P. papatasi midgut molecules: gene function and assessing TBV candidates

P. papatasi 中肠分子：基因功能和评估 TBV 候选者

• 批准号: 7787078
• 负责人: MARY A MCDOWELL
• 金额: $ 29.3万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787078
• 关键词: Affect; Anabolism; Antibodies; Binding; Binding Proteins; Blood; Blood coagulation; Bolus Infusion; Chest; Chitinase; Code; Competence; Country; Data; Development; Digestion; Diptera; Disease; Epithelial Cells; Epithelium; Exhibits; Food; Galactose Binding Lectin; Hematocrit procedure; Infection; Knowledge; Lead; Leishmania; Leishmania major; Leishmaniasis; Lutzomyia genus; Midgut; Molecular; Morbidity - disease rate; Nature; Parasites; Patients; Peptide Hydrolases; Phlebotomus; Play; Principal Investigator; Proteins; Prunella vulgaris; Psychodidae; RNA Interference; Research; Research Personnel; Role; Sand Flies; Species Specificity; Specificity; System; Testing; Thrombin; Transcript; Trypsin; Vaccines; Vector-transmitted infectious disease; Visceral; base; chymotrypsin; economic impact; effective therapy; fighting; fly; gene function; glycosylation; inhibitor/antagonist; insight; killings; knock-down; lipophosphonoglycan; mortality; novel; novel strategies; prevent; programs; receptor; skin lesion; social; transmission process; vector; vector-based vaccine

DESCRIPTION (provided by applicant): Leishmaniasis, a multi-spectrum disease transmitted by sand fly vectors, has an important social-economic impact in many countries. A strong relationship exists between sand flies and Leishmania such that, in nature, only certain species of sand flies are able to transmit certain species of Leishmania. Such species-specificity is driven by several molecular factors that allow the parasite to infect, survive and multiply within the midgut of the sand fly and be transmitted to a suitable host during a blood meal. Some sand fly species are considered permissive in that they are able to harbor experimental infections of several Leishmania species (e.g. Lutzomyia. longipalpis); other sand fly species are considered restrictive as they can only be infected with the Leishmania species that they carry in nature (e.g. Phlebotomus. papatasi). The precise interactions that lead to this vector competence, whether for permissive or restrictive vectors, remain to be completely elucidated. We previously defined one specific interaction between L. major lipophosphoglycan and a P. papatasi galectin-like molecule that is essential for vector competence and demonstrated that antibodies targeted to this midgut molecule prevent establishment of Leishmania major within the sand fly midgut. Here we propose a set of studies using this restrictive vector/parasite system, to identify additional sand fly molecules that participate in the development of Leishmania within the sand fly midgut. Our studies will specifically focus on the use of RNA interference to assess the roles of proteins such as PpChym2, a blood-induced chymotrypsin that may be involved in early killing of Leishmania; and PpChit1, a midgut-specific chitinase that is thought to play a role in Leishmania escape from the peritrophic matrix. Additionally, recently identified midgut transcripts such as those coding for peritrophins and thrombin-specific inhibitors will also be evaluated. Once identified, P. papatasi molecules that effectively interfere with the development of L. major also will be tested for their broad spectrum activity in other sand fly vector combinations, including P. argentipes and L. donovani. This research will advance the knowledge regarding sand fly-Leishmania interaction and will provide insights for the selection of transmission blocking candidates as a strategy to eliminate and/or reduce leishmaniasis. Project Narrative: Phlebotomine sand flies are the main vectors of leishmaniasis, a multi-spectrum disease that causes substantial morbidity and mortality in the developing world. As effective therapies are un-affordable to most patients and no vaccines are available, vector-based strategies, specifically transmission-blocking vaccines are becoming a choice strategy to control many vector transmitted diseases. Our studies aim at assessing the effect of silencing a selected number of sand fly proteins thought to be involved in Leishmania development within the sand fly; elucidating how these proteins interact with Leishmania parasites undoubtedly will lead to the development of novel strategies to fight parasite transmission.

描述（由申请人提供）：Leishmanisis是一种由Sand Fly向量传播的多光谱疾病，在许多国家都具有重要的社会经济影响。沙蝇和利什曼原虫之间存在牢固的关系，因此，在自然界中，只有某些种类的沙蝇才能传播某些利什曼尼亚物种。这种物种特异性是由几个分子因子驱动的，这些因素使寄生虫能够在沙蝇的中肠中感染，生存和繁殖，并在血液粉期间传播到合适的宿主。某些沙蝇被认为允许，因为它们能够怀有几种利什曼原虫物种（例如lutzomyia。longipalpis）的实验感染。其他沙蝇物种被认为是限制性的，因为它们只能感染它们在自然界中的利什曼原虫物种（例如，Phlebotomus。Papatasi）。导致该向量能力的确切相互作用，无论是允许的还是限制性矢量，都尚待完全阐​​明。我们先前定义了主要的脂磷酸杆菌和P. papatasi lectectin样分子之间的一种特异性相互作用，该分子对于矢量能力至关重要，并证明针对这种中肠分子的抗体可以防止在砂蝇中间建立Leishmania Major。在这里，我们建议使用这种限制性载体/寄生虫系统进行一系列研究，以确定参与沙蝇中肠内利什曼尼亚发展的其他沙蝇分子。我们的研究将专门针对使用RNA干扰来评估蛋白质（例如PPCHYM2）的作用，PPCHYM2是一种血液诱导的胰胆红蛋白，可能参与Leishmania的早期杀死； PPCHIT1是一种中肠中特异性几丁质酶，被认为在利什曼尼亚逃脱了嗜营养基质中发挥作用。此外，还将评估最近确定的中肠转录物，例如编码腹蛋白的编码和凝血酶特异性抑制剂。一旦确定，在有效干扰L. major的发展的P. papatasi分子也将在其他沙蝇载体组合（包括Argentipes和L. donovani）中的广泛光谱活性进行测试。这项研究将提高有关沙蝇相互作用的知识，并将为选择阻止候选者的选择作为消除和/或减少利什曼病的策略提供见解。项目叙述：肺泡沙蝇是利什曼病的主要媒介，这是一种多光谱疾病，在发展中国家引起大量发病率和死亡率。由于有效的疗法对大多数患者无法承受，并且没有可用的疫苗，因此基于媒介的策略，特别是传输阻滞疫苗正成为控制许多载体传播疾病的选择策略。我们的研究旨在评估沉默一定数量的沙蝇蛋白的影响，被认为与沙蝇内的利什曼原虫发育有关。阐明这些蛋白质如何与利什曼原虫寄生虫相互作用无疑将导致与寄生虫传播的新型策略的发展。