Summary: Researchers have found elevated levels of a blood biomarker that can persist for months in people with long COVID who experience neuropsychiatric symptoms.
Source: UCSF
In a study published March 13, 2022, in the Annals of Neurology, researchers at UC San Francisco reported that certain biomarkers remain elevated for many months in the blood of people with long COVID who have neuropsychiatric symptoms.
These findings could help create laboratory tests to assess long COVID risk and to measure responses to new treatments for a condition that has often been described as hard to define and quantify.
“During much of the early pandemic, many people with long COVID were told their symptoms weren’t real,” said Michael Peluso, MD, assistant professor of medicine at UCSF and the study’s first author. “Now we are beginning to identify objective biological measures that match what patients report about their long COVID symptoms.”
Long COVID describes a range of symptoms—fatigue, shortness of breath, cognitive difficulties, irregular heart rhythms, sleep disturbances, muscle and joint pain—that can persist for months after an initial SARS-CoV-2 infection.
Researchers estimate that between 10% and 30% of people infected with SARS-CoV-2 develop long COVID symptoms, although vaccination appears to reduce that risk. A recent U.S. Government Accountability Office report estimated that up to 23 million people in the United States may be affected by chronic health problems triggered by COVID-19.
Long COVID can occur even in individuals whose acute illness was mild or who were asymptomatic during their initial infection.
Viral proteins detected in neural-derived exosomes
For this study, clinicians surveyed 46 previously infected participants about 32 physical symptoms and a range of mental health and neuropsychiatric complaints, including memory loss, irritability, agitation, depression, anxiety, post-traumatic stress, and sensory changes. The team also analyzed plasma from 12 control subjects who had never been infected and who did not report neuropsychiatric symptoms.
All participants were enrolled in UCSF’s Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort between March 2020 and February 2021 after testing positive for SARS-CoV-2. While the original goal of LIINC was to follow natural immunity over time, persistent symptoms reported by returning participants shifted part of the study’s focus to long COVID.
The results reported here are from a single study time point; participants continue to be monitored for changes in symptoms, immune responses, and other potential biomarkers.
Blinded to clinical details, laboratory investigators used a plasma-based technique developed by corresponding author Edward Goetzl, MD, professor emeritus of medicine at UCSF, to measure viral proteins and neuronal proteins. They isolated extracellular vesicles, or exosomes, from plasma, then enriched for vesicles originating specifically from neurons and astrocytes. These neural-derived exosomes act as a window into cellular processes occurring in the brain after SARS-CoV-2 infection.
The analysis showed significantly higher average levels of two SARS-CoV-2 proteins—the nucleocapsid (N) protein and the spike S1 protein—in neural-derived exosomes from people with long COVID who had neuropsychiatric symptoms, when sampled six to 12 weeks after diagnosis, compared with those with long COVID who did not report neuropsychiatric problems. Even participants with long COVID but without neuropsychiatric symptoms had higher exosome levels of these viral proteins than uninfected controls.
Goetzl noted that SARS-CoV-2, like some other viruses, targets mitochondria within infected cells. The virus may disrupt mitochondrial functions, which are essential for cellular energy production and for proper immune responses.
The team found meaningful differences in several mitochondrial proteins between long COVID patients with neuropsychiatric symptoms and those without, suggesting altered mitochondrial function in neurons in affected individuals. While it is unlikely that residual viral particles remain infectious, Goetzl said, viral proteins lingering inside cells could still cause harm. He expressed optimism about developing small-molecule therapies capable of entering cells and targeting persistent viral proteins.
Implications for diagnosis and treatment
Many investigators believe persistent symptoms in long COVID arise from prolonged or dysregulated immune responses triggered by the initial infection. Persistent viral proteins could maintain chronic inflammation or provoke autoimmune reactions in which the immune system attacks the body’s own tissues.
“Identifying biomarkers like these will help clinicians more accurately diagnose long COVID and enable rigorous clinical trials to find effective treatments,” Peluso said. “This study represents an important step toward that goal.”
About this long-COVID and mental health research news
Author: Jeffrey Norris
Source: UCSF
Contact: Jeffrey Norris – UCSF
Image: The image is in the public domain
Original Research: Open access. “SARS‐CoV‐2 and Mitochondrial Proteins in Neural‐Derived Exosomes of COVID‐19” by Michael J. Peluso et al., Annals of Neurology
Abstract
SARS‐CoV‐2 and Mitochondrial Proteins in Neural‐Derived Exosomes of COVID‐19
Objective
Because SARS-CoV-2 can affect mitochondria within neural cells, the study used a plasma-based system to quantify central nervous system proteins in living people, aiming to explore neuropathogenic mechanisms that could underlie long COVID.
Methods
The investigators measured SARS-CoV-2 proteins and mitochondrial proteins in enriched plasma neuron-derived extracellular vesicles (NDEVs) and astrocyte-derived EVs (ADEVs). They compared samples from individuals with resolved acute COVID-19 without post-acute sequelae, people with post-acute sequelae of SARS-CoV-2 (PASC) without neuropsychiatric manifestations, PASC with neuropsychiatric manifestations, and healthy controls.
Results
Mean levels of SARS-CoV-2 S1 and nucleocapsid proteins in NDEVs and ADEVs were higher in all PASC subgroups than in controls; nucleocapsid levels were higher in PASC with neuropsychiatric manifestations than in PASC without. When normalized to the exosome marker CD81, NDEV levels of certain mitochondrial respiratory chain subunits and neuroprotective peptides (including Humanin and MOTS‑c) were significantly decreased in PASC with neuropsychiatric symptoms but not in PASC without neuropsychiatric symptoms, relative to controls. Other mitochondrial proteins and ion channel regulators showed patterns of decrease in both PASC groups or selectively in the PASC with neuropsychiatric symptoms group. ADEV levels of some mitochondrial calcium regulators were increased in both PASC groups.
Interpretation
Abnormal levels of SARS-CoV-2 N and S1 proteins and of mitochondrial proteins in neural-derived and astrocyte-derived exosomes correlate with neuropsychiatric manifestations and may serve as biomarkers for long COVID prognosis and therapeutic trials. ANN NEUROL 2022;91:772–781