Why do COVID-19 patients have trouble breathing?

The COVID-19 pandemic has resulted in over 145 million positive cases and 3.1 million deaths globally (32 million and 570,000 in the USA, respectively), as reported on April 26, 2021. Approximately 15% of infected patients with SARS-CoV-2 die from respiratory failure, making it the leading cause of death in COVID-19 patients.

A research group at Columbia University led by Dr. Benjamin Izar identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions in the lungs of COVID19 patients. These findings were published in the prestigious journal Nature. The team performed single-nucleus RNA sequencing, which is a method for profiling gene expression in cells, of the lungs of 19 patients who died of COVID-19 and underwent rapid autopsy. The control group included seven control patients who underwent lung resection or biopsy in the pre-COVID-19 era (Figure 1).

Figure 1: An overview of the study design wherein single-nucleus RNA sequencing was used to characterize lungs of patients who died from COVID-19-related respiratory failure. A) The lung tissue was extracted for mRNA, a genetic sequencing of a gene. B) The mRNA sequence will be read by a computer system. C) The gene expression of cells in the lung of COVID-19 patients samples and control samples. PMI: post-mortem interval. snRNA-seq: single nucleus RNA sequencing. QC: quality control.

The lungs from individuals with COVID-19 were highly inflamed but had impaired T cell responses. The single-nucleus RNA sequencing showed significant differences in cell fractions between COVID-19 and control lungs both globally and within the immune and non-immune compartments. There was a reduction in the epithelial cell compartment, which are the surfaces of organs in the body and function as a protective barrier. There was also an increase in monocytes (i.e., white blood cells that are important for the adaptive immunity process) and macrophages (i.e., cells involved in the detection, phagocytosis and destruction of bacteria and other harmful organisms), and a decrease in fibroblasts (i.e., cells that contribute to the formation of connective tissue) and neuronal cells. These observations were independent of donor sex. 

Monocyte/macrophage and epithelial cells were unique features of a SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. The reduction in the epithelial cell compartment was due to the loss of both alveolar type II and type I cells. Alveolar type II cells repopulate the epithelium after injury, and provide important components of the innate immune system. Alveolar type II cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type I cells, resulting in impaired lung regeneration. 

Myeloid cells (i.e., monocytes, macrophages, and dendritic cells) represented a major cellular constituent in COVID-19 lungs and were more prevalent as compared to control lungs. The authors found that the receptor tyrosine kinase that is important for coordinated clearance of dying/dead cells and subsequent anti-inflammatory regulation during tissue regeneration was downregulated. These data suggest that myeloid cells are a major source of dysregulated inflammation in COVID-19.

The authors also found significantly more fibroblasts in COVID-19 lungs than in control lungs. The degree of fibrosis correlated with disease duration, indicating that lung fibrosis increases over time in COVID-19. 

In this article, the authors mentioned the limitation of the study that they  analyzed lung tissues from patients who died of COVID-19, and therefore they only examined a subset of potential disease phenotypes. Based on the author’s observation, the rapid development of pulmonary fibrosis is likely to be relevant for patients who survive from severe COVID-19. This atlas may inform our understanding of long-term complications of COVID-19 survivors and provide an important resource for therapeutic development.

Read more about this article here: A molecular single-cell lung atlas of lethal COVID-19

Reviewed by: Molly Scott and Maaike Schilperoort

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