Deciphering the Link between Severe Acute Respiratory Coronavirus 2 Infection and Long-Term Neurological and Pulmonary Sequelae

项目概要/摘要 许多肺部疾病，包括哮喘，都与神经系统症状有关，如压力，焦虑， 和抑郁症加入这一名单的是COVID 19，其中SARS-CoV-2急性后后遗症的名单越来越多 感染（PASC）包括焦虑和抑郁。呼吸道感染是否以及如何被SARS-CoV-2感染 可能会影响神经系统的状态。在这篇增刊中，我们将继续讨论家长的主题。 该奖项旨在从分子水平上解剖大脑和肺之间的功能和神经解剖学联系， 和细胞水平。我们将检验SARS-CoV-2呼吸道感染通过慢性 肺和肺支配神经回路的变化，改变神经元活动和神经炎症， 导致压力加剧焦虑和抑郁我们将使用SARS-CoV-2的人源化小鼠模型 感染，以测试呼吸道感染是否改变中枢神经系统神经元活动，神经炎症， 感染慢性期的基因表达和行为变化（目的1）。我们还将使用单细胞 多基因组和空间转录组技术，以确定转录组和表观基因组的签名， SARS-CoV-2感染后慢性期的人类供体肺（目的2）。我们预计， SARS-CoV-2慢性期脑、肺及其连接的综合概况 感染将加深对PASC了解并提供控制信息。

PROJECT SUMMARY/ABSTRACT Many lung diseases, including asthma, are associated with neurological symptoms such as stress, anxiety and depression. Joining this list is COVID19, where the growing list of post-acute sequelae of SARS-CoV-2 infection (PASC) includes anxiety and depression. Whether and how respiratory infection by SARS-CoV-2 could impact neurological state is not understood. In this supplement, we will continue the theme of the parent award to dissect the functional and neuroanatomical connections between the brain and lung at the molecular and cellular level. We will test the hypothesis that SARS-CoV-2 respiratory infection, acting through chronic changes in lung and the lung-innervating neural circuit, alters neuronal activity and neural inflammation, leading to heightened stress, anxiety and depression. We will use humanized mouse models for SARS-CoV-2 infection to test if respiratory infection alters central nervous system neuronal activity, neural inflammation, gene expression and behavioral changes in the chronic phase of infection (aim 1). We will also use single cell multiome and spatial transcriptomic technologies to define the transcriptomic and epigenomic signature of the human donor lungs in the chronic phase following SARS-CoV-2 infection (aim 2). We anticipate that a comprehensive profile of the brain, the lung, and their connection in the chronic phase of SARS-CoV-2 infection will deepen understanding and inform control of PASC.