RAPID: How do vertebrate endolysosomal Ca2+ channels control coronaviral tropism?

RAPID：脊椎动物内溶酶体 Ca2 通道如何控制冠状病毒趋向性？

• 批准号: 2027748
• 负责人: Jonathan Marchant
• 金额: $ 19.99万
• 依托单位: Medical College of Wisconsin
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2027748&HistoricalAwards=false
• 关键词: RAPID; How; do; vertebrate; endolysosomal

This research advances the national prosperity and the bioeconomy and enhances our understanding of the mechanisms that allow the spread of corona viruses between species. Results of this research may be the basis for identifying biomarkers of severity of disease or spread of SARS-CoV-2 (COVID-19 or COVID). This project will produce an understanding of why some coronavirus strains that normally infect specific animals (such as birds and bats) sometimes also infect humans, whereas other strains do not. This knowledge is critical for understanding how viruses break species barriers to colonize new hosts and precipitate widespread infections, as experienced during the ongoing COVID pandemic. Coronaviruses infect cells by binding to specific cell surface receptors and passing through organelles known as endosomes and lysosomes to access the cell interior. This project will investigate how the environment within these cellular structures regulates the intensity of viral infection. Through the use of comparative biology across different vertebrate species, the goal will be to identify conditions in endosomes and lysosomes that facilitate infection in particular organisms. This research may be the basis for identifying biomarkers of severity of disease or COVID spread. This research will also provide tools to enable a broad research community working on COVID and other viruses. This proposal also uses funding to train graduate and undergraduate students. As such this funding is training the next generation of leaders in science. Results expected from this work will facilitate identification and control of COVID spread in humans and other animals. The coronoaviridae (CoVs) are a family of single-stranded RNA viruses that infect three vertebrate groups: mammals, birds and fish. Understanding the molecular determinants underpinning this tropism, namely why CoVs naturally and efficiently infect these species, and target specific tissues within these animals, is a fundamental biological concept. Definition of the mechanisms restricting CoV tropism is therefore critical for our understanding of how CoVs break species barriers and colonize new hosts. In this RAPID proposal, the role of the luminal microenvironment of the endolysosomal system in determining the efficiency of CoV infection will be studied for different CoVs in different vertebrate species. The central hypothesis is that the cellular proteins called ion channels resident in endosomes and lysosomes are differentially present in lower mammals and humans. Furthermore, these ion channels uniquely create environments within endosomes and lysosomes in lower mammals that are critical for supporting coronaviral infection and the differential expression of endolysosomal ion channels between tissues and species regulates the effectiveness of CoV infection. This hypothesis will be tested using a variety of cell models, imaging approaches and infection assays. This research is supported by the Symbiosis, Defense and Self-recognition program of the National Science Foundation.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这项研究促进了国家的繁荣和生物经济，并增强了我们对冠状病毒在物种之间传播的机制的理解。这项研究的结果可能是确定疾病严重程度或SARS-CoV-2（COVID-19或COVID）传播的生物标志物的基础。该项目将了解为什么一些通常感染特定动物（如鸟类和蝙蝠）的冠状病毒菌株有时也会感染人类，而其他菌株则不会。这一知识对于理解病毒如何打破物种障碍以定殖新宿主并促成广泛感染至关重要，就像在持续的COVID大流行期间所经历的那样。冠状病毒通过与特定的细胞表面受体结合并穿过称为内体和溶酶体的细胞器进入细胞内部来感染细胞。该项目将研究这些细胞结构内的环境如何调节病毒感染的强度。通过在不同脊椎动物物种中使用比较生物学，目标将是确定内体和溶酶体中促进特定生物体感染的条件。这项研究可能是确定疾病严重程度或COVID传播的生物标志物的基础。这项研究还将提供工具，使广泛的研究社区能够研究COVID和其他病毒。该提案还利用资金培训研究生和本科生。因此，这笔资金正在培养下一代科学领导人。这项工作的预期结果将有助于识别和控制COVID在人类和其他动物中的传播。冠状病毒科（CoV）是一个单链RNA病毒家族，感染三种脊椎动物：哺乳动物，鸟类和鱼类。了解支持这种向性的分子决定因素，即为什么CoV自然有效地感染这些物种，并靶向这些动物体内的特定组织，是一个基本的生物学概念。因此，限制CoV嗜性的机制的定义对于我们理解CoV如何打破物种屏障并殖民新宿主至关重要。在该RAPID提案中，将针对不同脊椎动物物种中的不同CoV研究内溶酶体系统的腔微环境在确定CoV感染效率中的作用。核心假设是，称为离子通道的细胞蛋白质驻留在核内体和溶酶体中，在低等哺乳动物和人类中存在差异。此外，这些离子通道在低等哺乳动物的内体和溶酶体内独特地产生环境，这对于支持冠状病毒感染至关重要，并且组织和物种之间的内溶酶体离子通道的差异表达调节CoV感染的有效性。将使用各种细胞模型、成像方法和感染测定来检验这一假设。这项研究由美国国家科学基金会的共生、防御和自我认可项目支持。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。