Proteins that COVID-19 leaves behind long after the initial infection can drive up cortisol levels in the brain, inflame the nervous system and cause immune cells to hyper-react when another stressor occurs. This is the result of 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 persistent syndrome that affects up to 35% of infected individuals.
Cortisol and Long COVID
These findings come at a time when COVID is making a striking summer comeback, with the number of cases rising in 84 countries and numerous prominent athletes testing positive at the Paris Olympics. According to lead author Matthew Frank, PhD, a senior research associate in the Department of Psychology and Neuroscience at CU Boulder, the study suggests that low cortisol levels may play a key role in many of these physiological changes that occur in people with Long COVID. Previous research has shown that SARS-CoV-2 antigens, immune-stimulating proteins secreted by the virus that causes COVID-19, remain in the blood of patients with Long COVID for up to a year after infection. They have also been detected in the brains of COVID patients who have died.
To investigate how such antigens affect the brain and nervous system, the research team injected an antigen called S1 (a subunit of the “spike” protein) into the spinal fluid of rats and compared them with a control group. After seven days, the level of the cortisol-like hormone corticosterone in the hippocampus, the brain region responsible for memory, decision-making and learning, fell by 31% in the rats exposed to S1. After 9 days, levels had dropped by 37%.Frank points out that cortisol is an important anti-inflammatory, helps convert fuel into energy, is important for regulating blood pressure and sleep-wake cycles, and keeps the immune response to infections under control. A recent study has shown that people with Long COVID tend to have low cortisol levels. This also applies to people with chronic fatigue syndrome, research shows.
Cortisol has so many beneficial properties that a reduction in cortisol levels can have a number of negative consequences. In another experiment, the researchers exposed different groups of rats to an immune stressor (a weakened bacterium) and monitored their heart rate, temperature and behavior, as well as the activity of immune cells in the brain, called glial cells. They found that the group of rats previously exposed to COVID protein S1 responded much more strongly to the stressor, with more pronounced changes in eating, drinking, behavior, core body temperature and heart rate, more neuroinflammation and greater activation of glial cells. The researchers show for the first time that exposure to antigens left behind by the virus can actually alter the immune response in the brain so that it overreacts to subsequent stressors or infections.
Identifying and Minimizing Different Stressors to Cope with Symptoms
They emphasize that the study was an animal experiment and that further research is needed to determine if and how low cortisol levels could lead to long COVID symptoms in humans. However, Frank theorizes that the process could go something like this: COVID antigens lower cortisol, which serves to keep inflammatory responses to stressors in the brain under control. Once a stressor occurs – be it a bad day at work, a mild infection or a tough workout – the brain’s inflammatory response is unleashed without these limits, and serious symptoms come screaming back, which can include fatigue, depression, brain fog, insomnia and memory problems. However, he doubts that cortisol treatments alone could be an effective treatment for Long COVID, as they would not get to the root cause and would come with a range of side effects. Instead, the results suggest that identifying and minimizing various stressors could help manage symptoms. Tracking down the source of the antigens – including tissue reservoirs where viral remnants continue to hide – could also be an approach worth exploring.