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      Anopheles gambiae Immune Responses to Human and Rodent Plasmodium Parasite Species

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          Abstract

          Transmission of malaria is dependent on the successful completion of the Plasmodium lifecycle in the Anopheles vector. Major obstacles are encountered in the midgut tissue, where most parasites are killed by the mosquito's immune system. In the present study, DNA microarray analyses have been used to compare Anopheles gambiae responses to invasion of the midgut epithelium by the ookinete stage of the human pathogen Plasmodium falciparum and the rodent experimental model pathogen P. berghei. Invasion by P. berghei had a more profound impact on the mosquito transcriptome, including a variety of functional gene classes, while P. falciparum elicited a broader immune response at the gene transcript level. Ingestion of human malaria-infected blood lacking invasive ookinetes also induced a variety of immune genes, including several anti- Plasmodium factors. Twelve selected genes were assessed for effect on infection with both parasite species and bacteria using RNAi gene silencing assays, and seven of these genes were found to influence mosquito resistance to both parasite species. An MD2-like receptor, AgMDL1, and an immunolectin, FBN39, showed specificity in regulating only resistance to P. falciparum, while the antimicrobial peptide gambicin and a novel putative short secreted peptide, IRSP5, were more specific for defense against the rodent parasite P. berghei. While all the genes that affected Plasmodium development also influenced mosquito resistance to bacterial infection, four of the antimicrobial genes had no effect on Plasmodium development. Our study shows that the impact of P. falciparum and P. berghei infection on A. gambiae biology at the gene transcript level is quite diverse, and the defense against the two Plasmodium species is mediated by antimicrobial factors with both universal and Plasmodium-species specific activities. Furthermore, our data indicate that the mosquito is capable of sensing infected blood constituents in the absence of invading ookinetes, thereby inducing anti- Plasmodium immune responses.

          Synopsis

          The malarial parasite Plasmodium has to traverse the gut wall of the Anopheles mosquito in order to complete its lifecycle and to be transmitted between hosts. At the midgut stage of infection, the mosquito activates immune responses to eliminate most invading parasites. The features of these immune responses are not very well understood and have mainly been examined using the rodent parasite model P. berghei. Here the authors investigated the relationship between the Anopheles gambiae responses against the human pathogen P. falciparum, the rodent parasite P. berghei, and bacterial infections, at both the gene expression and functional levels. The mosquito responses against these pathogens were quite diverse, and the defense against the two malaria parasite species involved both common and species-specific components. Malaria-infected blood was sufficient to activate anti- Plasmodium immune responses, even in the absence of midgut invasion. Through this mechanism, the mosquito can initiate its defense against Plasmodium prior to invasion of the gut. Mosquito genes that could negatively influence Plasmodium development were also capable of regulating the resistance to bacterial infection, but several of the antibacterial genes had no effect on Plasmodium; thus, the mosquito apparently utilizes its antibacterial defense systems against the malaria parasite.

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          Most cited references57

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          Cluster analysis and display of genome-wide expression patterns.

          A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data simultaneously in a form intuitive for biologists. We have found in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function, and we find a similar tendency in human data. Thus patterns seen in genome-wide expression experiments can be interpreted as indications of the status of cellular processes. Also, coexpression of genes of known function with poorly characterized or novel genes may provide a simple means of gaining leads to the functions of many genes for which information is not available currently.
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            LPS, TLR4 and infectious disease diversity.

            Innate immune receptors recognize microorganism-specific motifs. One such receptor-ligand complex is formed between the mammalian Toll-like receptor 4 (TLR4)-MD2-CD14 complex and bacterial lipopolysaccharide (LPS). Recent research indicates that there is significant phylogenetic and individual diversity in TLR4-mediated responses. In addition, the diversity of LPS structures and the differential recognition of these structures by TLR4 have been associated with several bacterial diseases. This review will examine the hypothesis that the variability of bacterial ligands such as LPS and their innate immune receptors is an important factor in determining the outcome of infectious disease.
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              Immunity-related genes and gene families in Anopheles gambiae.

              We have identified 242 Anopheles gambiae genes from 18 gene families implicated in innate immunity and have detected marked diversification relative to Drosophila melanogaster. Immune-related gene families involved in recognition, signal modulation, and effector systems show a marked deficit of orthologs and excessive gene expansions, possibly reflecting selection pressures from different pathogens encountered in these insects' very different life-styles. In contrast, the multifunctional Toll signal transduction pathway is substantially conserved, presumably because of counterselection for developmental stability. Representative expression profiles confirm that sequence diversification is accompanied by specific responses to different immune challenges. Alternative RNA splicing may also contribute to expansion of the immune repertoire.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                ppat
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                June 2006
                9 June 2006
                : 2
                : 6
                : e52
                Affiliations
                [1 ] W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States
                [2 ] Department of Human Genetics and Genome Quebec Innovation Centre, McGill University, Montreal, Quebec, Canada
                [3 ] European Molecular Biology Laboratory, European Bioinformatics Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
                National Institutes of Health, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: gdimopou@ 123456jhsph.edu
                Article
                05-PLPA-RA-0158R4 plpa-02-06-02
                10.1371/journal.ppat.0020052
                1475661
                16789837
                515e68ac-1009-4dbb-a0c4-39df245a1e25
                Copyright: © 2006 Dong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 13 September 2005
                : 24 April 2006
                Page count
                Pages: 13
                Categories
                Research Article
                Immunology
                Infectious Diseases
                Microbiology
                Parasitology
                Anopheles Gambiae
                Plasmodium Falciparum
                Plasmodium Berghei
                Malaria
                Immunity
                Custom metadata
                Dong Y, Aguilar R, Xi Z, Warr E, Mongin E, et al. (2006) Anopheles gambiae immune responses to human and rodent Plasmodium parasite species. PLoS Pathog 2(6): e52. DOI: 10.1371/journal.ppat.0020052

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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