In mouse models and human postmortem samples, SARS-CoV-2 spike protein was found in the skull marrow, meninges, and parenchyma, according to Ali Ertürk, PhD, of the Helmholtz Center Munich in Neuherberg, Germany, and co-authors.
Injecting spike protein into skull marrow niches of healthy mice triggered proteome changes and cell death in the brain parenchyma, the researchers reported in a preprint paper on bioRxiv, which has not yet been peer-reviewed.
The findings suggest that spike protein in the skull-meninges-brain axis may be a molecular mechanism or therapeutic target for neurologic long COVID, Ertürk and colleagues proposed.
"The lingering effects of SARS-CoV-2 infection and that of the persistent viral spike protein need to be decoded in detail," said co-author Saketh Kapoor, PhD, also of the Helmholtz Center Munich.
"Our paper suggests that the SARS-CoV-2 spike protein can accumulate in the brain and cause cell death, highlighting a direct effect on brain tissue," Kapoor told MedPage Today. "The dysregulated molecular maps may better explain clinical symptoms associated with neurological dysfunctions presented in long COVID."
One of the most important questions facing long COVID researchers is whether SARS-CoV-2 antigen persists after acute infection, and if it does, what role it plays in driving long COVID symptoms, noted Michael Peluso, MD, MPhil, MHS, of the University of California San Francisco (UCSF), who wasn't involved with the study.
"This preprint adds to a growing literature supporting the observation that spike protein may persist in the body in at least some individuals and provides a potential mechanistic connection between spike and neurologic symptoms," Peluso told MedPage Today.
"But we still don't know whether antigen persistence contributes directly to long COVID symptoms or whether it is a phenomenon that occurs more broadly in people who have had COVID-19, even in those without post-acute sequelae," Peluso added.
The clinical relevance of the findings is not clear, added Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, who also wasn't part of the study.
"Human data to support this are lacking," Nath told MedPage Today. "It is hard to envision that the miniscule amounts of viral products found in the brain of a few individuals can trigger this kind of pathology. To date, SARS-CoV-2 virus is not found in cerebrospinal fluid, even in the sickest of patients, except for a rare exception."
COVID's neurologic and psychiatric sequelae, including cognitive deficit or brain fog, can linger for years. Several studies have detected SARS-CoV-2 proteins in brain tissues, but most have failed to detect the actual virus in the brain.
One exception was a postmortem report of people that showed the virus persisted throughout the brain and body, albeit with little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Another was a case series that found SARS-CoV-2 viral protein or RNA in brain tissue, but it was not associated with severity of neuropathological changes. Both reports involved people who died in the early months of the COVID pandemic.
Last year, researchers led by UCSF's Edward Goetzl, MD, studied neuropathogenic mechanisms in living humans and found that nucleocapsid and spike proteins in astrocyte and neuronal exosomes correlated with neuropsychiatric manifestations in long COVID patients.
"I think the majority of scientists who have considered this might say it's very unlikely that the virus particles remain infectious at this stage, but these viral proteins hanging around in the cell can still do bad things," Goetzl observed.
In their study, Ertürk and colleagues injected spike protein intravenously in mice through the tail vein and by skull marrow micro-injection, which led to a spectrum of proteome changes and parenchymal cell death. Proteins related to neurodegeneration were dysregulated 3 and 28 days after the spike protein injection.
In humans, lingering spike protein was seen in 10 of 34 skull samples of people who had recovered from SARS-CoV-2 infection and died of non-COVID-related causes in 2021 and 2022. In humans who died of COVID, proteomics analyses of skull and meninges tissue showed dysregulation of complement and coagulation cascades and neutrophil pathways, and upregulation of pro-inflammatory proteins.
Though the spike protein appeared to act as an inflammatory stimulus leading to a immune response, the researchers acknowledged they could not distinguish between direct effects of viral factors and systemic effects of SARS-CoV-2.
They also did not know which COVID variant autopsied humans had. "It could be [the] Delta variant but we did not check for it," Kapoor said.
In addition, the findings were reported in a preprint paper and have not been certified by peer review.
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