Long-COVID research: new study provides insights into basic mechanisms

SARS-CoV-2 spike protein: accumulation in the craniocerebral axis

The prevalence of long-COVID is difficult to ascertain. Current estimates suggest that approximately ten percent of infected individuals are affected by the late effects of corona infection. This equates to approximately 65 million people worldwide. According to the World Health Organization (WHO), the most common symptoms after corona infection are morbid fatigue, shortness of breath and breathing difficulties, problems with memory and concentration, and chronic fatigue syndrome (ME/CFS). Depression and anxiety are also commonly observed. Thus, neurology takes a major role in the long-term course.

Detailed neuropsychological examinations of long-COVID patients showed that deficits can be identified, especially in the areas of attention, linguistic memory and cognitive control. Initial follow-up studies indicate that cognitive impairments last longer than other symptoms following corona infection. In addition, the severity of the acute illness appears to be associated with an increased risk for the onset and progression of cognitive impairment.

Long Covid study: the role of spike protein in the brain

About 60 percent of all people who had COVID may still have viral spikes in their brains, said Prof. Ali Ertürk of Munich’s Ludwig Maximilian University (LMU) and director of the Helmholtz Institute for Tissue Engineering and Regenerative Medicine in Munich, Germany, in an initial commentary on his new study investigating the mechanisms of Long Covid disease.

Spike protein and changes in the brain

Prof. Ertürk’s team examined the presence and distribution of the SARS-CoV-2 spike protein in the skull-brain axis using mouse models and human postmortem tissue. The study shows the accumulation of the spike protein in the cranial medulla, meninges, and brain parenchyma, which may contribute to brain changes and explain the neurological symptoms associated with COVID-19. Injection of the spike protein alone caused cell death in the brain, highlighting a direct effect on brain tissue.

The just pre-published work reports the presence of spike protein in the skull of deceased individuals long after their COVID-19 infection, suggesting that persistence of the spike may contribute to long-term neurological symptoms. In addition, the study identifies differentially regulated signaling pathways associated with the spike protein, including neutrophil signaling and dysregulation of proteins involved in PI3K-AKT, as well as complement and coagulation pathways.

New study shows spike protein circulates in organs even 15 months after infection

The scientists:inside have now made new findings that may lead to the neurological complications, because: The components of the virus leave traces in the body. Even a long time after a survived corona infection, the outer spikes of the virus surface, the so-called spike proteins, can be detected in the organism. In particular, spike molecules accumulate in large quantities in a very sensitive region of the body, namely in the area between the skull bone, the meninges and the brain tissue – the so-called craniocerebral axis.

The research team led by Ali Ertürk discovered evidence that the outer spike protein remains in the body for at least 15 months after an acute infection or is deposited in various organs without the virus continuing to actively replicate. The scientists from Munich examined both mice and human tissue from Covid 19 sufferers for the presence of the corona spike protein. They were not only able to detect the viral spikes in various tissues, but also to investigate how they influence the molecular processes in the affected cells.

Among other things, the researchers used the “Optical Tissue Clearing” method. This modern technique makes it possible to make fixed organs and even entire organisms – in this case mice – optically transparent in order to visualize sought-after target molecules.

After the scientists:injected spike molecules labeled with luminescent dye into the bloodstream of the mice, they were found in most organs: the heart, lungs, liver, kidneys, intestines, thymus, spleen, pancreas, testes, ovaries and the animals’ brains.

Most affected: The brain and meninges

A particularly high concentration of spike protein was found in the animals’ heads, especially at the boundary between the skull bone, the protective connective tissue surrounding the brain – the meninges – and the brain itself. The researchers discovered the viral spines mainly in the tiny channels that connect the bone marrow of the skull bone with the meninges. Such niches in the bone marrow generally serve as reservoirs for immune cells. In the skull, immune cells from the bone marrow can enter the meninges through these channels.

In the skulls of men and women who were shown to have died from Covid-19, the Munich team also discovered the spike protein in all tissue samples of the skull and meninges examined. Interestingly, the viral protein also appeared where the researchers could no longer detect any signs of active viral replication. Only half of the sample materials gave a positive PCR result.

In the mice as well as in the human sample material, the presence of the spike protein apparently led to changes in cellular signaling processes: Some immune responses were activated, others were dysregulated, and coagulation processes were impaired. The spike protein alone can activate immune defenses, for example by putting a group of phagocytes called neutrophils on excessive alert.

In the brains of the experimental mice, the processes triggered by the spike protein had direct consequences: Four weeks after the scientists:in administered the spike protein to the animals via the bloodstream, they discovered signs of damaged and dead neurons in the animals’ brains.

Research continues: search for single targets for diagnostics and therapy

The scientists:inside from Munich now want to specifically search for individual significant target molecules that are important in the context of the disease process of Long-COVID. In the brain, the viral spines activate various signaling pathways that the research team hopes to investigate further in order to derive biomarkers for improved diagnosis and therapy of neurological complications in the best case scenario.