Pathogen-driven evolution of innate antiviral defense mechanisms

先天抗病毒防御机制的病原体驱动进化

• 批准号: 10646458
• 负责人: Matthew Daugherty
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10646458
• 关键词: ADP ribosylation; Address; Adenosine Diphosphate Ribose; Affect; Area; Back; Binding; Biochemical; Cell physiology; Communicable Diseases; Conflict (Psychology); Coupled; Defense Mechanisms; Diagnosis; Evolution; Gene Family; Genes; Genetic; Genetic Variation; Host Defense Mechanism; Human; Immune Evasion; Immune system; Infection; Messenger RNA; Mission; Modeling; Modification; Nature; Pathway interactions; Predisposition; Proteins; Research; Role; Side; Viral; Virus; Virus Diseases; Work; cell growth regulation; fitness; genome-wide; global health; immune function; innovation; insight; interest; pathogen; posttranscriptional; pressure; prevent; tool; virology

PROJECT SUMMARY Infectious diseases are an enormous burden on global health. However, we only poorly understand the many mechanisms that hosts have evolved to defend against pathogens and that pathogens have counter-evolved to defeat those defenses. Importantly, the result of these host-pathogen evolutionary conflicts (i.e. whether the host or the pathogen is successful) ultimately determine our susceptibility to infection. It is therefore of paramount importance that we address the following questions: what are the critical genes and mechanisms that protect us from infection, how do pathogens counteract those defenses, and how does host genetic variation affect susceptibility to infection? Our research brings an evolution-guided perspective to answering these questions by exploiting the fact that the interests of pathogens and their hosts are necessarily at odds with one another. That is, if the host successfully defends against a pathogen, there is evolutionary pressure on the pathogen to evolve a way to overcome that defense. Likewise, if the pathogen establishes a successful infection, the host is pressured to adapt. These back and forth dynamics drive constant innovation on both sides of host-pathogen molecular interactions, resulting in the wide genetic and functional diversity we see today. Our research explicitly leverages this diversity to discover which host proteins have been driven to rapidly evolve by genetic conflicts with pathogens, in effect allowing pathogens to lead us to the host genes, mechanisms and pathways that are most important for fitness. Based on this evolution-guided approach, our current work focuses on the importance of several incompletely understood post-transcriptional and post- translational regulatory mechanisms in host antiviral defense. One current area of focus is investigating the antiviral mechanisms and evolutionary consequences of a dynamically evolving family of genes, known as IFITs, that distinguish host from viral mRNAs based on mRNA modifications. Another aim is to determine the immune functions of a poorly characterized but rapidly evolving family of genes known as PARPs that catalyze the post-translational addition of ADP-ribose to proteins. Using diverse virology models, coupled with genetic and biochemical approaches, these studies aim to not only determine the consequences of IFIT and PARP gene evolution on susceptibility to viral infection, but also to reveal the broader mechanistic roles for mRNA modifications and ADP-ribosylation in host antiviral defense and cellular regulation. Finally, we are developing genome wide tools to identify other rapidly evolving but understudied regulatory mechanisms that we hypothesize are additional determinants of human susceptibility to viral infection. The overall mission of our work is to use this evolution-guided approach to provide unique insights into mechanisms of host defense and pathogen immune evasion, species-specific barriers to pathogen replication, and pathogen-driven evolution of cellular functions.

项目总结

项目成果

Recurrent Loss of Macrodomain Activity in Host Immunity and Viral Proteins.

宿主免疫和病毒蛋白中大域活性的复发性丧失。

• DOI: 10.3390/pathogens12050674
• 发表时间: 2023-05-03
• 期刊: Pathogens (Basel, Switzerland)
• 作者: Delgado-Rodriguez SE;Ryan AP;Daugherty MD
• 通讯作者: Daugherty MD

Structure of LRRK1 and mechanisms of autoinhibition and activation.

• DOI: 10.1038/s41594-023-01109-1
• 发表时间: 2023-11
• 期刊: NATURE STRUCTURAL & MOLECULAR BIOLOGY
• 影响因子: 16.8
• 作者: Reimer, Janice M.;Dickey, Andrea M.;Lin, Yu Xuan;Abrisch, Robert G.;Mathea, Sebastian;Chatterjee, Deep;Fay, Elizabeth J.;Knapp, Stefan;Daugherty, Matthew D.;Reck-Peterson, Samara L.;Leschziner, Andres E.
• 通讯作者: Leschziner, Andres E.

Antiviral function and viral antagonism of the rapidly evolving dynein activating adaptor NINL.

• DOI: 10.7554/elife.81606
• 发表时间: 2022-10-12
• 期刊: eLife
• 影响因子: 7.7
• 作者: Stevens DA;Beierschmitt C;Mahesula S;Corley MR;Salogiannis J;Tsu BV;Cao B;Ryan AP;Hakozawki H;Reck-Peterson SL;Daugherty MD
• 通讯作者: Daugherty MD

Diverse viral proteases activate the NLRP1 inflammasome.

多种病毒蛋白酶激活NLRP1炎症体。

• DOI: 10.7554/elife.60609
• 发表时间: 2021-01-07
• 期刊: eLife
• 影响因子: 7.7
• 作者: Tsu BV;Beierschmitt C;Ryan AP;Agarwal R;Mitchell PS;Daugherty MD
• 通讯作者: Daugherty MD

Bacterial origin of a key innovation in the evolution of the vertebrate eye.

• DOI: 10.1073/pnas.2214815120
• 发表时间: 2023-04-18
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Kalluraya, Chinmay A.;Weitzel, Alexander J.;Tsu, Brian V.;Daugherty, Matthew D.
• 通讯作者: Daugherty, Matthew D.