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

这项研究将提供更多的知识，使不同的宿主（特别是蝙蝠与人类）能够耐受最近出现的SARS-Cov-2冠状病毒的分子因素。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质差异。拟议的研究将确定在不同细胞系模型中具有差异活性的蛋白质，以及免疫刺激因子和SARS-CoV-2蛋白对宿主细胞蛋白质活性的影响。这项研究的结果可能会导致对某些病毒，特别是SARS-CoV-2，为什么以及如何在某些物种中被容忍的新见解（例如，蝙蝠）而不是其它（例如，人类），并可能为未来可能导致动物和人类大流行的病毒的出现提供信息。跨学科研究团队由三位经验丰富的首席科学家组成，他们在互补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生涯。该研究的目标是进一步了解SARS-CoV 2细胞种特异性感染的分子过程。这项研究将提供深入了解蝙蝠来源的宿主细胞之间基于转录因子的差异，这些宿主细胞可以以非致病性的方式耐受SARS-CoV 2感染，而人类和其他蝙蝠细胞则没有表现出这种耐受性。这项研究涉及三个PI的合作，他们将为这个项目带来互补的方法。本研究的主要目的是：1）研究蝙蝠细胞的转录和核蛋白质组学特征，以区分不同的蝙蝠细胞系; 2）利用一种新的蛋白质结合微阵列技术研究蝙蝠细胞系中的活性转录因子; 3）研究SARS-CoV 2耐受细胞系和敏感细胞系中可能存在差异的候选免疫转录因子，如NF-κB和IRFs; 4）SARS-CoV 2基因产物对各种细胞系中已鉴定转录因子的影响; 5）新型SARS-CoV 2示踪病毒在不同蝙蝠细胞系中复制的潜力。这项研究将增加对SARS-SoV-2生物学的了解。此外，它还研究了蝙蝠细胞已经进化出分子免疫途径的假设，这些分子免疫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）。这些信息可能会导致人类和动物对抗冠状病毒的治疗方法的确定。该RAPID奖项由BIO综合有机系统部门的生理和结构系统集群颁发，使用冠状病毒援助，救济和经济安全（CARES）法案的资金。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。

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.