The infection rate of SARS-CoV-2, the virus that causes COVID-19, is 24 times higher in laboratory cultured respiratory cells from humans with chronic obstructive pulmonary disease (COPD) than in those from healthy people, a study shows.
This increased susceptibility to infection, which makes severe outcomes more likely, was associated with higher enzyme levels that the virus uses to penetrate cells, as well as higher pro-inflammatory molecular levels and lower levels of antiviral proteins.
“Together, these results have enabled us to understand the mechanisms behind increased COVID-19 susceptibility in COPD patients,” said Phil Hansbro, PhD, the study’s senior author in a Press release. Hansbro is Professor of Microbiology at the University of Newcastle and Director of the Centenary UTS Center for Inflammation, both in Australia,
“We believe in the new [therapies] Targeting relevant enzymes and pro-inflammatory responses in SARS-CoV-2 infection could have excellent therapeutic potential to reduce the severity of COVID-19 in patients with COPD, ”added Hansbro.
The study, “Increased SARS-CoV-2 infection, protease and inflammatory responses in COPD primary bronchial epithelial cells defined by single cell RNA sequencing“was published in American Journal of Respiratory and Critical Care Medicine.
Mainly associated with prolonged exposure to irritants such as cigarette smoke, COPD is characterized by excessive airway inflammation, pulmonary tissue remodeling and the progressive destruction of the alveoli – the small lung air sacs responsible for gas exchange.
Rising evidence shows COPD patients are more susceptible to severe COVID-19, but the underlying mechanisms of this susceptibility remain largely unclear.
One potential factor is the increased production of ACE2 – the cell surface receptor that SARS-CoV-2 binds to enter cells – in airway cells after exposure to cigarette smoke. Also, COPD patients’ lungs have higher than normal levels of proteases, a family of enzymes that include those used by SARS-CoV-2 to penetrate cells.
To learn more about what contributes to COPD patients’ increased susceptibility to SARS-CoV-2 infection, Hansbro’s research team, together with colleagues in Australia, analyzed the viral load and gene activity profiles of laboratory-grown airway cells – called primary bronchial epithelial cells (pBECs) – from four adults. with COPD and three healthy adults using a high-resolution technique called single-cell RNA sequencing.
Patients included two women and two men (age range, 67-85 years), while healthy controls included two women and one man (age range, 55-75 years). No participant had a history of respiratory infection within the past month or a lung cancer diagnosis.
The results showed that seven days after cells were exposed to SARS-CoV-2, “there was a 24-fold increase in the amount of virus in the COPD patient’s airway cells compared to the cells taken from healthy individuals,” Matt Johansen, PhD, the study’s first author from Centenary UTS Center for Inflammation, said.
Gene activity profiles between infected and present cells in both groups were generally similar, highlighting that “there are commonly used pathways in SARS-CoV-2 [infection]which are independent of pre-existing disease status, ”the researchers wrote.
Compared with controls, airway cells from COPD patients showed significantly increased levels of transmembrane protease serine 2 (TMPRSS2), cathepsin B (CTSB) and cathepsin L (CTSL), three proteases known to promote the entry of SARS-CoV-2 into cells.
In turn, the levels of more serpins – proteins known to suppress the activity of proteases – were significantly reduced in COPD cells compared to healthy controls, regardless of infection.
These results “highlight a protease imbalance in COPD-pBECs that may be crucial for increased SARS-CoV-2 infectivity and serious disease,” the researchers wrote.
“Simply put, milder and increased cell infection makes it far more likely that people with COPD will have more serious disease outcomes,” Johansen said.
The team also found that the levels of pro-inflammatory molecules associated with COPD’s sudden disease aggravating episodes and severe COVID-19 were significantly increased in both infected and uninfected respiratory cells from people with COPD.
“COPD is an inflammatory disease in which patients have increased inflammation… compared to healthy people,” and “it is highly likely that SARS-CoV-2 exacerbates this existing high level of inflammation, leading to even worse outcomes,” Johansen said.
Key antiviral responses involving proteins called interferons were also largely blunt-ended in respiratory cells from COPD patients compared to those from controls, which may be “a key driver for increased susceptibility to elevated inflammatory and viral responses. [infection]”, wrote the research team.
ACE2 was found to be significantly increased by infection in both COPD and control cells, but there were no significant differences between the groups, suggesting that ACE2 may not be a contributing factor to increased infection susceptibility in COPD.
In addition, therapeutic interventions that suppress either TMPRSS2, CTSB, inflammation, or all three at the same time significantly reduced SARS-CoV-2 load and pro-inflammatory molecules in especially COPD patient cells.
This is the “first study to show biological evidence that COPD pBECs are significantly more tolerant of SARSCoV-2 infection compared to healthy pBECs,” the researchers wrote.
The results also highlighted that this increased susceptibility is due to protease imbalances, major inflammatory responses, and reduced interferon responses, potentially describing “biological mechanisms responsible for exacerbations and severe COVID-19 in COPD,” the research team wrote.
Several studies are needed to analyze the relevance of these candidates, as well as the therapeutic potential of targeting protease imbalance, excessive inflammation, or deficient interferon response in COPD patients with COVID-19.
Hansbro said these findings are critical as hundreds of millions of people are affected by COPD globally and COVID-19 is likely to exist in the coming years.