Low Baseline Pulmonary Levels of Cytotoxic Lymphocytes as a Predisposing Risk Factor for Severe COVID-19

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.IMPORTANCE COVID-19 is caused by the highly contagious coronavirus 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 develop severe COVID-19 symptoms, which can be fatal, while others only develop mild symptoms. In the absence of an effective and widely available vaccine, it is of paramount importance that we identify risk factors for development of severe symptoms to be able to improve treatment approaches. The ACE2 gene encodes the receptor on human cells that the virus uses to infect these cells. This study finds that if the lungs of healthy individuals have high levels of ACE2, they typically have low levels of the immune cells that eliminate viruses. Therefore, some individuals may develop severe COVID-19 due to simultaneous high levels of the virus receptor and low levels of immune cells that eradicate the virus in their lungs.