The influence of host barriers on viral quasispecies diversity and pathogenesis

宿主屏障对病毒准种多样性和发病机制的影响

基本信息

批准号：
8212171
负责人：
Julie K Pfeiffer
金额：
$ 34.62万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-15 至 2013-07-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212171
关键词：
Animal Experiments Animals Antibodies Attenuated Attenuated Live Virus Vaccine Authorization documentation Biohazardous Substance Biological Assay Biological Models Blood Boxing Brain Cell Culture Techniques Cells Complex Critiques Data Development Disease Drug resistance Employee Environmental Health Equipment Equipment and supply inventories Evolution Exposure to Feces Genome Grant HIV Hair House mice Human Human poliovirus IACUC IFNAR1 gene Immune Infection Injection of therapeutic agent Integration Host Factors Interferons Intestines Lethal Dose 50 Life Measures Medical center Modeling Mus Mutagenesis Mutation Occupational Health Oral Pathogenesis Phenotype Plants Police Poliomyelitis Poliovirus Vaccines Polioviruses Population Principal Investigator Procedures Publishing RNA Viruses Research Research Design Research Methodology Risk Role Safety Shipping Ships Texas Tissues Universities Vaccination Vaccine Design Vaccines Viral Viral Genome Viral Vaccines Virulence Virulent Virus Work animal facility animal tissue base booster vaccine design face mask fitness in vivo laser capture microdissection member mutant novel prevent programs public health relevance research study transmission process vector wasting

项目摘要

DESCRIPTION (provided by applicant): Due to extensive genome variability, RNA virus populations exist as complex mutant populations called quasispecies. The diversity in the quasispecies complicates vaccine design, facilitates immune escape, and even confers drug resistance. For poliovirus, the ability to diversify its genome by mutagenesis is required for full virulence in infected animals. However, in infected mice, viral diversity is limited by bottlenecks that block quasispecies spread from the periphery to the CNS, thereby potentially limiting viral fitness. This bottleneck effect could explain why vaccine-associated poliomyelitis in humans is rare, despite the presence of virulent virus in the gut after vaccination with the attenuated Sabin poliovirus vaccine. The objective of this proposal is to use poliovirus as a model system to examine the mechanism of RNA virus bottlenecks, and to determine the effects of such bottlenecks on viral populations. The central hypothesis of this proposal is that physical barriers contribute to the bottleneck, and that the bottlenecked viral population has limited evolution capacity and reduced fitness. The contribution of physical barriers to the bottleneck following virus injection or oral inoculation will be determined in Aims 1 and 2 using a novel hybridization-based quasispecies diversity assay. Infected cells in the gut will be identified in Aim 3 using laser-capture microdissection and purification of live cells. In Aim 4, viral fitness and virulence thresholds will be measured in the presence or absence of the bottleneck. Elucidating this virulence threshold likely will be important for establishing the rational design of many live-attenuated viral vaccines. PUBLIC HEALTH RELEVANCE: RNA viruses such as poliovirus have incredible genome diversity, which complicates vaccine design, and can result in drug resistance. However, natural barriers called bottlenecks within an infected host can limit viral diversity, and possibly increase the safety of live-attenuated vaccines. The proposed research will determine which host factors contribute to the poliovirus bottleneck, and the effect of the bottleneck on the virulence of the virus.