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Role of viral fibroblast growth factor in pathogenesis

病毒成纤维细胞生长因子在发病机制中的作用

基本信息

批准号：
7498423
负责人：
A. LORENA PASSARELLI
金额：
$ 21.48万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-25 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7498423
关键词：
Affect Animal Diseases Apoptosis Arthropods Baculoviruses Basal lamina Binding Biochemical Biology Bypass Capsid Cell Differentiation process Cell Proliferation Cells Characteristics Chemotaxis Chimeric Proteins Chitin Confocal Microscopy Cultured Cells Cytoskeleton DNA Sequence Rearrangement DNA Transposable Elements Data Development Diffuse Diptera Dose Drosophila genus Epithelial Cells Family Fibroblast Growth Factor Fibroblast Growth Factor Receptors Gene Expression Gene Expression Regulation Genes Genome Genomics Growth Factor Homologous Gene Host Defense Mechanism Human Hymenoptera Individual Infection Injection of therapeutic agent Insect Vectors Insecta Invaded Knock-out Label Larva Laser Scanning Confocal Microscopy Lead Light Malaria Mammals Methods Microscopy Midgut Morphology Nucleopolyhedrovirus Oral Organ Organism Oxygen Parasites Pathogenesis Pattern Plasmodium Play Predisposition Process Production Property Protein Overexpression Reagent Role Route Running Scanning Services Signal Transduction Signal Transduction Pathway Site Source Spodoptera frugiperda Staging Staining method Stains Systemic infection Testing Time Tissues Transmission Electron Microscopy Travel Viral Virion Virulence Virus Virus Diseases Work cell motility enhanced green fluorescent protein expression vector extracellular killings mutant particle pathogen polypeptide research study tool transmission process vector

项目摘要

DESCRIPTION (provided by applicant): A long standing question in the field of vector biology is how pathogens gain access from the midgut of an insect vector to other organs in the hemocoel, bypassing cellular and non-cellular barriers as well as host defense mechanisms. Although different pathogens may have devised alternative methods to reach other tissues, all are faced with the same barriers. We propose to characterize a growth factor signaling mechanism used by an insect pathogen that can be applicable to pathogens such as malaria parasites and vector-borne viruses. Fibroblast growth factors (FGFs) are a large family of polypeptide growth factors widespread in multicellular organisms and are key regulators in cell differentiation, cell proliferation, and cell motility. In Drosophila, a single fgf, branchless, regulates tracheal cell motility, determining the pattern of its branches. Baculoviruses are large DNA-containing viruses that, similar to other eukaryotic viruses, encode genes that affect the development of their host. Most baculoviruses encode an fgf homolog, vfgf, with similar biochemical properties to the cellular homologs, however, the role of vfgf during virus infection is unknown. The specific mechanism used by baculoviruses to spread infection beyond the primary site of infection, midgut epithelial cells, has not been defined in detail, but tracheolar cells have been implicated as conduits for virus propagation beyond the midgut. We hypothesize that the virus utilizes vfgf to stimulate motility of uninfected tracheolar cells to spread infection systemically. We will characterize a vfgf-knockout baculovirus in insect hosts. Specifically, (1) the infectivity and virulence of vfgf- knockout and vfgf-overexpressing viruses will be determined using 4 insect species at different developmental stages; and (2) we will determine the mechanisms by which baculoviruses traverse the midgut barrier by examining the effect of vFGF on motility and morphology of tracheolar cells servicing the midgut using scanning confocal and transmission electron microscopy. We expect that our results will contribute valuable information to pathogen-vector interactions and pathogenesis. Many insect-vectored pathogens carry human and animal diseases. The specific mechanisms of how the pathogens travel from the insect midgut to the other tissues enabling their transmission are not known. The proposed studies will determine the mechanism used by an insect pathogen to move through its host, develop tools to study other insect pathogens, and in the long run, lead to the development of new strategies to control human pathogen transmission.

描述（由申请人提供）：媒介生物学领域中一个长期存在的问题是病原体如何从昆虫媒介的中肠进入血腔中的其他器官，绕过细胞和非细胞屏障以及宿主防御机制。尽管不同的病原体可能设计出替代方法来到达其他组织，但它们都面临着相同的障碍。我们建议描述昆虫病原体使用的生长因子信号传导机制，该机制可适用于疟疾寄生虫和媒介传播病毒等病原体。成纤维细胞生长因子（FGF）是广泛存在于多细胞生物中的一大类多肽生长因子，是细胞分化、细胞增殖和细胞运动的关键调节因子。在果蝇中，单个无分支的 fgf 调节气管细胞运动，决定其分支的模式。杆状病毒是含有 DNA 的大型病毒，与其他真核病毒类似，编码影响宿主发育的基因。大多数杆状病毒编码 fgf 同源物 vfgf，其生化特性与细胞同源物相似，然而，vfgf 在病毒感染过程中的作用尚不清楚。杆状病毒用于将感染传播到主要感染部位（中肠上皮细胞）之外的具体机制尚未得到详细定义，但气管细胞被认为是病毒传播到中肠之外的管道。我们假设该病毒利用 vfgf 刺激未感染气管细胞的运动，从而全身传播感染。我们将表征昆虫宿主中的 vfgf 敲除杆状病毒。具体来说，（1）将使用4种处于不同发育阶段的昆虫来测定vfgf敲除和vfgf过表达病毒的感染性和毒力； (2) 我们将通过使用扫描共聚焦和透射电子显微镜检查 vFGF 对服务中肠的气管细胞运动和形态的影响，确定杆状病毒穿过中肠屏障的机制。我们希望我们的结果将为病原体-载体相互作用和发病机制提供有价值的信息。许多昆虫传播的病原体携带人类和动物疾病。病原体如何从昆虫中肠传播到其他组织以实现传播的具体机制尚不清楚。拟议的研究将确定昆虫病原体通过宿主传播的机制，开发研究其他昆虫病原体的工具，并从长远来看，导致开发控制人类病原体传播的新策略。