Defining the Interplay Between Viral Adaptation and Host Proteostasis

定义病毒适应和宿主蛋白质稳态之间的相互作用

基本信息

批准号：
10587055
负责人：
Matthew Donald Shoulders
金额：
$ 60.86万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587055
关键词：
Adaptive Immune System Adjuvant Aging Ally Amino Acid Sequence Amino Acid Substitution Amino Acids Antibodies Antiviral Agents Antiviral Therapy Biochemical Biological Models Biology Biophysics Cells Chemicals Complex Computer Models Computing Methodologies Defect Dependence Endoplasmic Reticulum Environment Evolution Extinction (Psychology)Genetic Genomics HIV Human poliovirus Immune system Individual Influenza Influenza Hemagglutinin Innate Immune System Kinetics Knowledge Mediating Methods Missense Mutation Molecular Molecular Chaperones Mutagens Mutation Nucleoproteins Organism Pathologic Pathway interactions Pharmaceutical Preparations Play Population Predisposition Process Production Proteins Quality Control RNA RNA Viruses Research Resistance Resistance development Role Shapes Study models System Testing Therapeutic Thermodynamics Treatment Protocols Vaccines Variant Viral Viral Genome Viral Proteins Virus Work Zoonoses antiviral drug development biophysical analysis biophysical properties biophysical techniques cell type cost cross-species transmission design dynamic system genome-wide improved insight invention mutation screening neutralizing antibody novel pathogen predictive modeling pressure prevent protein folding proteostasis resistance mechanism stem targeted treatment transmission process virology

项目摘要

Exceedingly high mutation rates permit most RNA viruses to rapidly explore protein sequence space. On the other hand, high mutation rates also result in widespread production of viral protein variants with poor biophysical properties and severe folding defects. Protein variants that cannot fold successfully are removed from the population, even if they could otherwise confer a beneficial adaptive function. Recent work has revealed that the composition and activities of the host cell’s protein folding and quality control machinery (the proteostasis network) play a central role in defining the amino acid sequence space accessible to rapidly evolving RNA viral proteins. This phenomenon has so far largely been explored using proteostasis modulation itself as the selection pressure. It is not yet clear whether host cell chaperones are directly – by enhancing viral protein folding – impacting the ability of viruses to adapt to and escape from external selection pressures stemming from the host’s adaptive immune system, antiviral drugs, or other factors. Using influenza as a model system, this proposal integrates state-of-the-art chemical biology, genetic, biochemical, biophysical, and computational methods to comprehensively evaluate and elucidate, at the molecular-level, the emerging and complex interplay between host proteostasis and viral adaptation in the context of diverse selection pressures. Aim 1 focuses on the mechanism by which hijacked host chaperones promote influenza escape from innate immune system factors, establishing biophysical origins of host chaperone-dependence in influenza nucleoprotein evolution and elucidating whether and how the virus can readily adapt to challenging host proteo- stasis environments. Aim 2 establishes how the composition and activities of the host cell’s endoplasmic reticulum proteostasis network impact the ability of influenza hemagglutinin, the primary target of influenza-neutralizing antibodies, to escape selection pressure from the adaptive immune system. Aim 3 operates on a broader scale to understand how host proteostasis networks impact genome-wide mutational tolerance and influenza error catastrophe, a phenomenon in which increasing viral mutation rates past a certain threshold causes population extinction. Experimental findings from all these Aims are integrated with protein biophysical studies and computational modeling to illuminate molecular origins of host proteostasis-dependent viral adaptation. This work is expected to establish host proteostasis as a defining force that shapes viral adaptation, particularly in the context of highly relevant selection pressures. Beyond fundamental elucidation of viral evolution, findings will greatly enhance understanding of the factors involved in viral adaptation to host selection pressures and, in the longer-term, improve the ability to accurately predict viral evolution. Discoveries are also expected to highlight the potential of therapeutic adjuvants targeting host chaperones to enable treatment regimens to which viruses cannot easily evolve resistance. Contributions will impact fields ranging from basic virology and vaccine and antiviral drug development to evolutionary biology and protein folding biophysics.

极高的突变速率使大多数RNA病毒都可以快速探索蛋白质序列空间。另一方面，高突变速率还导致宽度生产病毒蛋白变异体具有较差的生物物理特性和严重的折叠缺陷。无法成功折叠的蛋白质变体从人群中删除，即使它们可以赋予有益的自适应功能。最近的工作表明，宿主细胞的蛋白质折叠和质量控制机制（蛋白质症网络）的组成和活性在定义可以快速演变的RNA病毒蛋白上可访问的氨基酸序列空间方面起着核心作用。到目前为止，这种现象已在很大程度上是使用蛋白质的调制本身作为选择压力来探索的。尚不清楚宿主细胞链酮是否直接（通过增强病毒蛋白折叠）会影响病毒适应并摆脱源于宿主的适应性免疫系统，抗病毒药物或其他因素的外部选择压力的能力。该提案使用actractza作为模型系统，整合了最先进的化学生物学，遗传，生化，生物物理和计算方法，以在分子水平上全面评估和阐明，在分子水平，宿主蛋白质之间的新出现和复杂的相互作用，宿主的蛋白质量和病毒性适应在多样选择压力的背景下。 AIM 1的重点是劫持宿主伴侣促进先天免疫系统因素的影响，从而建立了宿主链链依赖性的生物物理起源，并阐明了病毒是否以及如何轻松适应挑战宿主蛋白质 - 蛋白质 - 蛋白质stasis环境。 AIM 2确定了宿主细胞内质网的组成和活性如何影响影响Za Hemagglutinin的能力，Hemagglutinin是影响力中和中和抗体的主要目标，从适应性免疫系统中避免选择压力。 AIM 3在更广泛的范围内运行，以了解宿主蛋白抑制网络如何影响全基因组突变耐受性和影响力误差灾难，这种现象在这种现象中，在一定阈值中增加病毒突变率会导致人口扩展。所有这些目标的实验发现与蛋白质生物物理研究和计算建模集成，以阐明宿主蛋白stosisopis依赖性病毒适应的分子起源。预计这项工作将建立宿主蛋白质症作为塑造病毒适应的定义力，尤其是在高度相关的选择压力的背景下。除了阐明病毒进化的基本阐明之外，发现还将大大增强对病毒适应宿主选择压力中涉及的因素的理解，从而长期提高了准确预测病毒进化的能力。还希望发现靶向宿主伴侣的治疗调节剂的潜力使病毒无法轻易发展抗性。贡献将影响从基本病毒学和疫苗和抗病毒药物发展到进化生物学和蛋白质折叠生物物理学等领域。