Researchers have revealed how chronic lung diseases develop after viral infections, offering new clues to develop more effective treatment and prevention strategies for lung damage.
To the surprise of many, the most critical time in a viral respiratory illness can sometimes be after the virus is cleared from the body. A cascade of destructive processes that are set in motion during an infection can peak in the weeks after the body has successfully defeated the virus. These processes can lead to organ damage, which can cause chronic illness and even death. As seen in the case of COVID-19, some people still struggle with persistent cough, difficulty breathing, and shortness of breath – all of which are symptoms of ongoing lung disease – after an initial bout of the virus. But why does this happen?
A recent study by scientists at the Washington University School of Medicine in St. Louis has uncovered new clues to how lung damage develops in the aftermath of a respiratory infection. By studying mice, it was revealed that infections are triggered by the expression of a protein called Interleukin 33 (IL-33). IL-33 reportedly supports stem cells in the lung to overgrow into air spaces, which can lead to increased mucus production and inflammation. Alongside these findings, the team’s study, published in the Journal of Clinical Investigation, also suggests potential points of intervention to prevent chronic lung damage caused by viral infections.
“Vaccines, antivirals, antibody therapies are all helpful, but they are not a solution for people who are already on the road to progressive disease,” explained senior author Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine and a professor of cell biology & physiology. “We’ve gotten better at taking care of the acute illness due to COVID-19, but what happens after that initial injury phase is still a major obstacle to a better outcome. At this point, we are also faced with tens of millions of people who already had infection, and a high percentage of them are having long-term disease, especially with respiratory symptoms. We don’t have a treatment that can correct the problem.”
Acute respiratory infections have long been known to potentially cause chronic lung disease. Children who are hospitalised with respiratory syncytial virus, for example, are two to four times more likely to develop asthma that persists for long periods or maybe even for a lifetime. However, the exact mechanisms by which infections trigger chronic illnesses remain elusive, consequently preventing scientists from developing appropriate intervention strategies.
To fill this knowledge gap, first author Kangyun Wu, Holtzman, and colleagues analysed how respiratory infections affect mice. For this investigation, they chose to study the Sendai virus. While Sendai does not cause serious disease in humans, it naturally infects other animals like mice and causes respiratory infections that develop like those in people. This makes Sendai-infected mice suitable subjects for their study.
During the study, the researchers analysed lung tissues from mice 12 and 21 days after they were infected with the Sendai virus. They compared these samples to the lung tissues of uninfected mice and discovered that two populations of stem cells were mainly responsible for maintaining the barrier between the lung and the outside world in healthy mice. But after being infected by the Sendai virus, these two cell populations – basal cells and AT2 cells – began to separately multiply and spread into air spaces. The basal cells were found to take over small airways and air sacs while the AT2 cells remained confined to the air sacs. Some of the new basal cells differentiated into mucus-producing cells while others release molecules that recruit immune cells to the lungs. Combined together, these processes result in reduced air spaces, more mucus, and inflammation in the lungs that disrupt breathing.
When the team further examined the pathway leading up to the behaviour of the stem cells, they found that these processes occurred with the help of IL-33. Under normal circumstances, IL-33 increases in the nuclei of lung stem cells in response to stress or injury to help the lung repair damaged barriers. But during and after infection, this protein can result in detrimental effects.
To determine the exact role of IL-33 in post-viral lung damage, the researchers genetically modified mice to lack the protein IL-33 in the basal set of lung stem cells. They then infected the protein-lacking mice and a separate group of unmodified mice with the Sendai virus. The experiment revealed that both groups of mice could fight off an initial Sendai infection equally well. However, after three weeks of infection, the lungs of the mice that lacked IL-33 demonstrated less cellular overgrowth, mucus, and inflammation which are indicative of less harmful lung changes. In the seventh week, it was also discovered that the protein-lacking group showed higher oxygen levels in their blood and less airway hyperresponsiveness, both of which are signs of improvement in their post-infection chronic lung disease.
“These results were really nice to see because getting rid of IL-33 and in turn losing basal stem cells could have made things worse,” said Holtzman. “The engineered mice could have died because they were no longer able to perform the normal repair of the viral damage to the lung barrier. But that’s not the case. The mice lacking this population of basal cells instead had much better outcomes. That’s what we’re excited about. These findings put us on firm ground to find therapies that correct the bad behaviour of basal stem cells.”
One strategy, according to Holtzman, could be to target steps on the pathway between IL-33 and the activation of basal cells. If successful, he believes that this could become the basis of broadly effective therapies to prevent or treat lung diseases caused by various viruses. Moreover, it could potentially help to treat other forms of injuries in the lung as well as other sites where the body meets the outside world.
“The lung has a pretty stereotyped response to injury, including viral injury,” said Holtzman. “The specific type of virus, the genetics of the host, the severity of the initial illness — all of these things influence the outcome, but they’re just matters of degrees. You still see the same key elements across conditions, and that’s why we believe that there can be a common strategy for treatment. We have a drug discovery program to find such a common strategy, and this study fits well with that.”
Source: Wu et al. (2021). Basal-epithelial stem cells cross an alarmin checkpoint for post-viral lung disease. The Journal of Clinical Investigation.