INTRODUCTION
The past two decades have seen the emergence of highly pathogenic human coronavirus infections on a global scale, believed to be a result of zoonotic routes.[ 1 ] Compared to its recent predecessors, the SARS-CoV in 2002 and the Middle East respiratory syndrome coronavirus (MERS CoV) in 2012, the novel SARS-CoV2 has a lower fatality rate, however, it has more diverse pathophysiological implications with myriad manifestations.[ 2 ] One particularly concerning aspect of the SARS-CoV2 infection is higher mortality rates amongst the geriatric population.[ 3 ] One proposed hypothesis of such an eventuality is the occurrence of dysautonomia and dysfunction of brainstem cardiovagal centers in association with SARS-CoV2 infection.[ 4 ] The route of neurotropism of the virus, to reach the brainstem and central autonomic network is a matter of debate and introspection. Owing to the overwhelmingly high rates of olfactory and gustatory dysfunction in mild-to-moderate coronavirus disease 2019 (COVID-19) infections,[ 5 ] the olfactory route had been presumed to be the prime portal of entry. However, recent studies have provided evidence that angiotensin-converting enzyme 2 (ACE2), the principal binding target of SARS-CoV2 , is expressed on the non-neural olfactory elements such as sustentacular cells rather than the centrally projecting olfactory sensory afferents.[ 6 , 7 ] Furthermore, anosmia might further be the mere consequence of local mucosal inflammation leading to nasal congestion, a feature of all upper respiratory tract infections.[ 8 ]
These observations have led researchers to consider alternate pathways for penetration of the virus into the brain, most notably through perturbations in the gut-brain axis. Dorsal brainstem structures such as the dorsal motor nucleus of the vagus, and the nucleus of tractus solitarius (NTS) richly express ACE-2.[ 4 ] Apart from the CNS, the enteric nervous system (ENS) also expresses ACE-2 in ample amounts.[ 9 ] Gastrointestinal manifestations are a known component of the SARS-COV2 infective spectrum, and the role of the gut microbiome is deemed vital in its pathogenesis.[ 8 , 10 ] The intrinsic gut flora exerts anti-inflammatory effects and maintains the intestinal epithelial barrier, thereby keeping pathogens at bay.[ 8 ] Colonization by the SARS-CoV2 in the ENS, as evidenced by the detection of the viral RNA in fecal samples of infected patients, causes alteration in the composition of gut flora as well as downregulation of ENS ACE-2.[ 11 ] Thus, the vagus nerve , which innervates neurons of the ENS, might act as a messenger in transmitting abnormal gastrointestinal signals, brought about by the SARS-CoV2 infection, to the brain, i.e., a defective gut-brain axis.
In this review, we discuss the neurotropic potential of SARS-Cov2 through cranial nerve pathways with a particular focus on the enteric route and the vagus. We also explore possible pathways of transmission of abnormal molecular signals from the olfactory, respiratory, and enteric milieu to the central nervous system, the role of SARS-CoV2 in accelerating perturbations in cellular homeostasis and protein misfolding, and ultimately, the prospect of these interactions causing neurodegeneration . In this context, we look back on Parkinson’s disease pathophysiology, the role of the perturbed gut-brain axis, and environmental influences on nigrostriatal degeneration. Finally, we propose the role of multiple triggers or “hits” for initiating and perpetuating this neurodegenerative cascade, such as COVID19 induced systemic inflammation, hypoxic injury, mitochondrial and endoplasmic reticulum dysfunction, oxidative stress, and protein misfolding.
MATERIALS AND METHODS
The authors independently conducted searches of articles using the keywords, “Gut-brain axis”, “SARS-CoV2 ”, “COVID19”, “olfactory nerve ”, “vagus nerve ”, and “Parkinson’s disease pathogenesis”, through GOOGLE SCHOLAR and PUBMED between 1970 till 2021. Only English language articles in peer-reviewed journals were considered. Articles were selected by screening abstracts and keywords, and included as per strict eligibility criteria:
Inclusion criteria
Articles pertaining to pathogenesis of the Parkinson’s disease , with emphasis on the gut-brain axis and protein misfolding
Articles focusing on neurotropism of the SARS-CoV2 virus, with emphasis on the vagus, and olfactory nerves a portal of entry
Individual case reports on the development of parkinsonian features following SARS-CoV2 infection
Exclusion criteria
Case reports on post-SARS-CoV2 infection parkinsonism with associated use of anti-psychotic drugs or medication that could possibly cause extra-pyramidal symptoms were excluded
Non-English articles were not considered
Re-visiting the pathophysiology of Parkinson’s disease : The gut-brain axis, olfactory bulb, and environmental influences
Traditional concepts regarding PD were built upon the cardinal motor symptoms of rigidity, bradykinesia, and rest tremor, and hence revolved around nigro-striatal degeneration and loss of dopaminergic nerve terminals.[ 12 ] However, recent research has focused on the non-motor symptoms of PD and their genesis, which have led many to believe that these may be forerunners of the cardinal motor symptoms. Amongst these, anosmia/hyposmia and constipation, along with Rapid eye movement (REM) sleep behavioral disorders (RBD) might be the most important.[ 13 ] In recent years, the concept that PD pathogenesis might be heralded by perturbations of the gut-brain axis with the retrograde spread of gut pathology into the brain via the vagus, together with the contribution from the olfactory nerves, has received much attention and has been backed by histopathological evidence.[ 14 , 15 ]
The Braak staging describes a predictable pattern of progression of alpha-synuclein deposition in the brain, thereby delineating six distinct stages.[ 15 ] Initially, the pathology starts with the involvement of the dorsal motor nucleus of the vagus (DMNV) and olfactory bulb (Stage 1), followed by the affection of pontine tegmentum and medulla oblongata (Stage 2), amygdala and substantia nigra (Stages 4,5), ultimately progressing to involve the temporal mesocortex (Stage 5) and finally the neocortex (Stage 6).[ 14 ] Although this pathological staging bears correlation with the clinical progression of PD, with most patients experiencing gastrointestinal and autonomic symptoms prior to motor symptoms, it has been challenged subsequently by autopsy studies.[ 16 , 17 ] Nevertheless, the pathological staging system cannot be discounted in entirety, since any such staging system may be prone to deviations if subjected to scrutiny. The presence of Lewy bodies in the peripheral nervous system (PNS) of the gut and olfactory bulb is now established in PD patients.[ 18 , 19 ] The question as to how these Lewy body deposits ultimately migrate to the CNS remains to be answered. Studies have hypothesized cell-to-cell trans-synaptic spread of alpha-synuclein molecules with subsequent cauda-rostral spread into the substantia nigra.[ 20–22 ] What drives the protein misfolding and subsequently perpetuates the neurodegenerative process is a matter of debate; whether a stochastic protein misfolding is the index event or there is the participation of more predictable processes which lead to alpha-synuclein aggregation and propagation within the CNS, is largely obscure.[ 14 ] It is believed that alpha-synuclein aggregates exhibit neurotoxic effects through mitochondrial dysfunction, inflammation, and free radical-mediated cytotoxicity.[ 23 , 24 ]
The vagus as a route for SARS-CoV2 neurotropism into the brainstem: Lessons learned from cardio-respiratory failure and gastrointestinal symptoms
One of the more intriguing aspects of COVID-19 infection is the apparent lack of correlation between the degree of arterial hypoxemia and respiratory effort.[ 25 ] Recently, Tobin et al .[ 26 ] has objectively demonstrated the concept of “silent hypoxemia” [Figure 1 ]. It is now established, that the fundamental molecule which allows for the binding of the SARS-CoV2 pathogen to the host is the angiotensinogen-converting enzyme 2 (ACE2).[ 27 ] ACE2 is omnipresent throughout the human body, in sites that include the lung, intestine, kidney, testis, and brain.[ 28 ] One crucial consequence of SARS-CoV2 binding is the apparent downregulation of ACE2 in tissues resulting in a failure to degrade angiotensin II into its vasodilatory, anti-inflammatory metabolite angiotensin (1-7).[ 29 ] The chief site in higher primates for major respiratory and cardiovascular homeostatic responses is the vagal nucleus complex in the brainstem, comprising of the nucleus tractus solitaries (NTS), the dorsal motor nucleus of the vagus (DMNV), and the area postrema, with all three subunits richly expressing ACE2.[ 30–32 ] Naturally, perturbations of these angiotensin metabolic pathways in the vagal centers have been postulated to be a cause of dysautonomia and reduced baroreceptor sensitivity.[ 33 ] The route of spread of SARS-CoV2 from the periphery up to the brainstem autonomic centers is believed to take place via the vagal sensory afferents, juxtaposed on lung alveoli, with trans-synaptic transmission paving the way for viral neurotropism.[ 27 , 34 ] Recently, Jacob F et al. ,[ 35 ] have demonstrated in vitro neurotropism of SARS-CoV2 and its propensity to cause apoptotic cell degeneration, compelling the possibility of a virus-induced neurodegeneration of the brainstem autonomic integrative centers in the course of COVID-19 infection. ACE2 has been found to be richly expressed in the intestinal epithelium. The presence of GI symptoms along with the involvement of the respiratory tract in patients with SARS-CoV2 infection, as well as detection of viral genome in stool samples is strongly speculative of viral neurotropism via the GI tract and dysfunction of the so-called “gut-brain axis”.[ 36–38 ] Binding of intestinal ACE2 with SARS-CoV2 may initiate a local inflammatory cascade by promoting intestinal dysbiosis. Damage to the local mucosal barrier might cause the inflammatory milieu to spill over into the blood, contributing to a “cytokine storm”.[ 39 ] The vagus, which forms extensive afferent synaptic connections with the enteric nervous system (ENS), might play a thus undefined, yet fundamental role in transmitting this perturbed intestinal information to the brainstem vagal centers, namely NTS, which is conveyed to the brain.[ 8 ] Apart from direct invasion of the vagus, another plausible route of affection might be swallowing saliva and mucous, enabling the SARS-CoV2 virion to cross the stomach epithelial barrier and invade the vagal terminals [Figure 2 ].[ 40 ] Knowledge about the possible role of vagal nerve pathways in initiating and perpetuating pro-inflammatory responses has kindled optimism regarding the mitigation of such pathways in COVID19 infected individuals via vagal nerve stimulation techniques.[ 41 ]
Figure 1: Pathophysiology of silent hypoxia. Systemic inflammatory response and cytokine storm in the setting of severe SARS-CoV-2 infection causes upregulation of ACE2 receptors in various areas critical for respiratory control and feedback. Viral neurotropism via respiratory and gastrointestinal routes converge on the upregulated receptors and dampens the response to hypoxic stimulus
The olfactory route and SARS-CoV2 neurotropism
Olfactory derangements such as hyposmia/anosmia are one of the most common occurrences of SARS-CoV2 infection in humans; however, the etiology of such is still obscure. Immunohistochemical studies have revealed that two receptors, ACE2 and TMPRSS2, both crucial for SARS-CoV2 infection in hosts, are richly expressed in olfactory and respiratory epithelium.[ 7 , 42 ] Contrary to the ostensible assumption that anosmia was a result of the direct viral invasion of the olfactory sensory neurons (OSN) and the olfactory bulb (OB), its pathophysiological underpinnings are now believed to be due to perturbations of the olfactory supporting cells.[ 43 ] Infection of these support cells, local inflammatory milieu, and hypoperfusion are postulated to precipitate altered downstream signaling in odor perception neuronal pathways in OSN and OB.[ 44–46 ] Although not harboring ACE2 receptors per se, invasion of SARS-CoV2 into the OSN and OB neurons is the plausible consequence owing to loss of tropic support and disruption of local cell barriers and immune alterations. Studies in mice as well as autopsy studies from infected individuals have demonstrated presence of the SARS-CoV2 particles in brain regions such as piriform and limbic cortex, ventral pallidum, and dorsal raphe, which have established connections with OB neurons.[ 47 , 48 ] Previously, Hawkes CH et al. ,[ 40 ] had suggested an anterograde propagation of a then unknown viral pathogen via the olfactory route to temporal lobe structures, namely the olfactory tubercle, piriform cortex, and amygdala. Present knowledge of the possible viral invasion of peripheral neurons[ 46 ] through trans-synaptic spread has paved the way for future biomolecular research to elucidate exact pathways of olfactory spread of SARS-CoV2 virion into the central nervous system and hopefully, open new therapeutic avenues.
Involvement of other cranial nerves: The possible “third” pathway
Owing to the proximity of the SARS-CoV2 particles to the olfactory supporting cells and the tight junctions of the pseudostratified columnar olfactory epithelial cells, which in turn are innervated by the anterior ethmoidal branch of the ophthalmic division of trigeminal nerve (CN V), it might be sumptuous to presume an alternate pathway of spread to the medullary respiratory control nuclei. The trigeminal nerve is particularly interesting as it may facilitate the direct extension of the viral particles to caudal brainstem regions lying in propinquity to the respiratory nuclei [Figure 2 ]. Prior studies have demonstrated the rapid transport of intranasally applied radiolabeled macromolecules via the perivascular pathway of the trigeminal nerve to the vicinity of the caudal brainstem. Based on this concept, a putative glossopharyngeal (CN IX) pathway from the nasopharynx might also be proposed as a mode of direct spread to the brainstem respiratory centers.[ 49 , 50 ]
Figure 2: Proposed routes of neurotropism of SARS-CoV-2. The yellow arrow indicates direct anterograde spread via the olfactory nerve to the temporal lobe and limbic cortex. The red arrow indicates a caudo-rostral propagation to the brainstem via the vagus nerve in the gastrointestinal tract (after an olfactory to gastrointestinal spread by swallowing of secretions). The blue arrow indicates spread via the vagus nerve to the brainstem after a direct involvement of the gastrointestinal tract. The dashed green arrow is a putative pathway of spread to the brainstem via the trigeminal nerve
COVID-19 and Parkinsonism: At a crossroad
The origins of the idea of an infective etiology behind Parkinson’s disease stems from the observation of parkinsonian features in patients with influenza virus infection who developed encephalitis lethargica.[ 51 ] Although numerous genomic associations have recently been identified as risk factors for PD, owing to the sporadic pattern of disease prevalence, additional factors are believed to have a major role as well.[ 52 ] Observations by Von Economo regarding the delayed development of parkinsonian symptoms in survivors of an influenza illness, albeit a century old, still intrigues researchers worldwide.[ 53 ] Subsequent studies have supported such a relationship through the demonstration of serological and neuropathological evidence.[ 54 ] To date, only a handful of cases of post-COVID parkinsonism have been reported in the literature[ 55–63 ] [Table 1 ]. The cases described in the literature exhibited an overall male preponderance with a mean age of onset of parkinsonian symptoms of 57 years (range 35-74 years). Functional imaging of the brain was done in 6 of the 12 cases, demonstrating an asymmetrically reduced dopaminergic uptake in basal ganglia in two,[ 55 , 56 ] unilateral reduction in uptake in two patients,[ 57 , 58 ] and bilateral decreased uptake in two patients.[ 63 ] None of the patients had a family history of parkinsonism nor any history of exposure to culprit drugs or toxins. Only one patient had a prior prodromal history of prolonged constipation, which is one of the cardinals non-motor features of parkinsonism.[ 58 ] Two cases was reported by Cavallieri F et al .[ 63 ] were found to have underlying genetic mutations predisposing them to parkinsonism. These observations might be speculative of the unmasking of an underlying parkinsonian phenotype by COVID-19 infection. A positive response to levodopa/carbidopa in all the patients is indicative of dopaminergic dysfunction. However, there were no abnormalities in cerebrospinal fluid (CSF) in any of the patients nor the detection of SARS-CoV2 antigen or antibody in CSF, thereby failing to establish a concrete causative link.
Table 1: Comparison of reported cases of post COVID-19 Parkinsonism
Several of the patients in question had a history of severe COVID-19 infection requiring intensive care support, with high pro-inflammatory blood markers and the presence of encephalopathy at some point in the disease course. The authors also observed that a substantial proportion of reported cases had developed Parkinsonian features within days or weeks of a severe COVID-19,[ 55–60 ] with or without the presence of encephalopathy. These observations raise the possibility of a hypoxic brain injury to basal ganglia in the context of severe systemic inflammation and disruption of blood-brain barrier [Figure 3 ].[ 64–66 ] Endothelial damage is a well-recognized facet of COVID-19.[ 67 ] Brundin and co-workers[ 68 ] have suggested SARS-CoV2 invasion of endothelial cells and in conjunction with coagulopathy, induce injury to the frontal-subcortical connections of the brain thereby leading to extrapyramidal dysfunction. However, a post-infective process resulting in structural and/or functional brain damage would be expected to cause perturbations of cerebellar, pyramidal, and/or cortical pathways apart from the extrapyramidal tracts, leading to the development of myoclonus, spasticity, or cognitive dysfunction. The absence of viral RNA in the CSF of any of the patients makes the possibility of direct structural damage less likely, with an infection triggered immune-mediated mechanism seeming more plausible, although, to date, no antibodies have been recovered from survivors of post-COVID19 encephalopathy/parkinsonism.
Figure 3: Multiple possible mechanisms involved in the pathogenesis of post-COVID-19 Parkinsonism
COVID-19 and neurodegeneration : A multi-hit multi-step process
The olfactory (respiratory) and gastrointestinal routes of neurotropism of SARS-CoV2 is reminiscent of the dual-hit hypothesis of Parkinson’s disease pathogenesis.[ 40 ] It raises the possibility of the development of Parkinson’s disease as a long-term outcome of COVID-19. However, the mere presence of the SARS-CoV2 viral pathogen in the olfactory bulbs or vagus nerve terminals of affected individuals, might not be sufficient to act as a Trojan horse for the viral-activated lymphocytes to enter the central nervous system and disturb normal cellular homeostatic mechanisms. According to Sulzer,[ 69 ] a viral infection might be one trigger of a series of many such, which render the CNS susceptible to a neurodegenerative process by disturbing intrinsic cellular homeostatic mechanisms. Although researchers have provided robust evidence regarding increased susceptibility to developing PD in cohorts with a bona fide history of past infection, such studies mostly rely on epidemiological evidence to derive their inference.[ 70 , 71 ] Nevertheless, researchers have postulated numerous hypotheses regarding possible mechanisms of post-infectious parkinsonism.[ 64 ] Regarding SARS-CoV2 , in addition to neurotropism, perturbations of the normal cellular homeostatic mechanisms induced by the inflammatory milieu associated with the infection may lead to abnormal aggregation and propagation of alpha-synuclein. Akin to this hypothesis, a recent review has elucidated the possibility of alpha-synuclein induction by viral infection and inflammation.[ 72 ]
Considering the evidence gathered from the reports of post-COVID-19 parkinsonism, additional mechanisms, such as immune-mediated, hypoxic, and endothelial dysfunction, might contribute to promoting this neurodegeneration leading to Parkinson’s disease [Figure 3 ]. Moreover, COVID-19 survivors with a genetic predisposition to Parkinson’s disease would be at a higher risk of manifesting parkinsonian symptoms once these pathways get activated. Thus, the authors propose the possibility of a multi-hit multi-step process in the development of Parkinson’s disease after COVID-19 infection, which includes neurotropism and inflammation, augmented by other potential mechanisms, culminating in neurodegeneration [Figure 4 ].
Figure 4: Proposed multistep process in the pathogenesis of SARS-CoV-2 related neurodegeneration leading to Parkinson disease
SARS-Cov2 induced protein misfolding: The final piece of the puzzle?The neurological spectrum of SARS-Cov2 has been postulated to be the culmination of myriad processes such as endothelial dysfunction, coagulopathy, immune dysregulation, and cytokine storm.[ 73 ] Previously, Sinha et al. , 2021[ 74 ] had suggested a possible complex interaction between the SARS-Cov2 virion and alpha-synuclein, designating the latter as the route of neurotropism from olfactory and vagus terminals up to the basal forebrain and brainstem cardiorespiratory centers, respectively. Recently, there has been an emergence of strong evidence implicating SARS-Cov2 virion particles as a potential trigger for protein misfolding and aggregation, leading to neurodegeneration . Idrees V et al. ,[ 75 ] and Tavassoly et al. ,[ 76 ] have demonstrated the capacity of SARS-Cov2 spike protein to bind with amyloidogenic heparin binding proteins such as alpha-synuclein, tau, and Aß, thereby catalyzing their aggregation and making them resistant to autophagy and degradation. These aggregates, in turn, disrupt cellular protein homeostasis, and mitochondrial and endoplasmic reticulum function, and ultimately cause cell death via oxidative stress and apoptosis. Thus, the ability of SARS-Cov2 spike protein to bind and aggregate toxic amyloid proteins in the CNS milieu underscores its ability to induce neurodegeneration .
CONCLUSION
The gastrointestinal, respiratory, and olfactory involvement in COVID-19 implicates these pathways as possible routes of entry into the CNS. Although it is possibly the most important factor, the neurotropism of SARS-CoV2 might not be sufficient to actuate neurodegeneration . For the latter to occur, an inflammatory cascade is likely essential, which perturbs normal cellular homeostatic mechanisms and prevents degradation of aggregated alpha-synuclein particles induced by SARS-Cov2 neurotropism. The contemporaneous occurrence of both these events, albeit stochastic, appears to be a prerequisite for the initiation and propagation of alpha-synuclein in the brain. Moreover, other conceivable mechanisms such as immune-mediated, hypoxic, and endothelial dysfunction, are also possible contributors to this process. Genetic factors may play a role as well. Thus, the authors propose a possible multi-hit multi-step process after COVID-19 infection, triggering Parkinson’s disease . However, to gather further evidence, robust data in the form of well-designed, coordinated, prospective studies evaluating the long-term outcome of COVID-19 survivors is warranted.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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