2019年冠状病毒病(COVID-19)的心血管表现包括心肌损伤,心力衰竭,和心肌炎,并与长期残疾和死亡率有关。在COVID-19患者的心肌中发现了严重急性呼吸综合征冠状病毒2(SARS-CoV-2)RNA和抗原,和人心肌细胞在细胞或类器官培养物中容易感染。虽然这些观察结果提出了心肌细胞感染可能导致COVID-19心脏后遗症的可能性,但心肌细胞感染与心肌功能障碍和病理之间的因果关系尚未确定。这里,我们通过选择性表达人血管紧张素转换酶2(hACE2),SARS-CoV-2受体,在心肌细胞中。用祖先接种Myh6-CreRosa26loxP-STOP-loxP-hACE2小鼠,非小鼠适应的SARS-CoV-2株导致病毒在心脏内复制,巨噬细胞的积累,和中度左心室(LV)收缩功能障碍。该模型中的心脏病理学是短暂的,并且通过病毒清除得以解决。单核细胞运输的阻断减少了巨噬细胞的积累,抑制左心室收缩功能障碍的发展,并促进心脏的病毒清除。这些发现建立了SARS-CoV-2心肌细胞感染的小鼠模型,该模型概括了COVID-19心脏功能障碍的特征,并表明病毒复制和由此产生的先天免疫反应都有助于心脏病理学。严重急性呼吸综合征冠状病毒2(SARS-CoV-2)感染后的心脏受累有多种方式发生,并与2019年冠状病毒病(COVID-19)患者的不良预后相关。目前尚不清楚心脏病是否是由心脏的原发性感染或对病毒的免疫反应引起的。SARS-CoV-2能够在培养皿中进入心脏的收缩细胞。然而,目前尚不清楚这种感染如何影响心脏在体内的功能。这里,我们设计了一种小鼠,其中只有心肌细胞可以感染SARS-CoV-2菌株,以研究与其他器官系统隔离的心脏感染。在我们的模型中,受感染的小鼠表现出病毒感染,功能更差,和心脏中免疫细胞的积累。免疫细胞的子集促进这种恶化的心脏功能。由于该模型显示出与患者相似的特征,这可能有助于了解作为COVID-19一部分发生的心脏病。
Cardiovascular manifestations of coronavirus disease 2019 (COVID-19) include myocardial injury, heart failure, and myocarditis and are associated with long-term disability and mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antigens are found in the myocardium of COVID-19 patients, and human cardiomyocytes are susceptible to infection in cell or organoid cultures. While these observations raise the possibility that
cardiomyocyte infection may contribute to the cardiac sequelae of COVID-19, a causal relationship between
cardiomyocyte infection and myocardial dysfunction and pathology has not been established. Here, we generated a mouse model of
cardiomyocyte-restricted infection by selectively expressing human angiotensin-converting enzyme 2 (hACE2), the SARS-CoV-2 receptor, in cardiomyocytes. Inoculation of Myh6-Cre Rosa26loxP-STOP-loxP-hACE2 mice with an ancestral, non-mouse-adapted strain of SARS-CoV-2 resulted in viral replication within the heart, accumulation of macrophages, and moderate left ventricular (LV) systolic dysfunction. Cardiac pathology in this model was transient and resolved with viral clearance. Blockade of monocyte trafficking reduced macrophage accumulation, suppressed the development of LV systolic dysfunction, and promoted viral clearance in the heart. These findings establish a mouse model of SARS-CoV-2
cardiomyocyte infection that recapitulates features of cardiac dysfunctions of COVID-19 and suggests that both viral replication and resultant innate immune responses contribute to cardiac pathology.IMPORTANCEHeart involvement after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection occurs in multiple ways and is associated with worse outcomes in coronavirus disease 2019 (COVID-19) patients. It remains unclear if cardiac disease is driven by primary infection of the heart or immune response to the virus. SARS-CoV-2 is capable of entering contractile cells of the heart in a culture dish. However, it remains unclear how such infection affects the function of the heart in the body. Here, we designed a mouse in which only heart muscle cells can be infected with a SARS-CoV-2 strain to study cardiac infection in isolation from other organ systems. In our model, infected mice show viral infection, worse function, and accumulation of immune cells in the heart. A subset of immune cells facilitates such worsening heart function. As this model shows features similar to those observed in patients, it may be useful for understanding the heart disease that occurs as a part of COVID-19.