the antiplasmodial mechanism. The thioester-containing protein 1 (TEP1) and the fibrinogen-related protein 9 (FBN9) are important components of the mosquito complement-like system that are produced by hemocytes and secreted into the mosquito hemolymph; they bind to the ookinete surface and mediate parasite lysis [5], [6]. Activation of the Imd and Toll pathways decreases ookinete survival as parasites come in contact with the mosquito hemolymph by promoting TEP1-mediated lysis [1], [3], [7]. In contrast, the STAT pathway targets a later stage of the parasite, the early oocysts, through a TEP1-independent response [4].

The immune response of An. gambiae mosquitoes against Plasmodium parasites is mediated by activation of immune-related signal transduction pathways. We carried out a functional characterization of five An. gambiae orthologs of genes known to mediate JNK signaling in Drosophila. Our studies implicate the JNK pathway as an important mediator of two coordinated steps of the mosquito anti-Plasmodium immune response and as a major determinant of the killing mechanism in a highly refractory strain of An. gambiae.

 

Source:

http://doi.org/10.1371/journal.ppat.1003622

 

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