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Functional characterization of Anopheles matrix metalloprotease 1 reveals its agonistic role during sporogonic development of malaria parasites.

ABSTRACT: The ability to invade tissues is a unique characteristic of the malaria stages that develop/differentiate within the mosquitoes (ookinetes and sporozoites). On the other hand, tissue invasion by many pathogens has often been associated with increased matrix metalloprotease (MMP) activity in the invaded tissues. By employing cell biology and reverse genetics, we studied the expression and explored putative functions of one of the three MMPs encoded in the genome of the malaria vector Anopheles gambiae, namely, the Anopheles gambiae MMP1 (AgMMP1) gene, during the processes of blood digestion, midgut epithelium invasion by Plasmodium ookinetes, and oocyst development. We show that AgMMP1 exists in two alternative isoforms resulting from alternative splicing; one secreted (S-MMP1) and associated with hemocytes, and one membrane type (MT-MMP1) enriched in the cell attachment sites of the midgut epithelium. MT-MMP1 showed a remarkable response to ookinete midgut invasion manifested by increased expression, enhanced zymogen maturation, and subcellular redistribution, all indicative of an implication in the midgut epithelial healing that accompanies ookinete invasion. Importantly, RNA interference (RNAi)-mediated silencing of the AgMMP1 gene revealed a postinvasion protective function of AgMMP1 during oocyst development. The combined results link for the first time an MMP with vector competence and mosquito-Plasmodium interactions.

SUBMITTER: Goulielmaki E

PROVIDER: S-EPMC4249346 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Functional characterization of Anopheles matrix metalloprotease 1 reveals its agonistic role during sporogonic development of malaria parasites.

Goulielmaki Evi E Sidén-Kiamos I I Loukeris Thanasis G TG

Infection and immunity 20140902 11

The ability to invade tissues is a unique characteristic of the malaria stages that develop/differentiate within the mosquitoes (ookinetes and sporozoites). On the other hand, tissue invasion by many pathogens has often been associated with increased matrix metalloprotease (MMP) activity in the invaded tissues. By employing cell biology and reverse genetics, we studied the expression and explored putative functions of one of the three MMPs encoded in the genome of the malaria vector Anopheles ga ...[more]

PMID: 25183733

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Project description: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-kappaB 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.

Project description:BackgroundThe transcriptome of Plasmodium falciparum clinical isolates varies according to strain, mosquito bites, disease severity and clinical history. Therefore, it remains a challenge to directly interpret the parasite's transcriptomic information into a more general biological signature in a natural human malaria infection. These confounding variations can be potentially overcome with parasites derived from controlled-human malaria infection (CHMI) studies.MethodsWe performed CHMI studies in healthy and immunologically naïve volunteers receiving the same P. falciparum strain ((Sanaria® PfSPZ Challenge (NF54)), but with different sporozoite dosage and route of infection. Parasites isolated from these volunteers at the day of patency were subjected to in vitro culture for several generations and synchronized ring-stage parasites were subjected to transcriptome profiling.FindingsWe observed clear deviations between CHMI-derived parasites from volunteer groups receiving different PfSPZ dose and route. CHMI-derived parasites and the pre-mosquito strain used for PfSPZ generation showed significant transcriptional variability for gene clusters associated with malaria pathogenesis, immune evasion and transmission. These transcriptional variation signature clusters were also observed in the transcriptome of P. falciparum isolates from acute clinical infections.InterpretationOur work identifies a previously unrecognized transcriptional pattern in malaria infections in a non-immune background. Significant transcriptome heterogeneity exits between parasites derived from human infections and the pre-mosquito strain, implying that the malaria parasites undergo a change in functional state to adapt to its host environment. Our work also highlights the potential use of transcriptomics data from CHMI study advance our understanding of malaria parasite adaptation and transmission in humans. FUND: This work is supported by German Israeli Foundation, German ministry for education and research, MOE Tier 1 from the Singapore Ministry of Education Academic Research Fund, Singapore Ministry of Health's National Medical Research Council, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA and the German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung-DZIF).

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Functional characterization of Anopheles matrix metalloprotease 1 reveals its agonistic role during sporogonic development of malaria parasites.

Publications

Functional characterization of Anopheles matrix metalloprotease 1 reveals its agonistic role during sporogonic development of malaria parasites.

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