Viruses can hide in lung cells and cause chronic disease

Doctors have long known that children who become seriously ill with certain respiratory viruses, such as respiratory syncytial virus (RSV), are at elevated risk of developing asthma later in life. However, the reason why this happens has remained a mystery.

A new study by researchers at Washington University School of Medicine in St. Louis may have solved this puzzle.

Viruses linger in immune cells

The study, conducted in mice, found that respiratory viruses can remain hidden in immune cells in the lungs long after the initial symptoms of an infection have disappeared.

This lingering presence creates a persistently inflammatory environment that promotes the development of lung diseases like asthma.

Moreover, the researchers demonstrated that eliminating these infected cells could reduce signs of chronic lung damage before they progress into full-blown chronic respiratory illnesses.

Preventing chronic lung diseases

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

“Right now, children who have been hospitalized for a respiratory infection such as RSV are sent home once their symptoms resolve,” said senior author Carolina B. López, a professor of molecular microbiology at WashU Medicine.

“To reduce the risk that these children will go on to develop asthma, maybe in the future we will be able to check if all of the virus is truly gone from the lung, and eliminate all lingering virus, before we send them home.”

Persistent viruses and chronic lung disease

There are about 27 million people in the U.S. living with asthma. Several factors influence a person’s likelihood of developing this chronic breathing condition, such as living in areas with poor air quality, exposure to cigarette smoke, and having been hospitalized for viral pneumonia or bronchitis as a child.

Some researchers – including López – had suspected that the link between severe lung infections and later asthma diagnoses might be due to lingering viruses in the lungs causing ongoing damage.

Until now, however, a direct connection between the persistent presence of a virus and chronic lung disease had not been established.

Studying common respiratory viruses

López and first author Ítalo Araújo Castro, a postdoctoral researcher in her lab, developed a unique system using a natural mouse virus called Sendai virus and fluorescent markers to track infection.

Sendai virus is related to human parainfluenza virus, a common respiratory virus that has been associated with asthma in children, similar to RSV.

Since Sendai behaves in mice much like human parainfluenza behaves in people, it provides an excellent model for studying infections that may lead to chronic lung disease.

Viral RNA in lung immune cells

Using the fluorescent markers, the researchers were able to observe the presence of the virus throughout the infection.

While the mice seemed to recover after about two weeks, the viral RNA and protein could still be detected weeks later in their lungs, where it was hiding inside immune cells.

“Finding persistent virus in immune cells was unexpected,” said López. “I think that’s why it had been missed before.”

“Everyone had been looking for viral products in the epithelial cells that line the surface of the respiratory system, because that’s where these viruses primarily replicate. But they were in the immune cells.”

Persistent inflammatory response to viruses

Furthermore, the presence of the virus altered the behavior of the infected immune cells, causing them to become more inflammatory than the uninfected cells.

This persistent inflammation set the stage for the development of chronic lung disease, the researchers explained.

Seven weeks after the initial infection, the mice’s lungs exhibited signs of chronic lung damage – even though the mice appeared to have recovered.

These signs included inflammation of the air sacs and blood vessels, abnormal lung cell development, and excess immune tissue – all of which indicate long-term inflammatory lung damage. When the researchers eliminated the infected immune cells, these signs of lung damage decreased.

Broader implications of the study

“We use a perfectly matched virus-host pairing to prove that a common respiratory virus can be maintained in immunocompetent hosts for way longer than the acute phase of the infection, and that this viral persistence can result in chronic lung conditions,” Castro said.

“Probably the long-term health effects we see in people who are supposed to be recovered from an acute infection are actually due to persistence of the virus in their lungs.”

The findings offer new insights into how chronic lung diseases might develop and provide clues for future treatments, the researchers said.

“Pretty much every single child gets infected with these viruses before the age of 3, and maybe 5% get serious enough disease that they could potentially develop persistent infection,” said López.

“We’re not going to be able to prevent children from getting infected in the first place. But if we understand how these viruses persist and the effects that persistence has on the lungs, we may be able to reduce the risk of serious long-term problems.”

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