Understanding fusion peptide mutations in influenza hemagglutinin

描述(申请人提供)：流感既是一种主要的人类病原体，每年在美国造成大约50,000人死亡，也是一个经过充分研究的被包裹病毒进入细胞的模型系统。流感通过膜融合的过程进入细胞，但尽管有广泛的研究，但流感血凝素催化这一过程的机制尚不清楚。实验性突变已经产生了许多关于流感融合蛋白功能需求的数据，但我们没有可靠的理论来预测这些结果。这项建议试图对融合肽的机制有一个强有力的理解，足以预测这种血凝素突变。我们还希望确定哪些进入流感的元件是所有膜融合的共同因素，因为对脂质环境的修改也可以促进或阻止融合，以及哪些可能是病毒特异性的。我们正在开发高性能的模拟方法来分析膜融合；在这项工作中，我们将使用这些方法来预测流感融合肽的突变如何改变病毒感染细胞的能力，并研究脂质组成的变化如何与这些突变相互作用来控制病毒的传染性。计算预测将根据合作者施泰因豪尔的实验室进行的实验分析进行评估。 公共卫生相关性：该项目研究流感外壳蛋白如何与细胞膜相互作用以感染细胞。通过研究病毒突变如何干扰这一过程，我们希望发现抗病毒治疗的新策略。

DESCRIPTION (provided by applicant): Influenza is both a major human pathogen, causing approximately 50,000 deaths per year in the United States and a well-studied model system for cell entry by enveloped viruses. Influenza enters cells via a process of membrane fusion, but despite extensive study the mechanism by which influenza hemagglutinin catalyzes this process is not well understood. Experimental mutagenesis has yielded much data on the functional requirements of influenza fusion proteins, but we have no robust theory that could have predicted these results. This proposal seeks to develop a robust understanding of fusion peptide mechanisms sufficient to predict such mutations to hemagglutinin. We also wish to establish which elements of influenza entry are common to all membrane fusion, as modifications to the lipid environment can also promote or block fusion, and which may be virus-specific. We are developing high-performance simulation methods to analyze membrane fusion; in this work, we will use these methods to predict how mutations to influenza fusion peptides alter the virus's ability to infect cells and to investigate how lipid composition changes interact with these mutations to control viral infectivity. Computational predictions will be evaluated against experimental assays performed in the laboratory of collaborator Steinhauer. PUBLIC HEALTH RELEVANCE: This project studies how influenza coat proteins interact with cell membranes to infect the cell. By studying how viral mutations can interfere with this process, we hope to uncover new strategies for antiviral treatment.