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

• 批准号: 7314679
• 负责人: A. LORENA PASSARELLI
• 金额: $ 18.25万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7314679
• 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

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）：载体生物学领域的一个长期问题是病原体如何从昆虫载体的中肠进入血液中的其他器官，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已经设计了到达其他组织的替代方法，但所有病原体都面临着相同的障碍。我们建议表征昆虫病原体使用的生长因子信号传导机制，该机制可用于病原体，例如疟疾寄生虫和载体传播病毒。成纤维细胞生长因子（FGF）是多细胞生物中广泛的多肽生长因子家族，是细胞分化，细胞增殖和细胞运动的关键调节剂。在果蝇中，一个无分支的单一FGF调节气管细胞运动，确定其分支的模式。杆状病毒是大型含DNA的病毒，类似于其他真核病毒，编码影响宿主发育的基因。大多数杆状病毒编码具有与细胞同源物相似的生化特性的FGF同源物VFGF，但是，VFGF在病毒感染中的作用尚不清楚。杆状病毒用来传播感染的特定机制尚未详细定义，但尚未详细定义，但气管细胞已被视为Midgut以外的病毒传播的导管。我们假设该病毒利用VFGF刺激未感染的气管细胞的运动能够全身传播感染。我们将表征昆虫宿主中的VFGF敲除杆状病毒。具体而言，（1）将在不同发育阶段使用4种昆虫物种确定VFGF-敲除和过表达VFGF的​​病毒的感染和毒力； （2）我们将通过检查VFGF对使用扫描共聚焦和透射电子显微镜对中肠运动的运动性和形态的影响来确定杆状病毒对中肠屏障的横穿屏障的机制。我们预计我们的结果将为病原体 - 载体相互作用和发病机理提供宝贵的信息。许多昆虫载体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使其传播的特定机制尚不清楚。拟议的研究将确定昆虫病原体在其宿主中移动的机制，开发研究其他昆虫病原体的工具，从长远来看，导致了控制人类病原体传播的新策略。