Significance of heparan sulfate in HSV-1 spread

描述(申请人提供)：单纯疱疹病毒1型(HSV-1)在成人人群中高度流行。候选人的长期职业目标是在研究早期事件方面保持出色的研究计划，这些事件允许病毒进入细胞并建立生产性感染以进行传播。到目前为止，这位候选人的研究对理解HSV-1进入受体和摄取机制做出了重大贡献。最近，候选人的实验室在通过活细胞荧光显微镜了解HSV-1与宿主细胞的相互作用方面取得了新的进展。独立科学家奖(K.02)提供的薪酬支持将大大减少候选人从事一项新研究的教学和行政责任，并更多地用于在候选人的实验室培训研究生和研究员，这将提高他们的整体生产力。本提案扩展了候选人正在进行的关于HSV-1进入和传播机制的研究。它探讨了硫酸乙酰肝素(HS)在病毒传播和传播过程中的意义。它是基于一项新的观察结果，即最初的病毒与宿主的相互作用发生在膜过程中，例如表达HS的丝足。然后，这种相互作用被病毒利用，有效地和有针对性地传递到细胞体，进入并传播到邻近的细胞。尽管到目前为止所有候选疱疹病毒都存在这种现象，并模仿逆转录病毒报告的“冲浪”现象，但确切的运输过程的分子机制仍不清楚。目前也不清楚病毒是通过外源性还是细胞内的方式在膜过程中传播。候选人假设，病毒粒子在到达细胞体之前会以外源方式传播。根据进入受体的可及性，病毒粒子要么进入细胞，要么再次通过膜过程到达邻近的细胞体进入细胞。将进行实验，以确定疱疹病毒冲浪现象的外源性性质和分子基础。冲浪在病毒传播中的重要性将通过动物模型来解决。这项申请中提议的工作将为候选人实验室目前正在进行的工作提供一个新的维度，它还将为未来的研究开辟一个新的、具有生物医学意义的领域。 相关性：HSV-1感染在人类中高度流行。世界上大约80%的成年人口可能是该病毒的血清阳性。这种疾病的表现从较常见的发烧水泡到罕见的脑炎病例。病毒通过其包膜蛋白与我们细胞上的受体相互作用，这种相互作用对感染的启动至关重要。我们的研究可能会提出新的策略来阻止病毒在人类之间的传播和传播。

DESCRIPTION (provided by applicant): Herpes simplex virus type-1 (HSV-1) is highly prevalent among adult human population. The candidate's long-term career goal is to maintain an outstanding research program in studying early events that allow the virus to enter into cells and establish a productive infection for spread. To date, the candidate's research has made a significant contribution to the understanding of HSV-1 entry receptors and uptake mechanisms. Most recently the candidate's laboratory has made new advances in understanding the interactions of HSV-1 with host cells via live cell fluorescence microscopy. The salary support provided by an Independent Scientist Award (K.02) will significantly reduce teaching and administrative responsibilities for the candidate to pursue a new line of research and be more available for the training of graduate students and fellows in the candidate's laboratory, which will enhance their overall productivity. The present proposal extends the research being conducted by the candidate on HSV-1 entry and spread mechanisms. It explores the significance of heparan sulfate (HS) in viral transmission and spread processes. It is based on a novel observation that initial virus-host interactions occur at membrane processes such as filopodia that express HS. This interaction is then exploited by the virus for an efficient and targeted delivery to the cell body for entry and spread to neighboring cells. Although this phenomenon seems to exist for all the herpesviruses examined so far by the candidate and mimic "surfing" phenomenon reported with retroviruses, the exact molecular mechanism for the transport process remain unknown. It is also unclear whether the viruses travel exogenously or intracellularly on the membrane processes. The candidate hypothesizes that the virions travel exogenously until they reach the cell body. Depending on accessibility to entry receptor, the virions either enter into a cell or travel again via membrane processes to reach a neighboring cell body for entry. Experiments will be performed to determine the exogenous nature and the molecular basis of the herpesvirus surfing phenomenon. Significance of the surfing in virus transmission will be addressed using an animal model. The proposed work in this application will provide a new dimension to the current work being done in the candidate's laboratory and it will also open up a new and biomedically significant area for future research. RELEVANCE: HSV-1 infections are highly prevalent among humans. About 80% of world's adult population may be seropositive for the virus. The disease manifestations range from more common fever blisters to rare cases of encephalitis. The virus via its envelope proteins interacts with receptors on our cells and this interaction is crucial for the initiation of the infection. Our research may suggest new strategies to stop virus transmission and spread among humans.