C-type lectins in innate immune responses of Anopheles gambiae and Manduca sexta

冈比亚按蚊和天蛾先天免疫反应中的 C 型凝集素

• 批准号: 7679585
• 负责人: XIAO-QIANG YU
• 金额: $ 24.26万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679585
• 关键词: Affect; Affinity; Anopheles gambiae; Basement membrane; Binding; Biochemical; C-Type Lectins; Calcium; Carbohydrates; Cells; Characteristics; Complex; Culicidae; Deletion Mutation; Development; Epithelium; Evolution; Extracellular Matrix; Family; Figs - dietary; Genes; Goals; Hemocytes; Human; Immune; Immune response; Immune system; Insect Vectors; Insecta; Invertebrates; Knowledge; Laminin; Lectin; Leucine-Rich Repeat; Ligand Binding; Malaria; Manduca; Manduca sexta; Manduca sexta immulectin; Masks; Mediating; Membrane Glycoproteins; Membrane Proteins; Midgut; Molecular; Monophenol Monooxygenase; Mycoses; Names; Nature; Organism; Outcome; Parasites; Pattern; Pattern Recognition; Pattern recognition receptor; Peptide Synthesis; Phagocytosis; Plasma; Plasmodium; Plasmodium berghei; Plasmodium falciparum; Point Mutation; Polysaccharides; Principal Investigator; Progress Reports; Property; Protein Family; Proteins; RNA Interference; Receptor Gene; Regulation; Rodent; Specificity; Structure; Subgroup; Surface; Testing; Variant; Vertebrates; Work; antimicrobial peptide; beta-Glucans; killings; lipopolysaccharide-binding protein; microbial; pathogen; peptidoglycan recognition protein; prevent; pro-phenoloxidase; programs; protein protein interaction; prototype; public health relevance; receptor binding; research study; response; thioester; vector

DESCRIPTION (provided by applicant): Insects must recognize pathogens before they can mount an immune response. Recognition of pathogens in insects is mediated by pattern recognition receptors (PRRs) such as C-type lectins. In the tobacco hornworm, Manduca sexta, C-type lectins have been shown to function as stimulatory PRRs to enhance immune responses. In the mosquito Anopheles gambiae, a vector for malaria, and two C-type lectins, CTL4 and CTLMA2, somehow prevent Plasmodium berghei from melanization. But LRIM-1 and TEP-1 can enhance P. berghei melanization. However, silencing of CTL4, CTLMA2 and LRIM-1 in A. gambiae has no effect on development of P. falciparum, the human parasite, due to immune evasion. How can P. falciparum evade the immune system of A. gambiae, while P. berghei can not? We hypothesize that interaction of proteins from A. gambiae plasma or extracellular matrix with the surface of Plasmodium parasites are the keys. This proposal aims to investigate A. gambiae C-type lectins as putative PRRs to modulate immune responses against Plasmodium. The specific aims are: 1. Continue to investigate detailed molecular interactions of an insect prototype C-type lectin, Manduca immulectin-2, as a guide to understanding potential lectin-carbohydrate interactions and lectin-protein interactions that influence the outcome of pattern recognition and innate immune responses. We will construct deletions and point mutations in the carboxyl-terminal carbohydrate recognition domain of immulectin-2 predicted to affect interactions with microbial polysaccharides or with protein components of the prophenoloxidase activation complex. 2. Investigate the ligand-binding specificity and affinity of nine A. gambiae C-type lectins (including CTL4 and CTLMA2) and two chimeric lectins, as well as TEP-1 (thioester-containing protein-1) and LRIM-1 (leucine-rich repeat immune gene-1), study interactions of these proteins with P. berghei ookinetes and ookinete surface proteins, and identify P. berghei ookinete surface proteins that can be recognize by these A. gambiae proteins. 3. Study functions of nine A. gambiae lectins, two chimeric lectins, TEP-1 and LRIM-1 in encapsulation, melanization, phagocytosis and phenoloxidase activation in mosquitoes, and investigate interactions of these proteins during immune responses in A. gambiae. Our long term goal is to understand parasite recognition and parasite-pattern recognition receptor interaction in vector insects. PUBLIC HEALTH RELEVANCE Insects must recognize pathogens and parasites before they can mount an immune response. Recognition of nonself pathogens in insects is mediated by pattern recognition receptors (PRRs). We have some understanding of the proteins that serve as PRRs in insects to stimulate immune responses to bacterial or fungal infection. However, very little is known about how insect immune systems recognize non-fungal eukaryotic parasites: what are the pathogen-associated molecular patterns (PAMPs) on such organisms and what PRRs bind to them? This project is to investigate C-type lectins as potential PRRs in innate immune responses of Anopheles gambiae against Plasmodium parasites.

描述（由申请人提供）：昆虫必须识别病原体才能安装免疫反应。昆虫病原体的识别是由诸如C型凝集素等模式识别受体（PRR）介导的。在烟草中，甘达·塞克斯塔（Manduca Sexta）中，C型凝集素已被证明是刺激性PRR，可增强免疫反应。在冈比亚蚊帐，疟疾的载体和两个C型凝集素CTL4和CTLMA2中，某种程度上可以防止berghei疟原虫的黑色素化。但是LRIM-1和TEP-1可以增强Berghei P. berghei黑色化化。然而，由于免疫逃避，gambiae中CTL4，CTLMA2和LRIM-1的沉默对人类寄生虫的发育没有影响。恶性疟原虫如何逃避A. gambiae的免疫系统，而P. berghei不能逃避？我们假设来自冈比亚曲霉血浆或细胞外基质与疟原虫表面的蛋白质相互作用是钥匙。该提案旨在研究冈比亚曲霉凝集素作为假定的PRR，以调节针对疟原虫的免疫反应。具体目的是：1。继续研究昆虫原型C型凝集素，甘达免疫蛋白-2的详细分子相互作用，作为理解潜在的凝集素 - 碳水化合物相互作用和凝集素蛋白相互作用的指南，这些相互作用影响了模式识别和先天免疫反应的结果。我们将在预测的免疫蛋白-2的羧基末端碳水化合物识别结构域中构建缺失和点突变，这些碳水化合物识别结构域被预测会影响与微生物多糖的相互作用或与预苯酚酶活性活化复合物的蛋白质成分相互作用。 2。研究九种gambiae c型凝集素的配体结合特异性和亲和力蛋白质，并鉴定berghei ookinete表面蛋白，这些表面蛋白可以被这些gambiae蛋白识别。 3。在蚊子中，九种抗体凝集素，两个嵌合凝集素，两种嵌合凝集素，Tep-1和LRIM-1在封装，黑色素化，吞噬作用和酚氧化酶激活中的研究功能，并研究了A. gambiae免疫反应过程中这些蛋白质的相互作用。我们的长期目标是了解媒介昆虫中的寄生虫识别和寄生虫识别受体相互作用。公共卫生相关性昆虫必须识别病原体和寄生虫，然后才能产生免疫反应。昆虫中非自然病原体的识别是由模式识别受体（PRR）介导的。我们对在昆虫中充当PRR的蛋白质有所了解，以刺激对细菌或真菌感染的免疫反应。但是，关于昆虫免疫系统如何识别非真实真核寄生虫的了解很少：这种生物上的病原体相关分子模式（PAMP）是什么？该项目是将C型凝集素研究作为冈比亚对疟原虫寄生虫的先天免疫反应中的潜在PRR。