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）：利什曼病是一种由沙蝇媒介传播的多谱疾病，在许多国家具有重要的社会经济影响。白蛉和利什曼原虫之间存在着密切的关系，因此在自然界中，只有某些种类的白蛉能够传播某些利什曼原虫。这种物种特异性是由几个分子因素驱动的，这些分子因素使寄生虫能够在白蛉的中肠内感染、生存和繁殖，并在吸血期间传播到合适的宿主。一些白蛉物种被认为是允许的，因为它们能够携带几种利什曼原虫物种的实验性感染（例如 Lutzomyia. longipalpis）；其他白蛉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携带的利什曼原虫物种（例如白蛉）。导致这种向量能力的精确相互作用，无论是许可向量还是限制向量，仍有待完全阐明。我们之前定义了大利什曼原虫脂磷酸聚糖和 P. papatasi 半乳糖凝集素样分子之间的一种特异性相互作用，这种相互作用对于载体能力至关重要，并证明针对这种中肠分子的抗体可以防止大利什曼原虫在白蛉中肠内建立。在这里，我们提出了一系列使用这种限制性载体/寄生虫系统的研究，以确定参与白蛉中肠内利什曼原虫发育的其他白蛉分子。我们的研究将特别关注使用RNA干扰来评估蛋白质的作用，例如PpChym2，一种血液诱导的胰凝乳蛋白酶，可能参与早期杀死利什曼原虫； PpChit1，一种中肠特异性几丁质酶，被认为在利什曼原虫逃离围营养基质中发挥作用。此外，最近鉴定的中肠转录物，例如编码围营养蛋白和凝血酶特异性抑制剂的转录物也将被评估。一旦确定，有效干扰 L. Major 发育的 P. papatasi 分子也将在其他白蛉载体组合（包括 P. argentipes 和 L. donovani）中测试其广谱活性。这项研究将增进有关白蛉与利什曼原虫相互作用的知识，并将为选择传播阻断候选物作为消除和/或减少利什曼病的策略提供见解。项目叙述：白蛉是利什曼病的主要传播媒介，利什曼病是一种多谱系疾病，在发展中国家造成很高的发病率和死亡率。由于大多数患者无法负担有效的治疗方法，并且没有可用的疫苗，因此基于媒介的策略，特别是阻断传播的疫苗正在成为控制许多媒介传播疾病的选择策略。我们的研究旨在评估沉默选定数量的白蛉蛋白的效果，这些白蛉蛋白被认为与白蛉内利什曼原虫的发育有关。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开发对抗寄生虫传播的新策略。