Endogenous insulin-like peptides and control of malaria infection in the mosquito

内源性胰岛素样肽与蚊子疟疾感染的控制

• 批准号: 8313757
• 负责人: Jose Enrique Pietri
• 金额: $ 3.57万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313757
• 关键词: Address; Affinity; Africa South of the Sahara; Anabolism; Anopheles Genus; Anopheles gambiae; Antimalarials; Area; Biological; Biological Response Modifiers; Blood; Cameroon; Cause of Death; Communicable Diseases; Culicidae; Data; Development; Drug resistance; Exhibits; Family; Family member; Genes; Genetic Transcription; Genotype; Goals; Growth; Human; Immune; Immune response; Immune system; Immunity; In Vitro; India; Infection; Insecticide Resistance; Insulin; Insulin-Like Growth Factor I; Laboratories; Laboratory Study; Light; Link; Malaria; Mali; Mammals; Midgut; Mutation; Organism; Parasite Control; Parasites; Pathway interactions; Peptide Synthesis; Peptides; Phenotype; Plasmodium; Plasmodium falciparum; Population; Proteins; Publications; Regulation; Relative (related person); Resistance; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Somatomedins; Testing; Work; arm; base; field study; genetic manipulation; in vivo; insight; insulin signaling; novel; protein function; receptor; response; transmission process; vector; vector mosquito

DESCRIPTION (provided by applicant): The mosquito Anopheles gambiae is the primary vector of the deadly human malaria parasite Plasmodium falciparum in sub-Saharan Africa. While many laboratory studies have focused on how the mosquito immune system responds to and destroys these parasites, there is currently little available information on whether these responses are important under natural conditions. To address this need, the Luckhart laboratory is currently mapping single nucleotide polymorphisms (SNPs) in An. gambiae immune signaling genes to identify significant associations with P. falciparum infection in naturally occurring mosquito populations in endemic areas of Mali and Cameroon. In previous publications, the Luckhart laboratory demonstrated that human insulin in the blood meal and the insulin and insulin-like growth factor signaling (IIS) cascade can regulate malaria parasite development in Anopheles stephensi, a species closely related to An. gambiae. Hence, the IIS cascade proteins have been a major focus of these genotyping efforts. Thus far, we have identified numerous SNPs in the An. gambiae insulin-like peptide (AgILP) genes, including one in AgILP3 that is significantly associated with P. falciparum infection (Horton et al. 2010). Since this work, we have identified additional AgILP SNPs, including three SNPs in AgILP3 and AgILP4 that are predicted to alter protein function. Genotyping efforts are currently underway to determine whether any or all of these SNPs are also significantly associated with parasite infection in field collected mosquitoes. In light of data that demonstrate that human insulin and infection with P. falciparum can also induce the expression of ILP genes in the A. stephensi midgut, our genotyping data suggest that the AgILPs are involved in the regulation of P. falciparum infection under natural conditions. Based on these observations, we hypothesize that mosquito ILPs are produced in response to parasite infection, perhaps to amplify an earlier response to blood-derived factors or to insulin-like parasite factors, for sustained regulation of P. falciparum infection by the mosquito host. To test this hypothesis, we will determine which ILPs influence malaria parasite development in the mosquito midgut (Specific Aim 1), which pathways regulate ILP synthesis, secretion, and bioactivity (Specific Aim 2), and the effects of naturally occurring SNP mutations on ILP function (Specific Aim 3). These studies will not only provide key insights regarding immune cells signaling that is linked to parasite transmission under natural conditions, but will also provide novel targets for manipulating the mosquito immune response to reduce malaria transmission capacity. PUBLIC HEALTH RELEVANCE: Malaria is one of the leading causes of death from infectious diseases worldwide. The mosquitoes Anopheles stephensi and Anopheles gambiae are major vectors of the causative Plasmodium agents in India and Sub-Saharan Africa, respectively. Due to emerging challenges such as drug resistance in Plasmodium and insecticide resistance in the mosquito, there is an increasing need for novel malaria control strategies. The proposed project will identify and characterize new targets for genetic manipulation of the immune response in two major malaria vectors, with the potential of extending these findings to other Anopheles species in order to enhance malaria control.

描述（由申请人提供）：冈比亚按蚊是撒哈拉以南非洲致命的人类疟原虫恶性疟原虫的主要媒介。虽然许多实验室研究都集中在蚊子免疫系统如何响应和消灭这些寄生虫，但目前关于这些反应在自然条件下是否重要的​​可用信息很少。为了满足这一需求，Luckhart 实验室目前正在绘制 An 中的单核苷酸多态性 (SNP)。冈比亚免疫信号基因，以确定与马里和喀麦隆流行地区自然存在的蚊子种群中恶性疟原虫感染的显着关联。在之前的出版物中，Luckhart 实验室证明，血粉中的人胰岛素以及胰岛素和胰岛素样生长因子信号传导 (IIS) 级联可以调节史氏按蚊（与按蚊密切相关的物种）的疟原虫发育。冈比亚。因此，IIS 级联蛋白一直是这些基因分型工作的主要焦点。到目前为止，我们已经在 An 中鉴定出许多 SNP。冈比亚胰岛素样肽 (AgILP) 基因，包括 AgILP3 中的一个与恶性疟原虫感染显着相关 (Horton et al. 2010)。自这项工作以来，我们已经确定了其他 AgILP SNP，包括 AgILP3 和 AgILP4 中的三个 SNP，预计它们会改变蛋白质功能。目前正在进行基因分型工作，以确定这些 SNP 中的任何一个或全部是否也与田间寄生虫感染显着相关 收集了蚊子。根据数据表明，人胰岛素和恶性疟原虫感染也可以诱导史蒂芬西疟原虫中肠中 ILP 基因的表达，我们的基因分型数据表明 AgILP 参与自然条件下恶性疟原虫感染的调节。基于这些观察结果，我们假设蚊子 ILP 是响应寄生虫感染而产生的，可能是为了放大对血液源性因子或胰岛素样寄生虫因子的早期反应，以持续调节蚊子宿主对恶性疟原虫的感染。为了检验这一假设，我们将确定哪些 ILP 影响蚊子中肠中疟疾寄生虫的发育（具体目标 1），哪些途径调节 ILP 合成、分泌和生物活性（具体目标 2），以及自然发生的 SNP 突变对 ILP 的影响函数（具体目标 3）。这些研究不仅将提供有关自然条件下与寄生虫传播相关的免疫细胞信号传导的重要见解，还将提供操纵蚊子免疫反应以降低疟疾传播能力的新目标。 公共卫生相关性：疟疾是全世界传染病导致死亡的主要原因之一。史氏按蚊和冈比亚按蚊分别是印度和撒哈拉以南非洲地区疟原虫的主要传播媒介。由于疟原虫耐药性和蚊子杀虫剂耐药性等新出现的挑战，对新型疟疾控制策略的需求日益增加。拟议的项目将确定和描述两种主要疟疾病媒免疫反应基因操作的新目标，并有可能将这些发现扩展到其他按蚊物种，以加强疟疾控制。