Study explores link between long COVID, cortisol and transient stress response | CU Boulder Today

A protein left behind by COVID-19 long after the initial infection can plummet cortisol levels in the brain, cause inflammation in the nervous system and prime immune cells to overreact when another stressor arises, according to a new animal study by scientists at the University of Colorado Boulder.

The study, published in the journal Brain, Behavior and Immunity, sheds new light on what may underlie the neurological symptoms of long COVID, a difficult-to-treat syndrome that affects 35% of people infected with the virus.

The findings come as COVID is experiencing a surprising late-summer resurgence. Cases increase in 84 countries.

“Our study suggests that low cortisol may play an important role in driving many of these physiological changes that people are experiencing with long COVID,” said lead author Department of Psychology and Neuroscience At CU Boulder.

Previous studies have found that SARS-CoV-2 antigens, immune-stimulating proteins released by the virus that causes COVID-19, persist in the blood of long COVID patients for up to a year after infection, and have also been detected in the brains of deceased COVID patients.

Role of COVID spike protein subunits

To explore how such antigens affect the brain and nervous system, the team injected an antigen called S1 (a subunit of the “spike” protein) into the spinal fluid of rats and compared it with a control group.

After seven days, rats exposed to S1 had a 31% plummet in levels of the cortisol-like hormone corticosterone in their hippocampus, a region of the brain associated with memory, decision-making and learning. After nine days, levels had fallen by 37%.

“Nine days is a long time in a mouse's lifespan,” Frank said, noting that the average mouse lifespan is two to three years.

He noted that cortisol is an important anti-inflammatory, helps convert fuel into energy, regulates blood pressure and sleep-wake cycles, and is important in suppressing the immune response to infection. Recent studies have found that people with long COVID-19 tend to have lower cortisol levels, as do those with chronic fatigue syndrome.

“Cortisol has many beneficial properties, so a reduction in it can have a variety of negative effects,” Frank says.

In another experiment, the researchers exposed different groups of rats to an immune stressor (a weakened bacteria) and monitored the rats' heart rate, body temperature, behavior, and activity of glial cells (immune cells) in the brain.

The research team found that the group of rats previously exposed to the COVID protein S1 responded much more strongly to the stressor, showing significant changes in eating, drinking, behavior, core body temperature and heart rate, as well as increased neuroinflammation and stronger glial cell activation.

“We show for the first time that exposure to antigens left behind by this virus actually alters the immune response in the brain, potentially causing an overreaction to subsequent stress or infection,” Frank said.

Continuing Long-Term COVID Research

He stressed that this study was in animals and that more research is needed to determine whether and how lower cortisol levels lead to longer-lasting COVID-19 symptoms in humans.

He theorizes that the process might work like this: COVID antigens lower cortisol, a hormone in the brain that helps suppress the inflammatory response to stressors. When a stressor occurs — a bad day at work, a minor infection, or strenuous exercise — the brain's inflammatory response is unleashed unchecked, and severe symptoms return.

These can include fatigue, depression, brain confusion, insomnia, memory problems, and more.

Frank said he doubts cortisol treatment alone will be effective in treating long-term COVID-19 because it doesn't address the underlying cause and comes with many side effects.

Instead, research suggests that identifying and minimizing various stressors may help manage symptoms.

Eradicating sources of antigens, including tissue reservoirs where tiny pieces of virus continue to hide, may also be an approach worth exploring.

The research was funded by the nonprofit PolyBio Research Foundation.

“There are a lot of people who suffer from this debilitating syndrome, and this study brings us one step closer to understanding what's going on neurobiologically and what role cortisol plays,” Frank said.