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For COVID-19, immune system can be ‘a hero or a villain’

Pitt researchers seek to prevent long-lasting lung damage by predicting an overly aggressive immune response

PITTSBURGH (Sept. 30, 2020) — When a person contracts COVID-19, or any other respiratory virus, the immune system springs into action. Body aches and fever are two signs the body is trying to slow the infection and fight off the virus.

The problem is that sometimes, the body doesn’t know when to stop.

“In respiratory infection, the immune response can be the hero and the villain.” said University of Pittsburgh researcher Jason Shoemaker. “A reasonable immune response should control the infection while protecting our body, but aggressive immune responses can often lead to increased tissue damage or even death during infection.”

An overly aggressive immune response can make recovery from COVID-19 riskier and cause long-lasting damage, such as diminished lung capacity and increased tissue damage, or even death.

Why are some bodies able to fight off the virus without causing damage to healthy tissue when others cannot? Shoemaker, PhD, assistant professor of chemical engineering in the Swanson School of Engineering, and his team are determined to find out.

The team includes Pitt researchers Penelope Morel, MD, professor of immunology, and James Faeder, PhD, associate professor of computational and systems biology.

“It is clear that increased disease severity leads to permanent damage of the lung tissue, which in very extreme cases has necessitated lung transplantation,” said Morel.

Nearly six months after contracting COVID-19, Pitt undergrad Madeleine Biache said she has sustained lung damage and a cough. Read the Pittwire story.

“Even patients with relatively mild disease may take months to fully recover and may experience symptoms such as reduced lung function, chronic fatigue, clotting disorders and more,” she continued. “Thus, it is important to understand how the healing process may be dysregulated in COVID-19 patients.”

Using agent-based modeling, they are learning how the virus behaves by mapping the body’s immune response.

“Agent-based modeling is a modeling method more akin to video game design than most models in engineering,” explained Shoemaker. “It is based on choice: in this situation, based on what we know, what action would the cell be most likely to take?”

By following the virus’s path through the body, the team is creating a detailed simulation that can uncover the biomarkers and signs that may predict an overly aggressive immune response. That would allow doctors to treat those patients accordingly.

“Our modeling can help doctors determine when to use the drugs we already have on the market: We want an immune response that is strong enough to clear the virus, but we want to be able to suppress the immune system if necessary before it begins to cause damage,” explained Shoemaker. “The timing of drug intervention is one of the most difficult parts in treating disease, but engineering is great at working with that kind of precise timing.”

Shoemaker recently received a National Science Foundation CAREER Award for this work.

From mapping the virus’s actions in individual cells to understanding the effects on the lungs as a whole, each member of the team is working to piece together this puzzle, creating a comprehensive model that ideally will predict how the virus that causes COVID-19, SARS-CoV-2, infects the lungs, and the damage it leaves behind.

In addition to the Pitt team’s modelling work, the group is collaborating with an international team led by Indiana University researcher Paul Macklin, PhD, associate professor of intelligent systems engineering, to create larger-scale models that could inform pharmaceutical interventions. The initial agent-based model has been developed in close collaboration with James Glazier, PhD, professor of physics, also at Indiana University.

“Our work will enable us to identify the best means of controlling the infection by either regulating the immune system itself or by identifying new human proteins to consider for drug targeting,” said Shoemaker. “This virus is going to be with us for some time, so it’s important that we understand how to help our bodies react to it in the best possible way.”

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Contact: Maggie Pavlick