AP-1/Fos-TGase2 Axis Mediates Wounding-induced Plasmodium falciparum Killing in Anopheles gambiae

Sandrine E Nsango,Julien Pompon,Ting Xie,Annika Rademacher,Malou Fraiture,Martine Thoma,Parfait H Awono-Ambene,Roger S Moyou,Isabelle Morlais,Elena A Levashina

doi:10.1074/jbc.m112.443267

Abstract

Anopheline mosquitoes are the only vectors of human malaria worldwide. It is now widely accepted that mosquito immune responses play a crucial role in restricting Plasmodium development within the vector; therefore, further dissection of the molecular mechanisms underlying these processes should inform new vector control strategies urgently needed to roll back the disease. Here, using genome-wide transcriptional profiling, bioinformatics, and functional gene analysis, we identify a new axis of mosquito resistance to monoclonal Plasmodium falciparum infections that includes the AP-1 transcription factor Fos and the transglutaminase 2 (TGase2), a cross-linking enzyme with known roles in wound responses. We demonstrate that Fos regulates induction of TGase2 expression after wounding but does not affect expression of the components of the well characterized complement-like system. Silencing of Fos or of TGase2 aborts the wounding-induced mosquito killing of P. falciparum. These results reveal multiple signaling pathways that are required for efficient Plasmodium killing in Anopheles gambiae.

Highlights

Wounding renders mosquitoes resistant to human malaria parasites
Identification of Wound Response Genes by Genome-wide Expression Analysis—We posited that wounding-induced mosquito resistance to human malaria parasites resulted from a transcriptional up-regulation of wound response genes prior to P. falciparum infection
Our results strongly suggest that activator protein 1 (AP-1)/Fos contributes to the wounding-induced killing of P. falciparum through direct or indirect regulation of transglutaminase 2 (TGase2) expression and that Fos/TGase2 constitute a novel axis in the antiparasitic responses of A. gambiae

Summary

Background

Wounding renders mosquitoes resistant to human malaria parasites. Results: Genome-wide transcriptional profiling identified 53 wound response genes, including two transglutaminases. Using genome-wide transcriptional profiling, bioinformatics, and functional gene analysis, we identify a new axis of mosquito resistance to monoclonal Plasmodium falciparum infections that includes the AP-1 transcription factor Fos and the transglutaminase 2 (TGase2), a cross-linking enzyme with known roles in wound responses. Silencing of Fos or of TGase aborts the wounding-induced mosquito killing of P. falciparum These results reveal multiple signaling pathways that are required for efficient Plasmodium killing in Anopheles gambiae. In A. gambiae, homologues of the Toll and Imd pathways selectively induce target gene expression through the NF-␬B transcription factors Rel and Rel, respectively (9 –11) Activation of both the Rel and Rel pathways results in an efficient immune response against malaria parasites. Our study identifies the novel role of TGase in the elimination of P. falciparum and unravels the importance of the AP-1/Fos-TGase axis in immune responses of mosquitoes to human malaria parasites

EXPERIMENTAL PROCEDURES

RESULTS AND DISCUSSION

CONCLUSIONS