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：
10707348
负责人：
Matthew Donald Shoulders
金额：
$ 58.47万
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/10707348
关键词：
Adaptive Immune System Adjuvant Aging 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 Genetic Genomics HIV Human poliovirus Immune system Individual Influenza Influenza Hemagglutinin Innate Immune System Kinetics Knowledge Mediating Methods Missense Mutation Modeling 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 Serial Passage Shapes Study models System Testing Therapeutic Thermodynamics Treatment Protocols Vaccines Variant Viral Viral Genome Viral Proteins Virus Virus Replication 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 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.

极高的突变率使得大多数RNA病毒能够快速探索蛋白质序列空间，另一方面，高突变率也导致生物物理特性差和严重折叠缺陷的病毒蛋白变体广泛产生，无法成功折叠的蛋白变体被去除。最近的研究表明，宿主细胞的蛋白质折叠和质量控制机制（蛋白质稳态网络）的组成和活性在定义可访问的氨基酸序列空间方面发挥着核心作用。快速发展RNA病毒蛋白。迄今为止，这种现象主要是利用蛋白质稳态调节本身作为选择压力来探索的，目前尚不清楚宿主细胞伴侣是否通过增强病毒蛋白折叠来直接影响病毒适应和逃避的能力。来自宿主适应性免疫系统、抗病毒药物或其他因素的外部选择压力，使用流感整合作为模型系统，提出了最先进的化学生物学、遗传、生物化学、生物物理和计算方法。在分子水平上全面评估和阐明在不同选择压力的背景下宿主蛋白质稳态和病毒适应之间出现的复杂相互作用，目标1重点关注被劫持的宿主伴侣促进流感逃避先天免疫系统因素的机制，建立流感核蛋白进化中宿主伴侣依赖性的生物物理起源，并阐明病毒是否以及如何能够轻松适应具有挑战性的宿主蛋白质停滞环境。确定宿主细胞内质网蛋白稳态网络的组成和活性如何影响流感血凝素（流感中和抗体的主要靶标）逃避适应性免疫系统选择压力的能力，目的 3 在更广泛的范围内了解如何运作。宿主蛋白质稳态网络影响全基因组突变耐受性和流感错误灾难，在这种现象中，病毒突变率增加超过一定阈值会导致群体灭绝。与蛋白质生物物理研究和计算模型相结合，以阐明宿主蛋白质稳态依赖性病毒适应的高度分子起源，这项工作预计将确立宿主蛋白质稳态作为塑造病毒适应性的决定性力量，特别是在相关选择压力的背景下。病毒进化的研究结果将极大地增强对病毒适应宿主选择压力的因素的理解，并且从长远来看，提高准确预测病毒进化的能力，这些发现也有望突显针对宿主的治疗佐剂的潜力。分子伴侣使病毒不易产生耐药性的治疗方案将影响从基础病毒学和疫苗、抗病毒药物开发到进化生物学和蛋白质折叠生物物理学等领域。