Charnoly body (CB) is a pleomorphic, electron-dense, multilamellar, preapoptotic, mitochondrial biomarker of cell injury. Nutritional stress and environmental toxins can induce CB formation in highly vulnerable neurons because of compromised mitochondrial bioenergetics. Inhibition of charnolophagy (i.e autophagy of charnoly body) may lead to progressive neurodegenerative diseases accompanied by neuronal inclusions [13].

In general, viral infections can impair charnolophagy, a basic molecular mechanism of intra-cellular detoxification (ICD). Viruses can alter the pluripotency of neural progenitor cells in the brain and induce charnolosome (CS) destabilization which can cause inflammasome (particularly NRLP-3) activation. This whole process induces hypercytokinemia and charnoptosis (CB apoptosis) implicated in pyroptosis, apoptosis, and necrosis of sensitive hippocampal and other CNS neurons by releasing Panx-1, Viroporine, and gasdermins to cause Charnoly Body Molecular Pathogenesis (CBMP) implicated in the overall viral lytic cycle. It has been hypothesized that SARS-CoV-2 acts by same mechanism, causing compromise in neural immunity, mitochondrial bio-energetics and charnolophagy (a process of intracellular detoxification in the CNS) as a result, causing neural injury and death via charnolosome destabilization [14].

The binding of SARS-CoV-2 to angiotensin converting enzyme 2 (ACE2) is said to be a critical step in the pathophysiology of neurological manifestations in patients with COVID-19 [15]. ACE2 has a wide distribution in the chemical sense organs, the lungs, kidneys, liver, blood vessels, immune system, and the brain. When SARS-Cov2 binds ACE2 in respiratory and vascular epithelial cells it triggers the formation of a cytokine storm, with marked elevation in levels of interleukin-1, interleukin-6, and tumor necrosis factor. High levels of these cytokines increase vascular permeability, edema, hypercoagulation and widespread inflammation with resultant multiple organ damage. Combined hyperactivation of inflammatory markers, vascular injury, and coagulation factors contributes to acute respiratory distress syndrome (ARDS); multiple organ failure as well as multiple neurological disorders [11].

A recent report revealed that ACE2 binds to the SARS-CoV-2 ectodomain with an affinity of about 15 nM which translates to 10 to 20 fold higher affinity compared to SARS-CoV-1. This higher affinity of SARS-CoV-2 to human ACE2 may contribute to the rapid human to human spread [16]. To potentiate this, ACE2 can undergo an ADAM17 (a disintegrin and metalloproteinase 17)-mediated “shedding” from endothelial cells, resulting in the release of the ectodomain with a catalytic and bioactive power into the circulation [17].

A genetic study using infected ACE2 knockout mice verse wild-type mice revealed that there were significantly lower quantity of the virus in the lungs of the knockout mice when compared to control wild-type mice with SARS-CoV-1. Similarly, pathologic alterations in lungs were reduced in ACE2 mutant mice compared to wild-type mice, thus proving the genetic plausibility of ACE2 as indeed a crucial in vivo SARS receptor required for effective replication of the virus [18].

Accumulating evidences now reveal that a sub-group of COVID-19 patients have what is now described as a cytokine storm syndrome, resulting in blood brain barrier breakdown and features of acute necrotizing haemorrhagic encephalopathy. Imaging studies reveal multifocal infarcts and micro-hemorrhages in the brainstem, cerebrum, cerebellum and thalamus as well as nerve root enhancement [19] [10]. Magnetic resonance imaging (MRI) revealed varying levels of leptomeningeal space enhancement, bilateral fronto-temporal hypoperfusion, focal hyperintensity plus overlapping decreased apparent diffusion co-efficient. Electroencephalogram (EEG) findings also showed slowing of cortical activity which is consistent with encephalopathy [9].

There has been heightened speculation that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may also increase the risk of SARS-CoV-2 infection similar to SARS-CoV-1 outbreak in 2003. Also evidence exists to show that SARS-CoV-2 binds to ACE2 to gain entry to host cells on the respiratory tract epithelium. This explanation can be predicated on the fact that some animal studies have demonstrated increased ACE2 expression with ACE inhibitor or ARB administration, advancing a potential mechanistic link between SARS-CoV-2 infection, and these medications [20].

However, this has not been consistently demonstrated in human and animal studies. Paradoxically, mechanisms proposing that ACEIs and ARBs may be protective in SARS-CoV-2 infection are rapidly evolving. Animal studies have found that ACEIs and ARBs may promote and stabilize cell membrane complexes. In theory, these complexes may reduce the ability of the virus to enter host cells. Suppression of angiotensin II may also prevent virus-mediated acute lung injury and other organ dysfunction, which is another proposed mechanism by which use of ACEIs and ARBs may be beneficial in COVID-19 [21].

A study involving 2263 COVID-19 positive hypertensive patients showed a nearly 40% lower risk of hospitalization with the use of ACE inhibitors and ARBs. This finding gives some empirical evidence as to the potential benefits of ACE inhibitors in reducing the risk of severe illness especially among older individuals [22].

It is a known fact that a number of viruses (especially the zoonotic ones) are highly virulent and neurotropic. Viruses like the Japanese encephalitis virus, West Nile virus, Zika virus, Nipah virus, Rabies virus, Herpes simplex virus and Human immunodeficiency virus are able to penetrate the highly selective blood brain barrier of humans [23]. There is a possibility that the SARS-CoV-2 could penetrate the CNS from the periphery through neural pathways to cause neurological disease like encephalitis [24] [25]. The furin-like cleavage site on the spike protein of SARS-CoV-2 could be the facilitator of its neural invasion potential as seen in similar viruses like the MERS virus and SARS-CoV-1 [26]. The primary pulmonary explanation given for the respiratory failure in COVID-19 sufferers is recently being challenged as SARS-CoV-2 has been found to infiltrate the brainstem (the cardiopulmonary centres) of some patients [27].

Binding of SARS-CoV-2 to the pulmonary epithelium is known to generate a global systemic inflammatory response (SIRS) with production of IL-6, IL-12, IL-15, TNF-α and activated glial cells. This results in a massive pro-inflammatory state, severe hypoxia and resultant cerebral vasodilatation, decompensation, oedema and ischaemia within the CNS [24]. COVID-19 encephalopathy has been linked to patients with severe disease who have comorbidities and eventually develop multi-organ system damage, hypoxaemia and elevated markers of systemic inflammation [12].