Emerging Role of Kinin B1 Receptor in Persistent Neuroinflammation and Neuropsychiatric Symptoms in Mice Following Recovery from SARS-CoV-2 Infection.
Emerging Role of Kinin B1 Receptor in Persistent Neuroinflammation and Neuropsychiatric Symptoms in Mice Following Recovery from SARS-CoV-2 Infection.
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DOI：
10.3390/cells12162107
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发表时间：
2023-08-19
期刊：
影响因子：
6
通讯作者：
Eells, Jeffrey B.
中科院分区：
文献类型：
--
作者：
Sriramula, Srinivas;Theobald, Drew;Parekh, Rohan Umesh;Akula, Shaw M.;O'Rourke, Dorcas P.;Eells, Jeffrey B.
有证据表明，COVID时间长的患者会出现神经精神、神经和认知症状。然而，这些临床数据大多是复杂的混杂变量的关联研究，因此导致持续性症状的机制尚不清楚。在这里，我们建立了一个动物模型，通过在K18-hACE2小鼠中诱发轻度疾病来对大脑产生长期影响。用4×103TCID50的SARS-CoV-2TCID50感染K18-hACE2雄性和雌性K18-hACE2小鼠，在感染后30d开始在旷场、零迷宫和Y迷宫中进行检测。从SARS-CoV-2感染中康复后，K18-hACE2小鼠表现出与SARS-CoV-2感染相关的特征性肺纤维化，这与促炎激肽B1受体(B1R)的表达增加有关。这些小鼠大脑中B1R和炎症标志物的表达也增加，并表现出行为变化，如焦虑增加和探索行为减弱。我们的数据表明，K18-hACE2小鼠表现出SARS-CoV-2感染对脑组织的持续影响，揭示了使用这种对SARS-CoV-2高度敏感的模型来研究高危人群长期COVID症状的机制的可能性。这些结果进一步表明，B1R的高表达可能推动了与SARS-CoV-2感染相关的长期炎症反应。
Evidence suggests that patients with long COVID can experience neuropsychiatric, neurologic, and cognitive symptoms. However, these clinical data are mostly associational studies complicated by confounding variables, thus the mechanisms responsible for persistent symptoms are unknown. Here we establish an animal model of long-lasting effects on the brain by eliciting mild disease in K18-hACE2 mice. Male and female K18-hACE2 mice were infected with 4 × 103 TCID50 of SARS-CoV-2 and, following recovery from acute infection, were tested in the open field, zero maze, and Y maze, starting 30 days post infection. Following recovery from SARS-CoV-2 infection, K18-hACE2 mice showed the characteristic lung fibrosis associated with SARS-CoV-2 infection, which correlates with increased expression of the pro-inflammatory kinin B1 receptor (B1R). These mice also had elevated expression of B1R and inflammatory markers in the brain and exhibited behavioral alterations such as elevated anxiety and attenuated exploratory behavior. Our data demonstrate that K18-hACE2 mice exhibit persistent effects of SARS-CoV-2 infection on brain tissue, revealing the potential for using this model of high sensitivity to SARS-CoV-2 to investigate mechanisms contributing to long COVID symptoms in at-risk populations. These results further suggest that elevated B1R expression may drive the long-lasting inflammatory response associated with SARS-CoV-2 infection.
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ACE2小鼠模型：用于心血管和肺部研究的工具箱。
影响因子：
16.6
作者：
Jia H;Yue X;Lazartigues E
通讯作者：
Lazartigues E
DOI：
10.1016/j.bbih.2021.100387
发表时间：
2021-12
期刊：
Brain, behavior, & immunity - health
影响因子：
--
作者：
Benedetti F;Palladini M;Paolini M;Melloni E;Vai B;De Lorenzo R;Furlan R;Rovere-Querini P;Falini A;Mazza MG
通讯作者：
Mazza MG
影响因子：
2.5
作者：
Heiss R;Grodzki DM;Horger W;Uder M;Nagel AM;Bickelhaupt S
通讯作者：
Bickelhaupt S
影响因子：
29
作者：
Cocoros, Noelle M.;Svensson, Elisabeth;Henderson, Victor W.
通讯作者：
Henderson, Victor W.
影响因子：
6.7
作者：
De Chiara, Giovanna;Piacentini, Roberto;Palamara, Anna Teresa
通讯作者：
Palamara, Anna Teresa