Anopheles gambiae PGRPLC-Mediated Defense against Bacteria Modulates Infections with Malaria Parasites

PLoS Pathogens

Bogos Agianian¹  Stephan Meister²  George K. Christophides²  Fanny Turlure²  Angela Relógio³  Fotis C. Kafatos⁴  Isabelle Morlais⁵ 

[1] Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandropolis, Greece;Division of Cell and Molecular Biology, Department of Life Sciences, Imperial College London, London, United Kingdom;European Molecular Biology Laboratory, Heidelberg, Germany;Institut de Recherche pour le Développement - Laboratoire de Lutte contre les Insectes Nuisibles, UR 016, BP 64501, Montpellier, France;Organisation de Coordination de la lutte contre les Endémies en Afrique Centrale, Laboratoire de Recherche sur le Paludisme, Yaoundé, Cameroon

关键词: Mosquitoes;    Staphylococcus aureus;    Parasitic diseases;    Drosophila melanogaster;    Plasmodium;    Malarial parasites;    Bacterial diseases;    Escherichia coli infections;   

DOI  :  10.1371/journal.ppat.1000542

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Recognition of peptidoglycan (PGN) is paramount for insect antibacterial defenses. In the fruit fly Drosophila melanogaster, the transmembrane PGN Recognition Protein LC (PGRP-LC) is a receptor of the Imd signaling pathway that is activated after infection with bacteria, mainly Gram-negative (Gram−). Here we demonstrate that bacterial infections of the malaria mosquito Anopheles gambiae are sensed by the orthologous PGRPLC protein which then activates a signaling pathway that involves the Rel/NF-κB transcription factor REL2. PGRPLC signaling leads to transcriptional induction of antimicrobial peptides at early stages of hemolymph infections with the Gram-positive (Gram+) bacterium Staphylococcus aureus, but a different signaling pathway might be used in infections with the Gram− bacterium Escherichia coli. The size of mosquito symbiotic bacteria populations and their dramatic proliferation after a bloodmeal, as well as intestinal bacterial infections, are also controlled by PGRPLC signaling. We show that this defense response modulates mosquito infection intensities with malaria parasites, both the rodent model parasite, Plasmodium berghei, and field isolates of the human parasite, Plasmodium falciparum. We propose that the tripartite interaction between mosquito microbial communities, PGRPLC-mediated antibacterial defense and infections with Plasmodium can be exploited in future interventions aiming to control malaria transmission. Molecular analysis and structural modeling provided mechanistic insights for the function of PGRPLC. Alternative splicing of PGRPLC transcripts produces three main isoforms, of which PGRPLC3 appears to have a key role in the resistance to bacteria and modulation of Plasmodium infections. Structural modeling indicates that PGRPLC3 is capable of binding monomeric PGN muropeptides but unable to initiate dimerization with other isoforms. A dual role of this isoform is hypothesized: it sequesters monomeric PGN dampening weak signals and locks other PGRPLC isoforms in binary immunostimulatory complexes further enhancing strong signals.

【 授权许可】

CC BY