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.
Highlights
Malaria is a worldwide disease that is highly endemic in SubSaharan Africa and causes over half a million deaths annually
The mosquito Anopheles gambiae is a major vector of human malaria, a disease caused by Plasmodium falciparum parasites that results in more than half a million deaths each year
We found that Jun-N-terminal kinase (JNK) signaling is required for mosquito midgut cells to induce expression of two enzymes, HPx2 and NOX5, that mediate epithelial nitration in response to parasite invasion
Summary
Malaria is a worldwide disease that is highly endemic in SubSaharan 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 [1,2,3,4]. 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]. The STAT pathway targets a later stage of the parasite, the early oocysts, through a TEP1-independent response [4]
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