key: cord-0785810-jkwq15td
authors: Mahalaxmi, Iyer; Kaavya, Jayaramayya; Mohana Devi, Subramaniam; Balachandar, Vellingiri
title: COVID‐19 and olfactory dysfunction: A possible associative approach towards neurodegenerative diseases
date: 2020-07-22
journal: J Cell Physiol
DOI: 10.1002/jcp.29937
sha: e638eb076ec0939ab762ae07ca370aafccc0af73
doc_id: 785810
cord_uid: jkwq15td

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the agent of novel coronavirus 2019 (COVID‐19), has kept the globe in disquiets due to its severe life‐threatening conditions. The most common symptoms of COVID‐19 are fever, sore throat, and shortness of breath. According to the anecdotal reports from the health care workers, it has been suggested that the virus could reach the brain and can cause anosmia, hyposmia, hypogeusia, and hypopsia. Once the SARS‐CoV‐2 has entered the central nervous system (CNS), it can either exit in an inactive form in the tissues or may lead to neuroinflammation. Here, we aim to discuss the chronic infection of the olfactory bulb region of the brain by SARS‐CoV‐2 and how this could affect the nearby residing neurons in the host. We further review the probable cellular mechanism and activation of the microglia 1 phenotype possibly leading to various neurodegenerative disorders. In conclusion, SARS‐CoV‐2 might probably infect the olfactory bulb neuron enervating the nasal epithelium accessing the CNS and might cause neurodegenerative diseases in the future.

The novel pandemic coronavirus 2019 has expanded at an unprecedented rate around the globe where the researchers are striving to find a cure for this pandemic. This shattering viral infection has infected around 10.5 million people with a death toll of over five hundred thousand as of July, 2020. At this time, it is imperative to understand the possible connections between COVID-19 and other detrimental illnesses . The is highly prevalent in human and has the prospect to reach the brain without evident clinical symptoms. The central nervous system (CNS), a prodigy of convoluted cellular and molecular interactions, maintains life and orchestrates homoeostasis. Unfortunately, if there is any acute, tenacious or dormant form of viral infection inside the CNS, its immune system does not react subsequently, which results in neurological disorders. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has created chaos due to its possible ability of neuronal invasion, which might have a long-term effect on the affected patients in their future. Also, the study highlights that the mechanism or route of transmissions of the neuroinvasive property of SARS-CoV-2 remains scarce (Koralnik & Tyler, 2020; Li, Bai, & Hashikawa, 2020) . Such type of neuroinvasive propensity of coronaviruses has been documented in most of its beta-coronavirus form, including SARS-CoV, MERS-CoV, Abbreviations: AD, Alzheimer's disease; CNS, central nervous system; M1, microglia 1; PD, Parkinson's disease; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF-α, tumour necrosis factor-α. HCoV-229E, and SARS-CoV-2 (Vellingiri et al., 2020) . A study has indicated that, through this viral neuroinvasion, the SARS-CoV-N protein can invade various other organs such as the stomach, small intestine, kidney, sweat glands, parathyroid, pituitary gland and liver, resulting into multiorgan failure in human beings (Ding et al., 2004) .

While dealing with the aftermath of this pandemic, it is important to carefully consider the potential effects of SARS-CoV-2 and its diagnostics and treatment options in human body .

The blood-brain and blood-cerebrospinal fluid barrier play a decisive role in maintaining homeostasis as well as protecting the brain from free passages of pathogens like viruses (human coronavirus), where the entry often occurs via peripheral nerves especially the olfactory sensory neurons (Dahm et al., 2016; McGavern & Kang, 2011) . Recently, it was observed that loss of smell (hyposmia) was manifested among the COVID-19 patients who were admitted in the hospitals (Ling et al., 2020) . We propose a hypothetical mechanism for the entry of SARS-CoV-2 inside the CNS via olfactory bulb, where viral lesions have the possibility to trigger the microglia 1 (M1) phenotype which in response could activate the proinflammatory cytokines. This may result in the secretion of cytokines which may induce demyelination in the nervous system. Our hypothetical mechanism was also supported by Das, Mukherjee, and Ghosh (2020) where the authors have observed that SARS-CoV-2 might exhibit an intrinsic capability to infect the neural cells and could spread from CNS to the periphery via transneuronal routes.

Also Xydakis et al. (2020) and Gómez-Iglesias et al. (2020) have stated that the virus has neuroinvasive potential and has the possibility to enter the brain through the olfactory bulb. Similar various recent studies related to COVID-19 and neurological manifestations have been reported in Table 1 (2020) 13. Special editorial

The author have stated that ACE2 is also found in the endothelial cells of brain which could increase the possibility of stroke due to SARS-CoV-2 infection and also encephalitis as a potential complication.

Stroke, encephalitis Nath (2020) 14.

Case report United States of America 

bound ACE-2 receptors which are expressed not only in nasal and oral mucosa but also in the nervous system (Dinkin et al., 2020; Li et al., 2020; Marinosci et al., 2020) . In addition, the ACE2 receptors present in endothelial cells of the brain could be a possible reason for SARS-CoV-2 infection induced stroke as well as encephalitis (Nath, 2020 F I G U R E 1 Mechanism of action for COVID-19 neuroinvasion. Figure 1 depicts the hypothetical mechanism of entry of SARS-CoV-2 inside the CNS via olfactory bulb along with the mechanism involved in olfactory bulb dysfunction. This image is evident that both the pathways of mechanism are similar where the M1 phenotype of microglia gets activated which may further stimulate the pro-inflammatory cytokines that have the possibility of resulting in neuroinflammation. COVID-19, coronavirus 2019; CNS, central nervous system; M1, microglia 1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 MAHALAXMI ET AL.

| 5 that COVID-19 patients presenting with smell-related symptoms should be provided with appropriate precautions as they might have an impact on neurological conditions as well as immunosuppression.

De Santis (2020) has reported that SARS-CoV-2 could enter the CNS via olfactory bulb which might trigger cytokine storm, causing dysfunction in the brainstem and further leading to neuronal death.

This mechanism of SARS-CoV-2 inside CNS raises questions on the possible common link between COVID-19 and smell dysfunctions that might play a possible role in causing various neurodegenerative disorders. Reports have suggested that smell or olfactory dysfunction is a sensitive indicator for various neurodegenerative diseases such as Parkinson's diseases (PD), alzheimer's diseases (AD), and dementia (Ponsen et al., 2004; Richard, 2013; Velayudhan & Lovestone, 2009 ).

The major player in smell dysfunction is the basal forebrain cholinergic system which regulates various neurotransmitters in the brain.

The cholinergic neurons project into the olfactory bulb and modulate various neurological activities which stimulate immune response when a foreign agent invades the CNS. When there is a damage or defect in the cholinergic neurons, this might result into the activation of M1 phenotype and excite inflammatory mediators including IL-6, IL-12p40, IL-15, and tumour necrosis factor-α (TNF-α) at a high level which has the possibility of neuroinflammation and cell death (Doursout et al., 2013; Richard, 2013; Wang, Zhou, Brand, & Huang, 2009 ). This detailed hypothetical mechanism has been depicted in Figure 1 .

When this M1 phenotypes are activated, it might produce the proinflammatory cytokines or enhance phagocytosis or apoptosis which might contribute to the development of various neurodegenerative disorders (Seo, Kim, & Kang, 2018) . After the entry of SARS-CoV-2 into the olfactory bulb, it possibly results in viral replication forming the ORF3a, ORF8b, E and other viral proteins. These proteins may also activate the (nuclear factor kappa-light-chainenhancer of activated B cells) NF-Kb pathway followed by other proinflammatory cytokines such as TNF-α, interleukin -1b (IL-1b), and interleukin-6 (IL-6; Figure 2 ). This will bring to light the prominent proteins such as α-synuclein and amyloid fibres which could get aggregated in neurodegenerative disorders. This inflammatory environment in the brain could also trigger oxidative stress mediators such as reactive oxygen species and nitrogen species, finally resulting in loss of dopamine (DA) neurons or the aggregation of amyloid fibrils forms, soluble proteins which assemble to form insoluble fibres that are resistant to degradation, which is the major pathogenesis of PD and AD (Hassanzadeh & Rahimmi, 2019; Kaavya et al., 2020; Rambaran & Serpell, 2008; Venugopal, Mahalaxmi, Venkatesh, & Balachandar, 2019 enter the brain possibly via the olfactory bulb, following its spread to some specific brain parts such as thalamus and brainstem . In a recent study, it was observed that the postmortem reports of COVID-19 revealed that the virus was present in the neural and capillary endothelial cells in frontal lobe tissue (Paniz-Mondolfi et al., 2020) . Interestingly, the olfactory dysfunctions were also found in patients without other symptoms,

indicating that these abnormalities can be beneficial in early identification of disease (Lechien et al., 2020) . Considering the high similarity between SARS-CoV and SARS-CoV-2, the patients affected with COVID-19 or recovered patients have probable chances to infect various organs including lungs, heart, kidney, brain and gastrointestinal tracts (Baig, Khaleeq, Ali, & Syeda, 2020) . Hence, this review suggests that through olfactory bulb the SARS-CoV-2 might infect the brain which was also evaluated by Matthew (2020) and Ling et al. (2020) 

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The authors declare that there are no conflict of interests.

http://orcid.org/0000-0002-8378-6197Vellingiri Balachandar http://orcid.org/0000-0002-3043-6839