Summary: Researchers have identified elevated levels of a biomarker in the blood that persist for months in protracted COVID patients who exhibit neuropsychiatric symptoms.
In a new Long COVID study published on March 13, 2022, in the Annals of NeurologyUC San Francisco researchers identified biomarkers present at elevated levels that can persist for several months in the blood of study participants who had long COVID with neuropsychiatric symptoms.
The results hold promise for the development of laboratory tests to assess long-term COVID risks and to evaluate new therapies to combat a form of COVID that has sometimes been considered a subjective syndrome that is difficult to describe and measure.
“For much of the first year of the pandemic, many people with long COVID were told that what they were experiencing wasn’t even worthwhile,” said Michael Peluso, MD, assistant professor of medicine at UCSF and first author of the study.
“Now we’re starting to identify objective biological measures that match what people tell us about their long COVID symptoms.”
Long COVID is characterized by persistent or new symptoms such as fatigue, shortness of breath, cognitive difficulties, abnormal heart rhythms, sleep disturbances, and muscle and joint pain, which may persist for months after an infection. acutely by the SARS-CoV2 virus.
Researchers estimate that between 10% and 30% of people infected with the SARS-CoV-2 virus have prolonged COVID symptoms (although this appears to be less likely in vaccinated people). As many as 23 million people in the United States may have already suffered from chronic health conditions triggered by infection, according to a recent report by the US Government Accountability Office.
The long COVID may even affect people who initially presented with only mild illness and perhaps even those who were asymptomatic despite testing positive for the infection.
Viral proteins persist in brain cells
To conduct the study, clinicians asked 46 previously infected patients about 32 long-lasting physical symptoms of COVID as well as mental health symptoms such as memory loss, irritability, restlessness, depression, anxiety, post-traumatic stress and specific sensory losses.
Additionally, researchers in the lab analyzed blood plasma samples from 12 never-infected control subjects without neuropsychiatric symptoms for comparison.
All study participants were patients of the San Francisco-based COVID-19 Long-Term Impact of Novel Coronavirus Infection Study (LIINC), and were recruited from March 2020 to February 2021 , after testing positive for the infection.
The original intent of the study was to follow patients over time to track natural immunity following COVID infection, but when it became clear that patients on return visits were continuing to experience symptoms several weeks after infection, understanding these long COVID symptoms has become a major focus of study.
The new results are based on a single time point, but patients continue to be monitored for changes in symptoms and potential immunological and other biomarkers.
Unaware of the patient’s identity and symptom status, the team then used a technique based on blood plasma samples – developed by corresponding author Edward Goetzl, MD, professor emeritus of medicine at UCSF – to measure viral and patient proteins derived from neurons.
The researchers first isolated protein-filled sacs called exosomes released into the blood by all kinds of cells, then selected only exosomes derived from neurons and supporting cells called astrocytes. Goetzl views this approach as an indirect measure reflecting the disruption that occurs in brain cells as a result of SARS-CoV-2 infection.
The analysis detected much higher average levels of two SARS-CoV-2 viral proteins they measured – nucleocapsid protein and spike protein – in blood plasma samples taken between six and 12 weeks later. diagnosis of COVID-infected patients who had neuropsychiatric symptoms compared to samples from those who had long COVID, but did not have neuropsychiatric symptoms.
Levels of these proteins from neuronal exosomes in patients with long COVID without neuropsychiatric disease were consistently higher than levels in patients without long COVID.
Goetzl said SARS-CoV-2, like several other viruses, targets structures called mitochondria in the cells it invades. The virus most likely interferes with normal mitochondrial tasks, he said, which include providing the cell with a usable form of energy and contributing to the immune system’s ability to respond to infection.
The researchers measured significant differences in the levels of several mitochondrial proteins between long COVID patients with and without neuropsychiatric symptoms, indicating alterations in mitochondrial function in neurons, according to Goetzl.
“I think the majority of scientists who have considered this would say that viral particles are very unlikely to remain infectious at this point, but these viral proteins lying around in the cell can still do bad things,” he said. Goetzl. He is optimistic about the development of small molecule drugs that can penetrate infected cells and destroy specific viral proteins.
Towards diagnosis and treatment
Many researchers attribute chronic symptoms of long COVID primarily to prolonged or impaired immune responses, Peluso said. The initial acute infection can trigger long-term maladaptive changes in the immune system.
The continued presence of viral proteins in the body could cause chronic inflammatory responses. The presence of certain viral molecules could also trigger autoimmune responses in which the immune system attacks the body’s own tissues.
“By identifying biomarkers like these, we will be able to more accurately diagnose long COVID and identify effective treatments through well-designed clinical studies,” Peluso said. “With this study, we have taken an important step towards this goal.”
About this long-running COVID and mental health research news
Original research: Free access.
“SARS‐CoV‐2 and mitochondrial proteins in exosomes derived from COVID‐19 neurons” by Michael J. Peluso et al. Annals of Neurology
SARS‐CoV‐2 and mitochondrial proteins in exosomes derived from COVID‐19 neurons
As SARS-CoV-2 is known to invade the mitochondria of neural cells, a plasma system to quantify central nervous system proteins in living humans was used to study the neuropathogenic mechanisms of long-COVID-19.
SARS-CoV-2 proteins and mitochondrial proteins (MPs) in plasma-enriched neuron-derived extracellular vesicles (NDEV) and astrocyte-derived EVs (ADEV) were quantified in resolved acute COVID-19 without post-operative sequelae. acute SARS-CoV-2 (PASC), PASC without neuropsychiatric manifestations (NP), PASC with NP and healthy controls.
Mean levels of SARS-CoV-2 S1 NDEV and ADEV and nucleocapsid (N) proteins were higher in all PASC subgroups than controls, but only N levels were higher in PASC with than without NP. Mean levels of NDEV normalized by exosome marker CD81 of respiratory chain MP complex I subunit 6 and complex III subunit 10, and neuroprotective MPs Humanine and mitochondrial open reading frame of 12S rRNA-c (MOTS-c) were all significantly decreased in PASC with NP but not in PASC without NP compared to controls. NDEV levels of voltage-gated anion-selective channel protein 1 (VDAC1) and N-methyl-D-aspartate receptor 1 (NMDAR1) were decreased in PASC without and with NP, while those of the channel mitochondrial calcium uniporter (MCU) MP calcium, sodium/calcium exchanger (NCLX), and leucine zipper EF-main containing transmembrane protein 1 (LETM1) were decreased only in PASC with NP. MCU and NCLX only ADEV levels increased in PASC with and without NP.
Abnormal NDEV and ADEV levels of SARS-CoV-2 N and S1 proteins and MP correlate with NP and may be biomarkers for long-term prognosis and therapeutic trials. ANN NEUROL 2022;91:772–781
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