As described in chapter 2.5 in my current book on neurodegeneration, corona viruses infect cells in our brain. If neurons in the brainstem that produce dopamine or other biogenic amines are affected, symptoms similar to those of Parkinson's disease may occur. An increased incidence of neurological syndromes had already been observed during the Spanish flu more than 100 years ago. However, it is still unclear whether viruses that induce avian flu or SARS-Cov2 infections become persistent in our brains. Alternatively, long-lasting symptoms may be explained by chronic inflammation.
In the course of the global Corona pandemic, 5-10% of those infected will suffer from post-covid symptoms. These may impose as a chronic fatigue syndrome associated with aching limbs and decreased exercise tolerance. Moreover, mood swings, impaired concentration and memory, or dizziness may occur. In principle, neurological symptoms are to be expected as concomitants of any infection. However, in addition to headache and muscle pain or pronounced fatigue, olfactory and gustatory disturbances were frequently induced by early SARS-Cov2 variants. In histopathological examinations, clear inflammatory changes involving the brain's own immune cells, the microglia, were detected in addition to infected neurons. Furthermore, changes in the small blood vessels resulting in vascular damage and circulatory disorders were demonstrated by neuropathologists.
How does the virus actually enter our cells ? With the large, fungus-like spike protein contained in the viral envelope, it binds to special receptor molecules in the membrane of target cells. The spike protein is then cleaved and its hydrophobic (water-repellent) portion is drawn into neurons, glial and endothelial cells of the brain.
The genetic material (RNA) of the SARS Cov2 virus contains the information for all viral proteins, in particular for the structure-giving spike, envelope, membrane and the nucleocapsid protein, which binds to the ribonucleic acid. After infection and uptake of the virus into the cytoplasm, host cell ribosomes take over the production of these appr. 30 viral proteins. New virus particles are then assembled in the Golgi apparatus and discharged to infect further cells (Fig. 2.19 from Klimaschewski L.P. Aging and neurodegenerative diseases - why are nerve cells lost? In: Parkinson and Alzheimer today. Springer, 2021).
Following a SARS-Cov2 infection our immune system plays a key role in the disease process. Infected cells first transmit a molecular message that they have been infected by a virus. This general, non-specific response is mediated by interferons. Subsequently, cytotoxic T cells (CD8 positive) and helper T cells (CD4 positive) are activated. The latter in turn stimulate B lymphocytes, which then form antibodies against viral proteins. This suppresses the uptake of viruses into target cells.
Some interferons and other cytokines are released in such numbers as part of the inflammatory response to the virus that an exuberant immune reaction occurs, a so-called cytokine storm. This also explains why cortisone treatment leads to improvements in some patients, although such therapy is not normally appropriate for viral infections. Long term covid symptomatology may be related to 'exhausted' T cells, which show a reduced cellular metabolism after infection (similar to the precursors of macrophages in the body, the monocytes).
Interestingly, some patients suffering from Covid19 repeatedly tested positive for the virus even though they were in strict quarantine. In a study published last year in a respected journal (Proceedings of the National Academy of Science), a group led by Rudolf Jaenisch at MIT (Massachusetts Institute of Technology, USA) showed that the RNA of the SARS Cov2 virus can be transcribed into DNA (deoxyribonucleic acid), and thus becomes part of our basic genetic makeup. In cell cultures, but also in lung or brain tissue from infected patients, parts of the viral genetic RNA material have been found in the DNA.
This requires an endogenous reverse transcriptase (RT), which was not actually thought to be present in neurons, but can be, as we now know. However, the study mentioned above also clearly stated that not all of the RNA of the SARS-Cov2 virus is transcribed. Thus, no complete virus particles can be newly formed, which then infect neighboring cells. Nevertheless, it is possible that long after a person has been infected, viral proteins are still being produced that can trigger an immune response and possibly lead to a long-covid syndrome.
To what extent may all these changes in Covid19 patients lead to neuronal degeneration in the long term ? Interestingly, people at increased risk for Alzheimer's disease (ApoE4 carriers) are more likely to be infected than others, and in one-third of patients with dementia, Covid disease accelerates the loss of cognitive abilities. Similarly, neurologic symptoms worsen in Parkinson's disease patients who become infected with SARS-Cov-2. They complain of increased tremors, muscle stiffness, fatigue, depression and pain as the infection progresses.
The future will show whether the SARS virus can directly infect the substantia nigra and thus induce Parkinson's syndromes. So far, there are only single case reports pointing in this direction. However, longer-term neurological complications in the sense of a long-covid disease are to be expected in many covid19 patients, probably also in children and adolescents. The number of chronically ill patients has now become so large that the German Neurological Society has issued its own treatment guidelines.
References:
Pröbstel A-K, Schirmer L (2021) SARS-CoV-2-specific neuropathology: fact or fiction? Trends in Neurosciences 44:933-935
Zhang L, Richards A, Barrasa MI, Hughes SH, Young RA, Jaenisch R (2021) Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues. Proceedings of the National Academy of Sciences 118:e2105968118
Image credit: iStock/Andrey Zhuravlev, iStock/Jian Fan
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