RAPID: Transcription Factor Profiling for SARS-CoV2 Tolerance/Symbiosis Regulation

这项研究将提供更多关于使不同宿主（特别是蝙蝠与人类）耐受最近出现的SARS-Cov-2冠状病毒的分子因素的知识。该项目将使用蝙蝠细胞系模型来研究导致不同物种细胞免疫谱差异的细胞蛋白差异。拟开展的研究将确定在不同细胞系模型中具有差异活性的蛋白，以及免疫刺激因子和SARS-CoV-2蛋白对宿主细胞蛋白活性的影响。这项研究的结果可能会导致对某些病毒（特别是SARS-CoV-2）为何以及如何在某些物种（如蝙蝠）中被耐受，而在其他物种（如人类）中却不能耐受的新见解，并可能为未来可能在动物和人类群体中引起大流行的病毒的出现提供信息。跨学科研究团队由三名经验丰富的首席科学家组成，他们在互补的研究领域拥有专业知识。此外，该研究将为两名研究生提供培训，他们将能够在学术界、私营部门或政府的相关领域从事职业。这项研究的目标是进一步了解SARS-CoV2细胞物种特异性感染的分子过程。这项研究将深入了解蝙蝠宿主细胞与人类和其他蝙蝠细胞之间基于转录因子的差异，蝙蝠宿主细胞能够以非致病性方式耐受SARS-CoV2感染，而人类和其他蝙蝠细胞则不表现出这种耐受性。这项研究涉及三家私人投资机构的合作，他们将为这个项目带来互补的方法。五个主要实验目标：1)区分不同蝙蝠细胞系的转录和核蛋白质组学特征；2)使用一种新型的蛋白质结合微阵列来分析这些细胞系中的活性转录因子；3)表征候选免疫转录因子，如NF-κB和irf，可能在SARS-CoV2耐受性和易感细胞系之间存在差异；4) SARS-CoV2基因产物对多种细胞系中已鉴定转录因子的影响；5)新型SARS-CoV2示踪病毒在不同蝙蝠细胞系中复制的可能性。拟议的研究将增加对SARS-SoV-2生物学的认识。此外，它还调查了蝙蝠细胞进化出分子免疫途径的假设，这些途径促进或导致蝙蝠对冠状病毒的耐受性（甚至可能是共生）。这些信息可能有助于确定人类和动物对抗冠状病毒的治疗方法。该RAPID奖由综合有机体系统生物学部的生理和结构系统集群获得，资金来自《冠状病毒援助、救济和经济安全（CARES）法案》。该奖项反映了美国国家科学基金会的法定使命，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。

This research will provide increased knowledge of the molecular factors enabling different hosts (especially bats vs. humans) to tolerate the recently emergent SARS-Cov-2 coronavirus. This project will use bat cell line models to investigate differences in cellular proteins which lead to differences in immunity profiles of cells from the different species. The proposed research will identify proteins that are differentially active in different cell line models, and the effects that immune-stimulating factors and SARS-CoV-2 proteins have on host cell protein activities. Results from this research could lead to new insights into why and how certain viruses, in particular SARS-CoV-2, can be tolerated in some species (e.g., bats) but not others (e.g., humans), and could provide information for the emergence of future viruses that can cause pandemics in animal and human populations. The interdisciplinary research team comprises three experienced lead scientists with expertise in complementary areas of research. In addition, the research will provide training to two graduate students who will be able to pursue careers in related areas in academia, the private sector, or government.The goal of this research is to further knowledge of the molecular processes that underlie species-specific infection of cells with SARS-CoV2. This research will provide insights into transcription factor-based differences between host cells of bat origin, which can tolerate SARS-CoV2 infection in a non-pathogenic manner, vs human and other bat cells that do not show this tolerance. The research involves the collaboration of three PIs with complementary approaches that they will bring to this project. Five major experimental goals will be addressed: 1) characterization of transcriptional and nuclear proteomic profiles that distinguish different bat cell lines; 2) use of a novel protein-binding microarray to profile active transcription factors among these cell lines; 3) characterization of candidate immunity transcription factors, such as NF-κB and IRFs, that are likely different between SARS-CoV2 tolerant and susceptible cell lines; 4) effects of SARS-CoV2 gene products on identified transcription factors in the various cell lines; and 5) potential for replication of novel SARS-CoV2 tracer viruses in different bat cell lines. The proposed research will increase knowledge of SARS-SoV-2 biology. In addition, it investigates the hypothesis that bat cells have evolved molecular immunity pathways that promote or lead towards tolerance (perhaps even symbiosis) of bats with coronaviruses. Such information may lead to the identification of therapeutics for humans and animals against coronaviruses. This RAPID award is made by the Physiological and Structural Systems Cluster in the BIO Division of Integrative Organismal Systems, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.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.