Viruses that hid in the immune cells of the lungs long after the initial illness – Washington University School of Medicine in St. Louis

Doctors have long known that children who become severely ill with certain respiratory viruses, such as respiratory syncytial virus (RSV), have an increased risk of developing asthma later in life. What they didn't know is why.

A new study by researchers at Washington University School of Medicine in St. Louis may have solved the mystery. The study, conducted in mice, shows that respiratory viruses can hide in immune cells in the lungs long after the initial symptoms of an infection have subsided, creating a persistent inflammatory environment that promotes the development of lung diseases. In addition, they showed that eliminating the infected cells reduced signs of chronic lung damage before they progress to full chronic respiratory disease.

The findings, published Oct. 2 in Nature Microbiology, suggest a potential new approach to preventing asthma, chronic obstructive pulmonary disease (COPD) and other chronic lung diseases by eradicating the persistent respiratory viruses that promote these diseases.

“Currently, children hospitalized for a respiratory infection such as RSV are sent home once their symptoms resolve,” said senior author Carolina B. López, PhD, professor of molecular microbiology and BJC researcher at WashU Medicine. “To reduce the risk of these children developing asthma later, perhaps in the future we can check that all of the virus has truly cleared the lungs and eliminate any remaining virus before sending them home.”

Approximately 27 million people live with asthma in the United States. Many factors influence a person's likelihood of developing a chronic respiratory disease, including living in a neighborhood with poor air quality, exposure to cigarette smoke, and being hospitalized for viral pneumonia or bronchitis at a young age. Some researchers – including López – suspected that the connection between a severe lung infection and the subsequent diagnosis of asthma was due to a virus remaining in the lungs that caused lasting damage. However, a direct connection between the persistent presence of the virus and chronic lung disease has not yet been proven.

López and first author Ítalo Araújo Castro, PhD, a postdoctoral fellow in their lab, developed a unique system that includes a natural mouse virus called Sendai virus and fluorescent markers of infection. Sendai is related to human parainfluenza virus, a common respiratory virus that, like RSV, has been linked to asthma in children. Sendai behaves in mice much like the human parainfluenza virus behaves in humans, making it an excellent model for the types of infections that can lead to chronic lung disease.

Using the fluorescent trackers, researchers were able to observe signs of the virus throughout the infection. After about two weeks, the mice recovered, but viral RNA and proteins were still detectable in their lungs several weeks later, hidden in immune cells.

“It was unexpected to find persistent viruses in immune cells,” López said. “I think that’s why it was overlooked before. Everyone looked for viral products in the epithelial cells that line the surface of the respiratory system, which is where these viruses primarily multiply. But they were in the immune cells.”

In addition, the presence of the virus changed the behavior of the infected immune cells, causing them to react more inflammatoryly than the uninfected immune cells. Persistent inflammation sets the stage for the development of chronic lung disease, the researchers said. In fact, seven weeks after infection, the mice's lungs showed inflammation of the air sacs and blood vessels, abnormal development of lung cells, and excess immune tissue – all signs of chronic inflammatory lung damage, even though the mice outwardly appeared to have recovered. Once the infected immune cells were eliminated, signs of damage subsided.

“We use perfectly matched virus-host pairing to demonstrate that a common respiratory virus can be maintained in immunocompetent hosts for much longer than the acute phase of infection and that this viral persistence can lead to chronic lung disease,” Castro said. “It is likely that the long-term health effects we are seeing in people recovering from an acute infection are actually due to the persistence of the virus in their lungs.”

The results point to new ways of thinking about preventing chronic lung disease, the researchers said.

“Almost every single child becomes infected with these viruses before the age of three, and perhaps 5% become so severely ill that they could potentially develop a persistent infection,” López said. “We will not be able to prevent children from becoming infected in the first place. But if we understand how these viruses persist and what impact that persistence has on the lungs, we may be able to reduce the risk of serious long-term problems.”