Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and currently has detrimental human health, community, and economic impacts around the world. It is unclear why some SARS-CoV-2-positive individuals remain asymptomatic, while others develop severe symptoms. Baseline pulmonary levels of antiviral leukocytes, already residing in the lung prior to infection, may orchestrate an effective early immune response and prevent severe symptoms. Here, “in silico flow cytometry” was used to deconvolute the levels of all seven types of antiviral leukocytes in 1,927 human lung tissues. Baseline levels of CD8⁺ T cells, resting NK cells, and activated NK cells, as well as cytokines that recruit these cells, are significantly lower in lung tissues with high expression of the SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (ACE2). This is observed in univariate analyses, in multivariate analyses, and in two independent data sets. Importantly, ACE2 mRNA and protein levels very strongly correlate in human cells and tissues. The above findings also largely apply to the SARS-CoV-2 entry protease TMPRSS2. Both SARS-CoV-2-infected lung cells and COVID-19 lung tissues show upregulation of CD8⁺ T cell- and NK cell-recruiting cytokines. Moreover, tissue-resident CD8⁺ T cells and inflammatory NK cells are significantly more abundant in bronchoalveolar lavage fluids from mildly affected COVID-19 patients compared to severe cases. This suggests that these lymphocytes are important for preventing severe symptoms. Elevated ACE2 expression increases sensitivity to coronavirus infection. Thus, the results suggest that some individuals may be exceedingly susceptible to develop severe COVID-19 due to concomitant high preexisting ACE2 and TMPRSS expression and low baseline cytotoxic lymphocyte levels in the lung.

中文翻译：

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肺部细胞毒性淋巴细胞基线水平低是严重 COVID-19 的诱发危险因素。

2019 冠状病毒病 (COVID-19) 由严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起，目前对世界各地的人类健康、社区和经济产生有害影响。目前尚不清楚为什么一些 SARS-CoV-2 阳性个体仍然无症状，而另一些人则出现严重症状。抗病毒白细胞的基线肺部水平在感染前就已经存在于肺部，可以协调有效的早期免疫反应并预防严重症状。在这里，“计算机流式细胞术”被用来对 1,927 个人类肺组织中所有七种类型的抗病毒白细胞的水平进行解卷积。^{在 SARS-CoV-2 进入受体血管紧张素转换酶 2 高表达的肺组织中，CD8 +} T 细胞、静息 NK 细胞和活化 NK 细胞以及招募这些细胞的细胞因子的基线水平显着较低（ACE2）。这是在单变量分析、多变量分析和两个独立数据集中观察到的。重要的是，ACE2 mRNA 和蛋白质水平在人体细胞和组织中密切相关。上述发现在很大程度上也适用于 SARS-CoV-2 进入蛋白酶 TMPRSS2。SARS-CoV-2 感染的肺细胞和 COVID-19 肺组织均表现出 CD8 ⁺ T 细胞和 NK 细胞招募细胞因子的上调。此外，与重症病例相比，轻度感染的 COVID-19 患者的支气管肺泡灌洗液中组织驻留的 CD8 ^{+ T 细胞和炎性 NK 细胞的含量明显更高。}这表明这些淋巴细胞对于预防严重症状很重要。ACE2 表达升高会增加对冠状病毒感染的敏感性。因此，结果表明，由于肺部先前存在较高的 ACE2 和 TMPRSS 表达以及较低的基线细胞毒性淋巴细胞水平，一些个体可能极易患上严重的 COVID-19。