RAPID:The Effect of SARS-CoV-2 cellular entry in exacerbating monocyte activation

这项快速反应研究(RAPID)奖支持研究，以了解病毒与宿主之间的相互作用，这种相互作用可能会导致有既往炎症症状的COVID19患者的发病率增加。目前的数据表明，在所有美国新冠肺炎患者中，74%的患者既往有高血压，30%的患者有糖尿病。新冠肺炎的一个主要特征是急性呼吸窘迫综合征，它是由单核/巨噬细胞(MO)的渗透引起的。单核/巨噬细胞是维持组织动态平衡的先天免疫系统的关键成员。这是因为它们吞噬外来病原体和死亡细胞，这会刺激适应性免疫系统产生抗体。然而，新冠肺炎的病原体SARS-CoV-2感染是如何影响单核/巨噬细胞的，目前还不清楚。这项研究的目的是了解与糖尿病患者相比，SARS-CoV-2如何加剧健康个体单核细胞的单核细胞功能。这项研究的结果可能确定将新冠肺炎病降至最低的治疗方法。这项研究涉及多个学科，包括免疫学、病毒学和生物医学工程。这种多学科方法将有助于扩大代表性不足群体对研究的参与，并有助于对新冠肺炎健康差距人群的免疫学研究。该提案还支持培养一名博士后、一名研究生和一名本科生。在COVID19患者中观察到高单核/巨噬细胞活化的临床观察。然而，导致这种激活的细胞内事件尚不清楚。该项目将建立在其他细胞类型对SARS-CoV-2感染的现有测量的基础上，现在提供了关于单核/巨噬细胞功能和对感染的反应的重要缺失信息。这项研究的目的是确定(1)健康和糖尿病单核细胞在SARS-CoV-2感染诱导的细胞因子释放风暴中的作用，以及(2)病毒与宿主相互作用与单核细胞上的关键受体(与正常生理功能相比表达上调或下调)的全球作用。这项研究将增加对糖尿病患者巨噬细胞功能受损如何影响新冠肺炎预后的了解。这项研究的结果有助于开发新冠肺炎急需的治疗方法。这一快速奖项是由综合组织系统生物部的生理和结构系统集群利用冠状病毒援助、救济和经济安全(CARE)法案的资金颁发的。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This Rapid Response Research (RAPID) award supports research to understand virus-host interactions that may lead to increased morbidity in COVID19 patients with pre-existing inflammatory conditions. Current data suggests that of all US patients with COVID-19, 74% had pre-existing hypertension, and 30% had diabetes. A key feature COVID-19 is acute respiratory distress syndrome (ARDS), which is caused by the infiltration of monocyte/macrophages (MOs). Monocyte/macrophages are key members of the innate immune system that maintain tissue homeostasis. This is because they phagocytose foreign pathogens and dying cells, and this stimulates with the adaptive immune system to make antibodies. However, it is not well-understood how monocyte/macrophages are affected by SARS-CoV-2 infection, the causative agent of COVID-19. The goal of this study is to understand how SARS-CoV-2 exacerbates monocyte function in monocytes from healthy individuals as compared to individuals with diabetes. Results from this research may identify therapeutics to minimize COVID-19 disease. This research involves several disciplines including immunology, virology, and biomedical engineering. This multi-disciplinary approach will help broaden participation of under-represented groups in research, as well as contribute to the immunological study of COVID-19 health disparity populations. This proposal also supports the training of a post-doctoral fellow, a graduate and undergraduate student. There are clinical observations of high monocyte/macrophage activation observed in COVID19 patients. However, the intracellular events that lead to this activation are unknown. This project will build on existing measurements of SARS-CoV-2 infection from other cell types, and now provides vital missing information about monocyte/macrophage functions and responses to infection. The objective of the research is to determine (1) the contributions of healthy and diabetic monocytes to SARS-CoV-2 infection-induced cytokine release storms, and (2) the global role of virus-host interactions with key receptors on monocytes that are dysregulated (upregulated or downregulated expression compared to normal physiological function). The study will increase the knowledge of how impaired macrophage functions from diabetic people may affect outcomes of COVID-19 disease. Results from this study can help aid the development of desperately needed therapies for COVID-19. 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.