VEE PATHOGENESIS AND VACCINE DEVELOPMENT

VEE 发病机制和疫苗开发

• 批准号: 7208981
• 负责人: Slobodan Paessler
• 金额: $ 11.82万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7208981
• 关键词: Address; Aerosols; Age; Alphavirus; Attenuated; Binding; Biological; Categories; Cells; Characteristics; Chimera organism; Clinical; Complementary DNA; Culicidae; Cultured Cells; Data; Development; Doctor of Veterinary Medicine; Encephalitis; Encephalitis Viruses; Epidemic; Equus caballus; Exhibits; Florida; Genes; Genetic Transcription; Genome; Goals; Human; Immunity; In Vitro; Infection; Invertebrates; Laboratories; Latin America; Lead; Licensing; Military Personnel; Modeling; Mus; National Institute of Allergy and Infectious Disease; Nonstructural Protein; Organ; Pathogenesis; Pathogenicity; Population; Principal Investigator; Production; Property; RNA replication; Rate; Research; Research Personnel; Role; Signs and Symptoms; Sindbis Virus; Structural Protein; Toxin; Vaccine Design; Vaccines; Venezuelan Equine Encephalitis Virus; Viral; Viral Genes; Viral Pathogenesis; Virulence; Virus; Virus-Cell Membrane Interaction; base; cytokine; enzootic; experience; expression vector; flu; immunogenicity; in vivo; mortality; neutralizing antibody; pathogen; programs; therapeutic vaccine; tissue tropism; transmission process; user-friendly; vaccine development; virus culture; virus pathogenesis

DESCRIPTION (provided by applicant): The applicant, a D.V.M. with some clinical and laboratory experience, seeks support to become an independent researcher in the field of viral pathogenesis and vaccine development. His long-term goal is to better understand the pathogenesis of human alphaviral encephalitides, including the roles of each viral gene. This information will be used to develop safer and more effective vaccines and therapeutics. The proposed research focuses on Venezuelan equine encephalitis virus (VEEV), an important, naturally emerging human pathogen and a potent biological weapon categorized by the NIAID as a Category B Priority Pathogen. Although VEEV is an important human pathogen and an efficient vaccine expression vector, little is known about the role of the nonstructural proteins (replicative machinery) of this virus in pathogenesis. Furthermore, no licensed human VEEV vaccine is available. The goals are to1l) develop safe and effective VEEV vaccines using chimeric VEEV/Sindbis viruses (SINV) that are efficiently produced at large scale, and; 2) study VEEV pathogenesis using reciprocal SINV/VEEVchimeras to assess the roles of structural vs. nonstructural proteins in tissue tropism and pathogenicity. Two central hypotheses will be addressed: 1) The virulence potential of VEEV strongly depends on the nonstructural proteins and probably their interactions with cellular/organismal factors, and; 2) VEEV tissue tropism depends on the ability of the virus not only to bind and enter target cells, but also to establish productive infection. Better understanding of these VEEV-cell interactions will allow the applicant to generate highly attenuated SINV/VEEV chimeras that induce protective immunity against VEEV. The specific aims are: 1. Characterize the replication in vitro and in vivo, pathogenicity and immunogenicity of chimeric SINV/VEEV vaccine candidates in mice. 2. Determine the tissue tropism and pathogenicity of reciprocal, chimeric SINV/VEEV viruses in mice. Through this project, the applicant will create SINV/VEEV chimeric vaccine candidate viruses that are highly attenuated, immunogenie and replicate efficiently in cell culture. By dissecting the nonstructural proteins of VEEV from the structural proteins, the role of replieative machinery (nonstructural proteins) in the pathogenesis will be elucidated.

描述（由申请人提供）：申请人，D.V.M.凭借一些临床和实验室经验，寻求支持成为病毒发病机理和疫苗发育领域的独立研究人员。他的长期目标是更好地了解人α脑脑的发病机理，包括每个病毒基因的作用。该信息将用于开发更安全，更有效的疫苗和治疗剂。拟议的研究重点是委内瑞拉马脑炎病毒（VEEV），这是一种重要的，自然出现的人类病原体，是NIAID分类为B类优先病原体的有效生物学武器。尽管VEEV是一种重要的人类病原体，也是有效的疫苗表达载体，但对于该病毒在发病机理中的非结构蛋白（复制机械）的作用知之甚少。此外，没有获得许可的人VEEV疫苗。目标是TO1L）使用嵌合VEEV/Sindbis病毒（SINV）开发安全有效的VEEV疫苗，这些病毒是有效生产的，并且； 2）使用相互的SINV/VEEVCHIMERAS研究VEEV发病机理，以评估结构与非结构蛋白在组织的热门和致病性中的作用。将解决两个中心假设：1）VEEV的毒力潜力在很大程度上取决于非结构性蛋白质以及它们与细胞/生物因子的相互作用，以及； 2）VEEV组织的向流不仅取决于病毒结合和进入靶细胞的能力，还取决于建立生产性感染的能力。更好地了解这些VEEV细胞相互作用将使申请人能够产生高度减弱的SINV/VEEV嵌合体，从而诱导对VEEV的保护性免疫。具体目的是：1。表征小鼠嵌合SINV/VEEV疫苗的体外和体内复制，致病性和免疫原性。 2。确定小鼠中相互，嵌合sinv/veev病毒的组织偏向主义和致病性。通过该项目，申请人将创建高度减毒，免疫原子并在细胞培养中有效复制的SINV/VEEV嵌合疫苗候选病毒。通过从结构蛋白中剖析VEEV的非结构蛋白，将阐明补充性机械（非结构蛋白）在发病机理中的作用。

项目成果

Production of IL-8, IL-17, IFN-gamma and IP-10 in human astrocytes correlates with alphavirus attenuation.

• DOI: 10.1016/j.vetmic.2012.11.021
• 发表时间: 2013-05-03
• 期刊: Veterinary microbiology
• 影响因子: 3.3
• 作者: Peng BH;Borisevich V;Popov VL;Zacks MA;Estes DM;Campbell GA;Paessler S
• 通讯作者: Paessler S

CD4+ T cells provide protection against acute lethal encephalitis caused by Venezuelan equine encephalitis virus.

CD4 T 细胞可预防由委内瑞拉马脑炎病毒引起的急性致死性脑炎。

• DOI: 10.1016/j.vaccine.2009.04.015
• 发表时间: 2009
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Yun,NadezhdaE;Peng,Bi-Hung;Bertke,AndreaS;Borisevich,Viktoriya;Smith,JenniferK;Smith,JeanonN;Poussard,AllisonL;Salazar,Milagros;Judy,BarbaraM;Zacks,MicheleA;Estes,DMark;Paessler,Slobodan
• 通讯作者: Paessler,Slobodan

Encephalitic alphaviruses.

• DOI: 10.1016/j.vetmic.2009.08.023
• 发表时间: 2010-01-27
• 期刊: Veterinary microbiology
• 影响因子: 3.3
• 作者: Zacks MA;Paessler S
• 通讯作者: Paessler S

Novel linear DNA vaccines induce protective immune responses against lethal infection with influenza virus type A/H5N1.

• DOI: 10.4161/hv.4.6.6177
• 发表时间: 2008-11
• 期刊: HUMAN VACCINES
• 作者: Kendirgi, Frederic;Yun, Nadezda E.;Linde, Nathaniel S.;Zacks, Michele A.;Smith, Jeanon N.;Smith, Jennifer K.;McMicken, Harilyn;Chen, Yin;Paessler, Slobodan
• 通讯作者: Paessler, Slobodan

Injectable peramivir mitigates disease and promotes survival in ferrets and mice infected with the highly virulent influenza virus, A/Vietnam/1203/04 (H5N1).

注射帕拉米韦可减轻感染高毒力流感病毒 A/Vietnam/1203/04 (H5N1) 的雪貂和小鼠的疾病并促进其存活。

• DOI: 10.1016/j.virol.2007.12.029
• 发表时间: 2008
• 期刊: Virology
• 影响因子: 3.7
• 作者: Yun,NadezhdaE;Linde,NathanielS;Zacks,MicheleA;Barr,IanG;Hurt,AeronC;Smith,JeanonN;Dziuba,Natallia;Holbrook,MichaelR;Zhang,Lifang;Kilpatrick,JohnM;Arnold,CShane;Paessler,Slobodan
• 通讯作者: Paessler,Slobodan