The coronavirus disease (COVID-19) pandemic, triggered by SARS-CoV-2, has impacted our respiratory, gastrointestinal systems and nervous systems. People infected with the virus can exhibit various types of cognitive impairment, such as brain fog, anxiety, loss of taste, psychosis, anosmia, strokes, and seizures, depending upon the severity of the infection. There have been reports of recurring neuropsychological impairments following recovery from moderate COVID-19. The long-term effects of this virus, such as premature brain ageing, dementia, neuropathy, among others, will be revealed soon.
Where are the gateways in brain for coronavirus?
This SARS-CoV-2 virus enters human cells through Angiotensin-converting enzyme 2 (ACE2) receptors found on the cell membranes of various organs, including the kidney, heart, and alimentary canal (Figure 1). However, the presence of these entry points or ACE2 receptors in the brain is negligible, leading to our question – how can the virus harm the brain and impact its normal function?As a result, it is unclear whether this novel coronavirus penetrates the nervous system after attaching with ACE2 or whether apparent cognitive impairments result from SARS-CoV-2 infection of peripheral tissues. Our investigation and literature review attempts to identify the elements causing SARS-CoV2-induced cognitive deficits in patients.
Credit Source: The Conversation
Note: SARS-CoV-2 gains entry into the host cell after interacting with the ACE2 receptors present on the cell membrane of the host cell
A tight link between blood capillaries and neuronal cells, known as the blood-brain barrier (BBB), protects the brain from foreign chemicals, free radicals, and infectious particles (bacteria, viruses, etc.) circulating in the blood. Following SARS-CoV-2 infection, the BBB appears to be weakened and leaky. Most probably, the infection starts from the olfactory mucosa in the nasal cavity and gustatory epithelial cells, moving upwards to the cribriform plate and olfactory bulb via synapse signalling (Fig. 2).
So what exactly happens in the brain after virus infection?
This virus hijacks the immunological protectors which are present in the blood and forces them to produce an excessive cytokine. Cytokines are proteins that regulate the development and function of other immune systems and blood cells in a healthy individual. Moreover, SARS-COV-2 assaults the pericytes (cells present on the lining of blood capillaries) and reduces the blood flow towards the brain, leading to the deficiency of oxygen flow to the most energy-demanding of the body, i.e., the brain.
Credit Source: Wikipedia
Note: Location of nasal cavity, cribriform plate, olfactory bulb and other regions, present near to the brain.
These factors, i.e., the overreaction of the immune system (neuroinflammation) and impaired blood flow to the brain (cerebral ischemia), causes the virus to affect the brain tête-à-tête due to the nearby blood circulation, a process known as primary encephalitis. In comparison, contamination can arise in any organ, which results in a persistent impact on the central nervous system via peripheral nerves during secondary encephalitis.
Severity of COVID-19 and associated changes in the brain
Both of these factors also determine the seriousness of COVID-19 infection on brain functions, which neuroscientists can categorise as rare (stage I), mild (stage II), and severe (stage III). Rare infection is restricted to nasal and gustatory epithelium cells, with a little cytokine storm and patients suffering only smell or taste impairment. Blood clots inside the brain represent the mild stage due to a robust immune response and elevated cytokine levels. Patients may experience stroke-like symptoms, resulting in severe damage to cranial nerves, peripheral nerves, and muscles. In the severe case, high cytokine levels breach the BBB, allowing inflammatory agents, viruses etc., to penetrate the brain, resulting in brain swelling, brain injury, intracranial haemorrhage, seizure-like situation or neurodegeneration-associated peptide build-up.
Virus hijacks mitochondria and makes the brain deprived of energy
Recent studies by neuroscientists show the involvement of mitochondria in the novel coronavirus-induced brain dysfunctions. ACE2 is widely known for its ability to modulate the functioning of the mitochondria (the cell’s powerhouse). ACE2 binding with the viral spike proteins can alter energy uptake and bioenergetics in COVID-19 patients. At the molecular level, there is the interaction of mitochondrial proteins and mitochondrial DNA with SARS-CoV-2-viral proteins. This interaction also can affect mitochondria-associated control of immune cells in the brain.
Long-term energy deficiencies will undoubtedly result in brain dysfunctions and cognitive impairments. SARS-CoV-2 alters the mitochondrial metabolic route, causing a decrease in energy levels while enhancing the glycolysis pathway in COVID-19 patients’ peripheral blood mononuclear cells. Many neurodegenerative illnesses, including Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD), are characterised by mitochondrial dysfunction. Despite these preliminary studies, neuroscientists and medical doctors have to wait a little longer to know the exact molecular mechanisms of this virus-induced brain damage and to design suitable therapeutic strategies for COVID-19-infected persons.
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Journal reference
Maurya, S. K., Baghel, M. S., Gaurav, Chaudhary, V., Kaushik, A., & Gautam, A. (2022). Putative role of mitochondria in SARS-COV-2 mediated brain dysfunctions: A Prospect. Biotechnology and Genetic Engineering Reviews, 1–26. https://doi.org/10.1080/02648725.2022.2108998
