Is Low Alveolar Type II Cell SOD3 in the Lungs of Elderly Linked to the Observed Severity of COVID-19?
Is Low Alveolar Type II Cell SOD3 in the Lungs of Elderly Linked to the Observed Severity of COVID-19?
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DOI：
10.1089/ars.2020.8111
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发表时间：
2020-05-08
影响因子：
6.6
通讯作者：
Sen, Chandan K.
中科院分区：
文献类型：
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作者：
Abouhashem, Ahmed S.;Singh, Kanhaiya;Sen, Chandan K.
分析来自健康供体（老年人和年轻人; GEO登录号GSE 122960）的人肺单细胞RNA测序数据，以分离和特异性研究肺泡II型细胞中的基因表达。血管紧张素转换酶2（ACE 2）和TMPRSS 2的共定位使得严重急性呼吸综合征冠状病毒2（SARS-CoV 2）能够进入细胞。这些基因在老年和年轻患者肺泡II型细胞中的表达水平相当，因此，似乎不是2019年冠状病毒病（COVID-19）影响老年人的更差结果的原因。在老年人的细胞中，263个基因下调，95个基因上调。超氧化物歧化酶3（SOD 3）被确定为在老年人中下调最多的顶级基因。在老年人细胞中也下调的其他氧化还原活性基因包括激活转录因子4（ATF 4）和金属硫蛋白2A（M2 TA）。ATF 4是一种内质网应激传感器，通过诱导血红素加氧酶1来保护肺。对已知由ATF 4诱导的下游因子的研究，根据Inhibitity Pathway Analysis（TM），确定了24个候选者。其中21个在老年人的细胞中显著下调。使用Reactome数据库对这些下调的候选物进行富集，鉴定在老年人中，响应血红素缺乏的能力和响应内质网应激的ATF 4依赖性能力显著受损。基于S 0 D3的治疗策略在治疗包括纤维化的肺病方面提供了有益的结果。这项研究的发现提出了一个假设，即SOD 3/ATF 4相关抗氧化剂的肺部特异性递送将与有前景的抗病毒药物如瑞德西韦协同作用，以进一步改善老年人的COVID-19结局。
Human lungs single-cell RNA sequencing data from healthy donors (elderly and young; GEO accession no. GSE122960) were analyzed to isolate and specifically study gene expression in alveolar type II cells. Colocalization of angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 enables severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) to enter the cells. Expression levels of these genes in the alveolar type II cells of elderly and young patients were comparable and, therefore, do not seem to be responsible for worse outcomes observed in coronavirus disease 2019 (COVID-19) affected elderly. In cells from the elderly, 263 genes were downregulated and 95 upregulated. Superoxide dismutase 3 (SOD3) was identified as the top-ranked gene that was most downregulated in the elderly. Other redox-active genes that were also downregulated in cells from the elderly included activating transcription factor 4 (ATF4) and metallothionein 2A (M2TA). ATF4 is an endoplasmic reticulum stress sensor that defends lungs via induction of heme oxygenase 1. The study of downstream factors known to be induced by ATF4, according to Ingenuity Pathway Analysis (TM), identified 24 candidates. Twenty-one of these were significantly downregulated in the cells from the elderly. These downregulated candidates were subjected to enrichment using the Reactome Database identifying that in the elderly, the ability to respond to heme deficiency and the ATF4-dependent ability to respond to endoplasmic reticulum stress is significantly compromised. SOD3-based therapeutic strategies have provided beneficial results in treating lung disorders including fibrosis. The findings of this study propose the hypotheses that lung-specific delivery of SOD3/ATF4-related antioxidants will work in synergy with promising antiviral drugs such as remdesivir to further improve COVID-19 outcomes in the elderly.