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: 7580160
• 负责人: MARCELO JACOBS-LORENA
• 金额: $ 41万
• 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/7580160
• 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）：估计每年有 1-200 万人（主要是儿童）死于疟疾。为了发生传播，疟疾的病原体疟原虫必须在蚊子体内完成一个复杂的发育周期。只有一小部分寄生虫能够在整个周期中存活下来。因此，蚊子是可用于疾病控制的潜在薄弱环节。动合疟原虫入侵蚊子中肠是至关重要的一步，但人们对这一阶段运作的分子机制知之甚少。在当前资助期间，我们进行了两项意想不到的观察：1）动动疟原虫（侵入中肠的形式）的表面衬有烯醇酶样蛋白质，2）动动疟原虫可以通过多种途径侵入中肠，其中一种途径是可以被 SM1 肽阻断，而另一种则不能。该提案的目的之一是在分子水平上研究中肠侵袭的机制。我们的首要目标将解决以下工作假设。中肠动动植物表面表达的烯醇化酶从周围的血粉中捕获纤溶酶原。中肠上皮表面的蚊子 II 型膜联蛋白与血粉中的组织型纤溶酶原激活剂 (tPA) 和动动蛋白表面烯醇化酶结合。我们假设该桥促进动动分子与中肠上皮表面的对接以及纤溶酶原 tPA 激活为纤溶酶（一种蛋白酶）。这两个独立但紧密交织的事件的结合导致了中肠的成功入侵。我们的第二个目标是确定伯氏疟原虫动动基因，这些基因负责不同的入侵途径。 这是对疟原虫入侵中肠上皮机制的首次全面研究。这些研究产生的知识可能对多价传播阻断疫苗的开发具有重要意义。公共卫生相关性 疟疾、艾滋病和结核病是导致全球死亡人数最多的三种传染病。其中，只有疟疾需要中间媒介才能发生传播。因此，蚊媒是传播周期中的潜在弱点。对蚊子体内寄生虫发育的更好了解可能会转化为对抗这种致命疾病的新策略的发现。