Scientists have discovered that patients with chronic lung disease (CLD) have genetic expression programs that make them more susceptible to catching COVID-19 and experiencing greater disease severity, according to research published this year in Nature Communication

CLD is an umbrella term that is used to refer to any disease of the lung that is chronic in nature. It includes lung diseases such as idiopathic pulmonary fibrosis (IPF), cystic fibrosis, COPD, and asthma.  

The COVID-19 virus requires entry receptors to help facilitate infection. The virus “utilizes the host ACE2, and other putative factors, such as BSG, NRP1 and HSPA5 as entry receptors, and TMPRSS2, CTSL or FURIN as priming proteases to facilitate cellular entry.” 

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Researchers of this study sought to establish whether CLD patients express higher levels of entry receptors and priming proteases that facilitate COVID-19 infection and worsen outcomes. They analyzed the transcriptomes of 611,398 single cells isolated from healthy and CLD lungs in order to identify molecular characteristics of lung cells that may explain why patients with CLD tended to have poorer COVID-19 outcomes. 

The results show that, although there were no significant differences in the proportion of ACE+ cells in any cell-type in CLD versus control groups, there is a regional congregation of ACE2+ cells within the distal IPF lung, which may provoke a more severe localized viral response.

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In addition, the COVID-19 entry gene score in CLD samples (calculated on the average expression levels of all COVID-19 entry factors over a random control gene set) is significantly increased in many epithelial cell types, including AT1, AT2, Basal, Club cells, as well as KRT5-/KRT17 + cells, an ECM-producing epithelial cell type enriched in the fibrotic lung.This suggests that a modest change in the expression of established COVID-19 entry factors in CLD patients works synergistically with other mechanisms to increase susceptibility to COVID-19. 

This study, alongside previously published research, suggests that, while overall differences in ACE2 expression and other entry factors are minimal in CLD, the localization of susceptible cells in the distal lung may make it easier for COVID-19 infection to occur and for the disease outcome to be more severe once infection has taken place. 


Bui LT, Winters NI, Chung MI, et al. Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity. Nat Commun 12, 4314 (2021). lung disease, National Cancer Institute, accessed July 17, 2021.