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

项目摘要/摘要 许多肺部疾病，包括哮喘，都与神经症状有关，如压力、焦虑 和抑郁症。加入这一名单的还有COVID19，在那里，SARS-CoV-2急性后遗症的名单越来越多 感染(PASC)包括焦虑和抑郁。SARS-CoV-2是否以及如何引起呼吸道感染 是否会影响神经状态尚不清楚。在本增刊中，我们将继续家长的主题 在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。我们将测试SARS-CoV-2呼吸道感染，通过慢性作用的假设 肺和肺神经回路的变化，改变神经元活动和神经炎症， 导致高度的压力、焦虑和抑郁。我们将使用人源化的小鼠模型来研究SARS-CoV-2 感染以测试呼吸道感染是否改变中枢神经系统的神经活动，神经炎症， 感染慢性期的基因表达和行为变化(目标1)。我们还将使用单细胞 用多组和空间转录组学技术确定细胞的转录组学和表观基因组特征 SARS-CoV-2感染后慢性期的人类供肺(目标2)。我们预计会有一个 SARS-CoV-2慢性期的脑、肺及其联系的综合概况 感染将加深对PASC的了解，并告知PASC的控制。

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.