Mechanisms of mosquito midgut invasion by Plasmodium ookinetes

动合疟原虫入侵蚊子中肠的机制

• 批准号: 7742621
• 负责人: MARCELO JACOBS-LORENA
• 金额: $ 40.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742621
• 关键词: ANXA2 gene; Accounting; Acquired Immunodeficiency Syndrome; Address; Affect; Alteplase; Amino Acids; Annexins; Anopheles gambiae; Antibodies; Binding; Biological Assay; Blood; Blood-Borne Pathogens; Candidate Disease Gene; Cells; Cessation of life; Child; Communicable Diseases; Complex; Culicidae; Development; Disease; Docking; Epithelium; Erythrocytes; Event; Figs - dietary; Future; Gene Conversion; Gene Expression; Genes; Genome; Goals; Grant; In Vitro; Invaded; Investigation; Isotope Labeling; Knockout Mice; Knowledge; Lead; Libraries; Life Cycle Stages; Link; Literature; Liver; Malaria; Measures; Mediating; Methodology; Midgut; Modeling; Molecular; Molecular Models; Organism; Parasites; Pathway interactions; Peptide Hydrolases; Peptides; Phage Display; Phenotype; Plasmin; Plasminogen; Plasminogen Activator; Plasmodium; Plasmodium falciparum; Play; Predisposition; Proteins; Proteomics; RNA Interference; Reagent; Recombinant Antibody; Recombinant Proteins; Recombinants; Resistance; Role; Salivary Glands; Screening procedure; Series; Specificity; Staging; Surface; System; Testing; Tissues; Transgenic Organisms; Translating; Tuberculosis; Vaccines; Validation; Work; asexual; base; cell type; disorder control; enolase; fighting; homologous recombination; in vivo; killings; molecular modeling; parasite invasion; pathogen; public health relevance; receptor; research study; tandem mass spectrometry; tool; transcriptomics; transmission process; vector mosquito; vector transmission

DESCRIPTION (provided by applicant): Malaria kills an estimated 1-2 million people (mostly children) every year. For transmission to occur, Plasmodium, the causative agent of malaria, has to complete a complex developmental cycle in the mosquito. Only a small proportion of the parasites survive the entire cycle. Thus, the mosquito is a potential weak link that can be exploited for disease control. Invasion of the mosquito midgut by Plasmodium ookinetes is a crucial step, yet little is known about the molecular mechanisms that operate at this stage. We made two unexpected observations during the current grant period: 1) The surface of Plasmodium ookinetes (the form that invades the midgut) is lined with an enolase-like protein and 2) ookinetes can invade the midgut by more than one pathway, one that can be blocked by the SM1 peptide and another that cannot. One aim of this proposal is to investigate, at the molecular level, the mechanism of midgut invasion. Our first aim will address the following working hypothesis. Enolase expressed on the surface of midgut ookinetes captures plasminogen from the surrounding blood meal. A mosquito type II annexin on the surface of the midgut epithelium binds to both tissue type plasminogen activator (tPA) from the blood meal and to ookinete surface enolase. We hypothesize that this bridge facilitates both ookinete docking to the surface of the midgut epithelium and tPA activation of plasminogen into plasmin (a protease). The combination of these two separate but intimately entwined events results in successful midgut invasion. Our second aim is to identify P. berghei ookinete genes that are responsible for the different invasion pathways. This is the first comprehensive study of the mechanisms of Plasmodium invasion of the midgut epithelium. Knowledge generated by these studies may have important implications for the development of multivalent transmission-blocking vaccines. PUBLIC HEALTH RELEVANCE Malaria, AIDS and tuberculosis are three infectious diseases that cause the largest numbers of deaths worldwide. Of these, only malaria requires an intermediate vector for transmission to occur. Therefore, the mosquito vector is a potential weak point in the transmission cycle. A better understanding of parasite development in the mosquito may translate in the discovery of new strategies to fight this deadly disease.

描述（由申请人提供）：每年疟疾估计杀死约1-200万人（主要是儿童）。为了进行传播，疟疾的致病药质子必须完成蚊子中复杂的发育周期。在整个周期中，只有一小部分寄生虫可以生存。因此，蚊子是一种潜在的弱环节，可以利用用于控制疾病的疾病。疟原虫对蚊子中肠的侵袭是一个关键的步骤，但对于此阶段运行的分子机制知之甚少。我们在当前赠款期间进行了两个意外的观察：1）疟原虫的表面（侵入中肠的形式）衬有类似烯醇酶的蛋白质和2）ookinetes可以用超过一个途径侵入中肠，一种可以被SM1肽和另一个无法阻止的途径。该建议的目的之一是在分子水平上调查中肠侵袭的机理。我们的第一个目标将解决以下工作假设。在Midgut Ookinetes表面表达的烯醇酶从周围的血液粉中捕获纤溶酶原。中肠上皮表面上的II型蚊子与来自血液粉和Ookinete表面烯醇酶的两种组织型纤溶酶原激活剂（TPA）结合。我们假设这座桥促进了将卵形扩展到中肠上皮表面和纤溶酶原激活纤溶酶（一种蛋白酶）的TPA激活。这两个独立但紧密纠缠的事件的结合导致成功的中肠入侵。我们的第二个目的是确定负责不同入侵途径的伯格氏菌基因。 这是对中肠上皮疟原虫浸润机制的首次全面研究。这些研究产生的知识可能对多价传输阻断疫苗的发展具有重要意义。公共卫生相关性疟疾，艾滋病和结核病是三种传染病，导致全球死亡人数最多。其中，只有疟疾需要中间载体才能进行传播。因此，蚊子矢量是传输周期中的潜在弱点。更好地了解蚊子中的寄生虫发展可能会转化为发现这种致命疾病的新策略。