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Virus Egress Pathways

病毒出口途径

基本信息

批准号：
10929183
负责人：
Nihal Altan-Bonnet
金额：
$ 303.36万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10929183
关键词：
2019-nCoV Adaptive Immune System Aerosols Animals Antigen Presentation Architecture Area Astrovirus Biophysics Breast Feeding COVID-19 pandemic COVID-19 patient Cell physiology Cells Cellular biology Cooperative Behavior Coronavirus Cytolysis Diagnostic Disabled Persons Docking Economics Enteral Enterovirus Enterovirus 68 Environment Enzymes Evolution Exhibits Exocytosis Feces Gastrointestinal tract structure Genetic Transcription Golgi Apparatus Health Hepatitis C Human Human poliovirus Image Immune System Diseases Immune response Individual Infant Infection Inflammatory Innate Immune System Intestines Investigation Life Cycle Stages Lipids Lung Lysosomes Mammary gland Membrane Messenger RNA Molecular Morbidity - disease rate Mothers Norovirus Oral Pathway interactions Persons Pharmacologic Substance Phosphatidylinositols Phosphotransferases Population Process Public Health RNA Viruses Rhinovirus Rotavirus Route SERPINA4 gene Saliva Salivary Salivary Glands Sanitation Side System Translations Travel Universities Variant Vesicle Viral Viral Physiology Viral Proteins Virion Virulent Virus Virus Assembly Virus Replication Water extracellular vesicles infant infection lipid metabolism live cell microscopy lysosomal proteins mortality mutant pandemic disease particle pathogen peer protein degradation recruit response salivary assay skills small molecule suckling tool transmission process viral transmission virology

项目摘要

Much of the field of virology has long viewed the cell as a passive supplier of viral building blocks and focused on how viruses exploit individual cellular enzymes for transcription of their messenger RNAs or translation of the viral proteins. Dr. Nihal Altan-Bonnet using the dynamic tools of live-cell microscopy has made fundamental discoveries, revealing how viral exploitation of the host goes beyond individual molecules and rather induces a complete shake up of cell physiology and architecture. As an outsider with a background in cellular biology and biophysics, Dr. Altan-Bonnet came into the field of virology without any allegiance to a particular virus- something unusual in this field as most virologists focus on the study of one virus. Instead she intentionally sought to study a wide variety of different viruses in order to search for general principles and common strategies viruses employ to exploit the host cell. This broader approach resulted in several groundbreaking discoveries. The first of which was the discovery that many viruses alter the host lipid metabolism to assemble viral replication platforms. Specifically, Dr. Altan-Bonnet showed that a host encoded lipid kinase, phosphatidyl inositol 4-kinase, can be hijacked by multiple different RNA viruses (including poliovirus, hepatitis C, Enterovirus D68, Rhinovirus). The reason for multiple viruses to converge on this lipid kinase she showed was to generate PI4P lipid enriched replication compartments where this PI4P lipid was used as a membrane dock to recruit, stabilize and stimulate the catalytic activities of viral replication enzymes. Her studies have been the basis of multiple initiatives by pharmaceutical companies (Glaxo, Novartis) and universities (Project Four Stanford ViRX) to develop small molecules against host PI4 kinases as panviral targets. Dr. Altan-Bonnet 's second groundbreaking discovery was the identification of a new form of viral infectious unit: viruses traveling en masse, cloaked inside vesicles. Before this discovery, it was not only assumed that viruses traveled as free single particles from host to host but this form of travel was considered to be the most virulent as it allowed viruses to spread wide and infect as many hosts as possible. Nihals findings challenged the classical concept of virus transmission as individual units of infection and accounted for their evolution of populations as quasi-species or viral variants. Dr. Altan-Bonnet revealed that many different viruses exit cells without lysis, inside extracellular vesicles and most remarkably as multiple virus particles all traveling together. She went on to show that this form of transmission is much more infectious and virulent than viruses as single particles because by entering cells in high numbers they could easily overcome barriers to replication- barriers from not only the host side but also intrinsic barriers such as mutant viral variants or quasi-species that alone would be handicapped but by traveling en masse benefit from cooperative behavior. Additionally, cloaked under a vesicular membrane, viruses were protected from inflammatory and/or neutralizing immune responses: this is particularly significant for enteroviruses that must traverse the harsh environment of the gastrointestinal tract while maintaining their infectiousness. Recently Dr. Altan-Bonnet has demonstrated that these extracellular vesicles carrying viruses are highly stable in the gastrointestinal tract, in stool, in aerosol and are copiously shed by humans and animals. Dr. Altan-Bonnet's investigations into what makes viruses efficient at transmission led also to her recent discovery of an entirely new and likely more public health relevant transmission route for the enteric viruses norovirus, rotavirus and astrovirus, which combined infect 1.5 billion people globally causing much mortality and morbidity (not to mention economic hardship). Until her findings, enteric viruses were thought to solely replicate in intestines and spread through the oral-fecal route among hosts. She demonstrated that these enteric viruses replicate in salivary glands robustly ( on par with intestines) and spread through saliva, not only among individuals but also between mothers and infants through suckling. This finding potentially opens the way to simpler diagnostics for these viruses, such as saliva tests, and also may prompt revision of public health sanitary practices, which until now have been solely focused on limiting viral transmission by the oral-fecal route, to include masking. Finally during the COVID-19 pandemic, Dr. Altan-Bonnet applied her imaging skills to peer inside coronavirus infected cells to reveal how these viruses exit from cells and spread to others- an area that has remarkably not been studied. Most viruses, including hepatitis C, rely on the biosynthetic secretory pathway (e.g. Golgi apparatus) to exit out of cells and this was assumed to be the case for coronaviruses too. But Nihal discovered that these viruses are unique in that they piggy-back on a more exotic cellular pathway, lysosomal exocytosis, to exit from the cells. In the process, viruses can evade cell defenses as their passage through the lysosomal pathway inactivates lysosomal protein degradation and alter cellular antigen presentation. This discovery of a fundamental aspect of the coronavirus lifecycle, using lysosomes for exit, maybe one, if not the root cause, of the system wide immune dysfunction exhibited by COVID patients. To conclude, the extraordinary circumstances brought upon by the recent pandemic, emphasize even more the need for investigations, like Dr. Altan-Bonnet s, into the general principles and molecular/cellular details of host-pathogen interactions.

长期以来，病毒学领域的许多人都将细胞视为病毒构件的被动提供者，并专注于病毒如何利用单个细胞酶转录其信使RNA或翻译病毒蛋白。Nihal Altan-Bonnet博士使用活细胞显微镜的动态工具取得了根本性的发现，揭示了病毒如何利用宿主超越单个分子，而是导致细胞生理和结构的彻底颠覆。作为一名有细胞生物学和生物物理学背景的局外人，阿尔坦-博内特博士进入病毒学领域时并不忠于一种特定的病毒--这在该领域是不寻常的，因为大多数病毒学家专注于一种病毒的研究。相反，她有意寻求研究各种不同的病毒，以寻找病毒利用宿主细胞的一般原理和共同策略。这种更广泛的方法导致了几项突破性的发现。第一个发现是许多病毒改变宿主的脂代谢来组装病毒复制平台。具体而言，Altan-Bonnet博士表明，宿主编码的脂蛋白激酶--磷脂酰肌醇4-激酶可被多种不同的RNA病毒(包括脊髓灰质炎病毒、丙型肝炎病毒、肠道病毒D68、鼻病毒)劫持。她指出，多种病毒汇聚在这种脂酶上的原因是产生了PI4P脂类富集区，在那里这种PI4P脂类被用作膜码头，以招募、稳定和刺激病毒复制酶的催化活性。她的研究一直是制药公司(葛兰素史克、诺华)和大学(斯坦福大学ViRX项目四)的多项倡议的基础，这些倡议旨在开发针对宿主Pi4激酶的小分子作为泛病毒靶标。阿尔坦-博内特博士的S博士的第二个突破性发现是发现了一种新的病毒感染单位：病毒成群结队地传播，伪装在小泡内。在这一发现之前，人们不仅假设病毒作为游离的单一粒子从一个宿主传播到另一个宿主，而且这种形式的传播被认为是最具毒性的，因为它允许病毒广泛传播并感染尽可能多的宿主。Nihals的发现挑战了将病毒传播作为个体感染单位的经典概念，并解释了它们作为准物种或病毒变体的种群进化。Altan-Bonnet博士透露，许多不同的病毒在没有溶解的情况下离开细胞，在细胞外的小泡内，最显著的是以多个病毒颗粒一起旅行的形式。她接着证明，这种传播形式比病毒作为单颗粒传播的传染性和毒性要强得多，因为通过大量进入细胞，它们可以很容易地克服复制障碍--不仅来自宿主端的障碍，而且还有内在障碍，如突变病毒变体或准物种，这些障碍单独存在，但通过集体旅行，从合作行为中受益。此外，病毒被包裹在泡状膜下，免受炎症和/或中和免疫反应的影响：这对必须穿越恶劣的胃肠道环境同时保持感染性的肠道病毒来说尤其重要。最近，Altan-Bonnet博士证明了这些携带病毒的细胞外小泡在胃肠道、粪便和气雾剂中高度稳定，并被人和动物大量排出。 Altan-Bonnet博士对是什么使病毒能够有效传播的研究还导致她最近发现了一种全新的、可能更有利于公共卫生的肠道病毒传播途径，即诺沃克病毒、轮状病毒和星状病毒，这些病毒加在一起感染全球15亿人，导致大量死亡和发病率(更不用说经济困难)。在她的发现之前，肠道病毒被认为只在肠道内复制，并通过口腔-粪便途径在宿主之间传播。她证明，这些肠道病毒在唾液腺中复制强劲(与肠道相同)，并通过唾液传播，不仅在个体之间，而且在母亲和婴儿之间通过哺乳传播。这一发现可能会为这些病毒的更简单诊断开辟道路，比如唾液测试，也可能会促使公共卫生做法的修订，到目前为止，这些做法只专注于限制通过口腔-粪便途径传播病毒，包括口罩。最后，在新冠肺炎大流行期间，阿尔坦-博内特博士运用她的成像技术窥探了冠状病毒感染细胞的内部，揭示了这些病毒是如何离开细胞并传播给其他细胞的--这是一个明显尚未被研究的领域。大多数病毒，包括丙型肝炎病毒，依靠生物合成的分泌途径(例如高尔基体)退出细胞，冠状病毒也是如此。但尼哈尔发现，这些病毒的独特之处在于，它们借助一种更奇异的细胞途径--溶酶体胞吐作用--从细胞中退出。在这个过程中，病毒可以逃避细胞防御，因为它们通过溶酶体途径抑制溶酶体蛋白的降解，并改变细胞抗原呈递。冠状病毒生命周期的一个基本方面的发现，使用溶酶体退出，可能是COVID患者表现出的全系统免疫功能障碍的一个(如果不是根本原因)。最后，最近的大流行带来的特殊情况更加强调了像阿尔坦-博内特·S博士那样调查宿主-病原体相互作用的一般原则和分子/细胞细节的必要性。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Extracellular vesicles are the Trojan horses of viral infection.

DOI：
10.1016/j.mib.2016.05.004
发表时间：
2016-08
期刊：
Current opinion in microbiology
影响因子：
5.4
作者：
Altan-Bonnet N
通讯作者：
Altan-Bonnet N

Lipid Tales of Viral Replication and Transmission.

DOI：
10.1016/j.tcb.2016.09.011
发表时间：
2017-03
期刊：
Trends in cell biology
影响因子：
19
作者：
Altan-Bonnet N
通讯作者：
Altan-Bonnet N

Insane in the Membrane: Glial Extracellular Vesicles Transmit Polyomaviruses.

膜中的疯狂：胶质细胞外囊泡传播多瘤病毒。

DOI：
10.1128/mbio.01024-19
发表时间：
2019
期刊：
mBio
影响因子：
6.4
作者：
Santiana,Marianita;Altan-Bonnet,Nihal
通讯作者：
Altan-Bonnet,Nihal

Membrane-assisted assembly and selective secretory autophagy of enteroviruses.

DOI：
10.1038/s41467-022-33483-7
发表时间：
2022-10-10
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Dahmane, Selma;Kerviel, Adeline;Morado, Dustin R.;Shankar, Kasturika;Ahlman, Bjorn;Lazarou, Michael;Altan-Bonnet, Nihal;Carlson, Lars-Anders
通讯作者：
Carlson, Lars-Anders

Enterovirus Transmission by Secretory Autophagy.

肠道病毒通过分泌性自噬传播。