In a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania reveal the mechanism of how the persistent inflammation that occurs after infection with the SARS-CoV-2 coronavirus leads to long-term neurological symptoms. They found that patients with LONG COVID - long-term symptoms such as brain fog, fatigue, or memory loss that occur months or years after infection with SARS-CoV-2 - have decreased circulating levels of the neurotransmitter serotonin. The findings were published online Oct. 16, 2023, in the journal Cell under the title "Serotonin reduction in post-acute sequelae of viral infection."
According to the Centers for Disease Control and Prevention (CDC), nearly one in five U.S. adults who have been infected with SARS-CoV-2 will experience symptoms of growing new crowns. Most patients complain of brain fog, inability to concentrate on tasks, memory problems, generalized fatigue and headaches. The mechanisms that lead to new crown growth have not been studied in depth, nor have treatments been developed that are broadly effective in alleviating these long-term symptoms.
Dr. Maayan Levy, co-corresponding author of the paper and assistant professor at the Perelman School of Medicine at the University of Pennsylvania, said, "Many aspects of the underlying biology behind long new crowns remain unclear. As a result, we lack effective tools to diagnose and treat this disease. Our findings may not only help unravel some of the mechanisms that lead to long new crowns, but also provide us with biomarkers that can help clinicians diagnose patients and objectively measure their response to treatment."
Pathway from acute SARS-CoV-2 infection to long new crowns
These authors assessed the effects of long neoguan on blood and fecal samples from a variety of clinical studies and small animal models. They found that traces of the SARS-CoV-2 virus remained in fecal samples from a subset of patients with SARS-CoV-2 even months after acute SARS-CoV-2 infection, suggesting that components of the virus remained in the intestinal tracts of some patients long after infection. They found that this residual virus, called a virus reservoir, triggers the immune system to release proteins called interferons that fight the virus. These interferons cause inflammation, which reduces the absorption of the amino acid tryptophan in the gastrointestinal tract.
Tryptophan is the building block for several neurotransmitters, including serotonin, which is produced primarily by the gastrointestinal tract and transmits messages between nerve cells in the brain and throughout the body. It plays a key role in regulating memory, sleep, digestion, wound healing, and other functions that maintain homeostasis. Serotonin is also an important regulatory molecule in the vagus nerve, a system of neurons that mediates communication between the body and the brain.
These authors found that when uptake of tryptophan is reduced by ongoing viral inflammation, serotonin is depleted, leading to disruption of vagus nerve signaling, which in turn causes some of the symptoms associated with growing new crowns, such as memory loss.
Possible targets for long new crown therapy revealed
Possible targets for long new crown therapy revealed
Dr. Sara Cherry, co-corresponding author of the paper and Professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania, said, "Clinicians treating patients with long new crowns have always relied on patients' personal reports to determine whether their symptoms have improved. Now, our study suggests that we may be able to use a number of biomarkers to match patients to treatments or clinical trials that target the specific cause of long new crown symptoms and more effectively assess their progress."
Image from Cell, 2023, doi:10.1016/j.cell.2023.09.013.
These authors took this insight a step further to determine whether supplementation of tryptophan or serotonin for patients deficient in tryptophan or serotonin could treat symptoms of long new crowns. They demonstrated that treatment with serotonin precursors or selective serotonin reuptake inhibitor (SSRI) restored serotonin levels and reversed memory deficits in a small animal model.
Dr. Benjamin Abramoff, co-corresponding author of the paper and Assistant Professor of Clinical Physical Medicine at the Perelman School of Medicine at the University of Pennsylvania, said, "There has been some evidence to suggest that SSRIs may be effective in preventing the growth of new crowns, and our study provides an opportunity for future research to select specific patients with serotonin depletion for clinical trials and to be be able to measure response to treatment."
Additionally, revealing how viral infections affect the uptake of tryptophan provides additional opportunities to further study other processes affected by tryptophan. While this new study focused on serotonin, tryptophan is the building block for many other important metabolites, such as niacin (which helps the body convert food into energy) and melatonin (a hormone that regulates circadian rhythms and sleep).
Dr. Christoph Thaiss, co-corresponding author of the paper and assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania, said, "Growing a new crown varies from person to person, and we don't yet fully understand what causes the differences in symptoms. Our study provides a unique opportunity for further research to determine how many patients with long new crowns are affected by the pathways that link viral persistence, serotonin deficiency, and vagal dysfunction, and to discover additional targets for treating patients' varying symptoms."
