Yee Min, Cohen E David, Haak Jeannie, Dylag Andrew M, O'Reilly Michael A
The Department of Pediatrics, School of Medicine and Dentistry, The University of Rochester, Rochester, NY 14642.
bioRxiv. 2020 Jul 22:2020.07.22.215962. doi: 10.1101/2020.07.22.215962.
The severity of COVID-19 lung disease is higher in the elderly and people with pre-existing co-morbidities. People who were born preterm may be at greater risk for COVID-19 because their early exposure to oxygen at birth increases their risk of being hospitalized when infected with RSV and other respiratory viruses. Our prior studies in mice showed how high levels of oxygen (hyperoxia) between postnatal days 0-4 increases the severity of influenza A virus infections by reducing the number of alveolar epithelial type 2 (AT2) cells. Because AT2 cells express the SARS-CoV-2 receptors angiotensin converting enzyme (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2), we expected their expression would decline as AT2 cells were depleted by hyperoxia. Instead, we made the surprising discovery that expression of and mRNA increases as mice age and is accelerated by exposing mice to neonatal hyperoxia. ACE2 is primarily expressed at birth by airway Club cells and becomes detectable in AT2 cells by one year of life. Neonatal hyperoxia increases ACE2 expression in Club cells and makes it detectable in 2-month-old AT2 cells. This early and increased expression of SARS-CoV-2 receptors was not seen in adult mice who had been administered the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia. Our finding that early life insults such as hyperoxia enhances the age-dependent expression of SARS-CoV-2 receptors in the respiratory epithelium helps explain why COVID-19 lung disease is greater in the elderly and people with pre-existing co-morbidities.
新型冠状病毒肺炎（COVID-19）肺部疾病在老年人和已有合并症的人群中更为严重。早产出生的人感染COVID-19的风险可能更高，因为他们出生时早期接触氧气会增加感染呼吸道合胞病毒（RSV）和其他呼吸道病毒时住院的风险。我们之前在小鼠身上的研究表明，出生后第0 - 4天的高氧水平（高氧）如何通过减少肺泡Ⅱ型上皮细胞（AT2）的数量来增加甲型流感病毒感染的严重程度。由于AT2细胞表达严重急性呼吸综合征冠状病毒2（SARS-CoV-2）受体血管紧张素转换酶（ACE2）和跨膜蛋白酶/丝氨酸亚家族成员2（TMPRSS2），我们预计随着AT2细胞因高氧而减少，它们的表达会下降。相反，我们有一个惊人的发现，即随着小鼠年龄增长，ACE2和TMPRSS2 mRNA的表达增加，并且通过使小鼠暴露于新生儿高氧环境而加速。ACE2主要在出生时由气道Club细胞表达，到一岁时在AT2细胞中可检测到。新生儿高氧增加了Club细胞中ACE2的表达，并使其在2个月大的AT2细胞中可检测到。在高氧期间给予线粒体超氧化物清除剂mitoTEMPO的成年小鼠中未观察到SARS-CoV-2受体的这种早期和增加的表达。我们的发现，即高氧等早期生活损伤会增强呼吸道上皮中SARS-CoV-2受体的年龄依赖性表达，有助于解释为什么COVID-19肺部疾病在老年人和已有合并症的人群中更为严重。
