Mayo Clinic researchers and collaborators report that persistent lung changes after COVID-19 in patients over 60 may be linked to specific populations of T cells. The small study of recovered patients, reported in Science Immunology, gets researchers closer to the cause of chronic respiratory disease kicked off by SARS-CoV-2 infection and suggests new potential avenues for therapy.

The team, led by longtime collaborators Jie Sun, Ph.D., a Mayo Clinic immunologist, and Robert Vassallo, M.D., a Mayo Clinic pulmonologist, recruited 10 participants two to three months after they had been hospitalized for COVID-19. They also recruited a control group of five participants who had not experienced a SARS-CoV-2 infection but were scheduled for a bronchoscopy for other reasons.

"I take care of COVID patients, but I also have a lab next to Dr. Sun," says Dr. Vassallo. "We talk all the time, and especially in the early days of the pandemic. So we were able to build off of Dr. Sun's previous work on the role of certain immune cell subsets as a cause of persistent lung injury in influenza."

Dr. Sun has previously researched memory T cells' management of inflammation in the lung after influenza infection, and he published research on a cellular "coordinator" for immune memory after the flu. Most recently, his lab has investigated the renewal of lung macrophages.

"We initially started with pure scientific animal models," says Dr. Sun. "But with COVID, we wondered if our prior work could be meaningful to COVID pneumonia."

At first the team, like all early SARS-CoV-2 researchers, had little information. But by combining their expertise of patient care and discovery science, the researchers came up with a patient need and a way to study it.

"Even early in the pandemic one thing we noticed was that some individuals who survived severe COVID were going home and not recovering," says Dr. Vassallo. "We had a sense that there are some people who are getting chronic complications that we just didn't understand at the time. "

To examine these cases, Drs. Sun and Vassallo came up with a plan. They recruited participants older than 60. None had preexisting lung conditions prior to becoming infected with SARS-CoV-2 and developing COVID-19, and none smoked cigarettes. The researchers obtained lung imaging, lung fluid samples and blood samples.

About 70% of the post-COVID-19 study participants had moderate to severe abnormalities on their lung images which, the authors write, indicates either that the tissue hadn't completely recovered after two months or the participants developed a condition called "fibrosis," where they body lays down abnormal scar tissue.

The research team tested participant lung function, examined lung fluid samples and sifted through the myriad immune system characteristics of the samples. They investigated the specific genome of immune cells and tested their findings in a mouse model. In response, they found that the immune cells most associated with the damage in lung tissue were two subsets of lung-residing T cells tasked with killing invaders, both in the category of tissue-resident CD8+ T cells.

"Our results provide the basis for the identification of the etiology of chronic lung diseases induced by acute SARS-CoV2 infection, which will open the door for the identification of targeted therapy for chronic COVID-19 syndromes," says Dr. Sun.

Next, the team plans to use aged mouse models of SARS-CoV-2 infection to identify the mechanisms underlying this finding. The goal is to identify potential therapeutic targets for chronic respiratory illness related to COVID-19.

The study is limited by the small number of participants and the single collection of bronchial fluid. Also, the findings might not apply to younger people who have recovered from COVID-19. Finally, the authors write that they have not examined this finding in the context of other respiratory illnesses to know whether this response is specific to COVID-19.

In general, this publication suggests that tissue-resident CD8+ T cells are cells of interest when it comes to preventing long-term damage from COVID-19.

In addition to Drs. Sun and Vassallo, other authors from Mayo Clinic include In Su Cheon, Ph.D.; Chaofan Li, Ph.D.; Young Min Son, Ph.D.; Haidong Dong, M.D., Ph.D.; Hu Li, Ph.D.; Rana Chakraborty, M.D., D.Phil.; Aaron J. Johnson, Ph.D.; and Brian Bartholmai, M.D. Review additional Mayo authors, as well as collaborators from La Jolla Institute for Immunology, University of California, San Diego; Fred Hutchinson Cancer Research Center; and Indiana University School of Medicine, online. Funding for this work came from Mayo Clinic's Center for Biomedical Discovery and federal grants.

See the full paper for a complete list of grants and authors, and the authors' disclosed competing interests related to these findings.

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