微循环
活体显微镜检查
病理
内皮
血脑屏障
呼吸道
生物
血小板
发病机制
上皮
免疫学
呼吸系统
医学
中枢神经系统
解剖
内分泌学
内科学
作者
Fernanda V. S. Castanheira,Ruby H.N. Nguyen,Michelle Elizabeth Willson,Marcela Davoli‐Ferreira,Bruna Araújo David,Margaret M. Kelly,Woo-Yong Lee,Rachel M. Kratofil,Wen Xuan Zhang,Maxwell P. Bui-Marinos,Jennifer A. Corcoran,Paul Kubes
出处
期刊:Blood Advances
[American Society of Hematology]
日期:2023-08-01
卷期号:7 (15): 4170-4181
被引量:3
标识
DOI:10.1182/bloodadvances.2022009430
摘要
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters the respiratory tract, where it infects the alveoli epithelial lining. However, patients have sequelae that extend well beyond the alveoli into the pulmonary vasculature and, perhaps, beyond to the brain and other organs. Because of the dynamic events within blood vessels, histology does not report platelet and neutrophil behavior. Because of the rapid nontranscriptional response of these cells, neither single-cell RNA sequencing nor proteomics report robustly on their critical behaviors. We used intravital microscopy in level-3 containment to examine the pathogenesis of SARS-CoV-2 within 3 organs in mice expressing human angiotensin converting enzyme 2 (ACE-2) ubiquitously (CAG-AC-70) or on epithelium (K18-promoter). Using a neon-green SARS-CoV-2, we observed both the epithelium and endothelium infected in AC70 mice but only the epithelium in K18 mice. There were increased neutrophils in the microcirculation but not in the alveoli of the lungs of AC70 mice. Platelets formed large aggregates in the pulmonary capillaries. Despite only neurons being infected within the brain, profound neutrophil adhesion forming the nidus of large platelet aggregates were observed in the cerebral microcirculation, with many nonperfused microvessels. Neutrophils breached the brain endothelial layer associated with a significant disruption of the blood-brain-barrier. Despite ubiquitous ACE-2 expression, CAG-AC-70 mice had very small increases in blood cytokine, no increase in thrombin, no infected circulating cells, and no liver involvement suggesting limited systemic effects. In summary, our imaging of SARS-CoV-2-infected mice gave direct evidence that there is a significant perturbation locally in the lung and brain microcirculation induced by local viral infection leading to increased local inflammation and thrombosis in these organs.
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