Researchers from the Centenary Institute and the University of Technology Sydney have published the first study showing why people with chronic obstructive pulmonary disease (COPD) are at higher risk of developing severe COVID-19.
Dr. Matt Johansen. Image credit: Centenary Institute
The results, reported in American Journal of Respiratory and Critical Care Medicinecould lead to the development of new therapeutic interventions that reduce COVID-19 infection in COPD patients.
An inflammatory lung disease, COPD causes airway obstruction and makes it difficult to breathe. It affects about 400 million people globally. The increased susceptibility to COVID-19 in COPD patients still needs to be fully understood.
In the study, the researchers infected differentiated respiratory cells from COPD patients and healthy people with SARS-CoV-2 (the virus that causes COVID-19).
The researchers found that the COPD respiratory cells had 24 times greater infection with SARS-CoV-2 than the healthy cells.
We examined the genetic information about infected cells through advanced single-cell RNA sequencing analysis. Seven days after SARS-CoV-2 infection, there was a 24-fold increase viral load in COPD patient airway cells compared to cells taken from healthy individuals. “
Dr. Matt Johansen, study leader author, Centenary UTS Center for Inflammation
Importantly, the team found that the infected COPD cells had increased levels of transmembrane protease serine 2 (TMPRSS2) and cathepsin B (CTSB). Both are enzymes that SARS-CoV-2 uses to penetrate the host cell.
“These two enzymes increase in COPD patients and favor larger SARS-CoV-2 infection compared to healthy people. Simply put, easier and increased cell infection makes it much more likely that people with COPD will have more serious disease outcomes,” said Dr. Johansen.
Other results from the study showed additional reasons for COPD patients’ susceptibility to severe COVID-19.
Key antiviral proteins (interferons) that protect against infection were largely dull in the COPD patient’s airway cells. This was a likely trigger to cause increased viral production in COPD patients.
Dr. Johansen said that infected COPD patient’s airway cells also had higher levels of pro-inflammatory cytokines, which are associated with more severe COVID-19 and COPD outcomes.
“COPD is an inflammatory disease in which patients have increased inflammation at baseline compared to healthy people. It is highly likely that SARS-CoV-2 exacerbates this existing high level of inflammation, leading to even worse outcomes,” he said.
Initial laboratory drug tests performed by the researchers to inhibit the enzymes TMPRSS2 and CTSB and target the high levels of inflammation, successfully and significantly reduced SARS-CoV-2 viral levels in COPD patient cells, ultimately confirming the results of the study.
Together, these results have enabled us to understand the mechanisms behind increased COVID-19 susceptibility in COPD patients.
We believe that new drug therapies targeting relevant enzymes and pro-inflammatory responses in SARS-CoV-2 infection may have excellent therapeutic potential to reduce the severity of COVID-19 in patients with COPD. “
Phil Hansbro, Study Senior Author and Professor, Director of the Centenary UTS Center for Inflammation
Professor Hansbro said the research was critical with hundreds of millions of people affected by COPD globally, and with COVID-19 likely to exist for many years to come.
Johansen, dr.med. et al. (2022) Increased SARS-CoV-2 infection, protease, and inflammatory responses in COPD primary bronchial epithelial cells defined by single-cell RNA sequencing. American Journal of Respiratory and Critical Care Medicine. doi.org/10.1164/rccm.202108-1901OC.