**1. Introduction**

The last two decades have seen epidemic outbreaks by novel viruses including SARS, MERS, and influenza which shared certain commonalities such as a likely zoonotic origin, high mortality rates, and less available therapeutic methods to counteract them. The COVID-19 pandemic shows no signs of slowing down with affecting 223 countries, with 224,811,910 cases, and 4,633,797 death tolls till date [1]. With what history on earlier pandemics has made us understand and with the rapidly mutating nature of the SARS-CoV-2 virus, it is not unreasonable to say that the pandemic is here to stay, and the world must learn to co-exist with it. The first reported case of COVID-19 was found in Wuhan, China in December 2019. By March 2020, the disease had spread across the globe and had become a public health emergency. The WHO declared a pandemic state to the disease spread on March 11, 2020 [2]. With more than a year since the declaration of the pandemic, the scientific community has yet not developed a definitive anti-viral drug to combat the disease

spread. Even though the advent of vaccination has set the pace in favour of global health, we have a long way to go to eradicate if at all suppress the disease spread.

SARS-CoV-2 is highly virulent and highly contagious with the R0 value of 3.77 [3]. Though it predominantly affects the respiratory system, other organ systems like the gastrointestinal system, heart, kidney, and central nervous system are also targeted by the virus. Fever, chills, cough, shortness of breath or breathing difficulty, sore throat, nasal congestion, diarrhoea, nausea, vomiting, generalised body aches are some of the common symptoms noted in patients infected with COVID-19 [4].

Neurological manifestations of COVID-19 include non-specific symptoms like headache, dizziness, fatigue, and myopathy and more specific symptoms like anosmia, ageusia, impaired consciousness, stroke, meningitis, acute transverse myelitis, and Guillian-Barre syndrome [5, 6]. More than one third of the individuals with COVID-19 were found to present with neurological symptoms [7, 8]. The presence of viral RNA in cerebrospinal fluid and the brain was observed in COVID-19 patients [9]. Preliminary *in vitro* studies have found that SARS-CoV-2 can replicate in neuronal cells [10]. A post-mortem study has found that 48% of the studied cases had human CoV RNA in the CNS that was detectable [11]. SARS-CoV-2 is found to exhibit organotropism for the nervous system and SARS-CoV and MERS-CoV which are closely related to SARS-CoV-2 have neuro-invasive potential. Hence, apart from the secondary impact on the brain as a result of systemic complications like coagulopathy and hypoxia, the direct effect of SARS-CoV-2 infection on the brain and spinal cord is plausible and is being thoroughly studied by researchers globally. The neuropsychiatric symptoms in COVID-19 could be attributed to a variety of factors apart from the direct effect of the virus on the brain like psychological distress due to social isolation, the novelty of the disease spread and pandemic, concerns about family and friends contracting the disease, social stigma, etc. [12]. This chapter will, however, focus on the direct effects of the SARS-CoV-2 virus on the brain which could be attributed to the pathophysiology of neuropsychiatric symptoms with a special focus on ACE2 and monoaminergic neurotransmitters.

### **2. SARS-CoV-2**

Coronaviruses are the largest among RNA viruses. They have a crown-like spikes on their surface and hence the name. SARS-CoV-2 is the latest/seventh coronavirus to become pathogenic to humans. It belongs to the Coronaviridae family which includes four genera; α−, β−, γ−, and δ-CoV. Out of these human pathogens include HCoV- 229E, HCoV- NL63 [α − CoV] and OC43, and HKU1 [β − CoV] that in most cases cause mild self-limiting respiratory disease. γ − and δ-CoV strains mainly affect avian species [13]. SARS-CoV and MERS-CoV, causatives of SARS and MERS, are beta coronaviruses that caused up to 9.6% and 34.3% mortality rates which were responsible for earlier pandemics that resulted in a death toll of 812 and 866, respectively [14]. SARS-CoV-2 is more similar to SARS-CoV and MERS-CoV while being far more pathogenic and transmissible than the earlier known coronaviruses.

SARS-CoV-2 is a beta coronavirus that is positive-sense single-stranded RNA virus with 29–30 kb in size. It has four structural proteins and 16 non-structural proteins. Nucleocapsid protein [N], membrane protein [M], spike protein [S], and envelope protein [E] are the four structural proteins (**Figure 1**). The capsid of the genome is formed by N protein and the genome is further surrounded by an envelope that is made up of M, E, and S proteins. Like other coronaviruses, SARS-CoV-2 has enveloped with a crown-like spikes on its surface. It is the spike protein that is responsible for the variations in host specificity and tissue tropism of the different coronavirus. Spike protein is a type-I membrane glycoprotein and has two functional *Does COVID-19 Affect Adult Neurogenesis? A Neurochemical Perspective DOI: http://dx.doi.org/10.5772/intechopen.101179*

#### **Figure 1.**

*(a) Structure of ACE2 and SARS-CoV-2; (b) Interaction of spike protein and ACE2; (c) Shedding of ACE2 and entry of SARS-CoV-2 into the cell.*

subunits S1 and S2 with different functional domains in the amino and carboxy terminal. S1 subunit contains the receptor-binding domain [RBD] and binds with the receptor in the host cells. S2 subunit fuses the membranes of the host cells and the virus. The entry of the virus into the host cell involves binding of the S protein [S1 subunit] to a specific cell receptor followed by priming of the S protein by proteases in the host cell. This leads to the fusion of the spike protein to the cell membrane which is mediated by the S2 subunit [15]. The specific cell receptor through which SARS-CoV-2 enters the host cell is the ACE2 receptor and the protease in the host cell that processes the spike protein to reveal the fusion peptide between S1 and S2 subunits facilitating its entry, is a TMPRSS2 serine protease, member of the hepsin/ TMPRSS subfamily [16]. Another protein named furin or paired basic amino acid cleaving enzyme [PACE], a member of the subtilisin-like proprotein convertase family, mediates proteolytic cut of the S protein at S1-S2 boundary, is required for TMPRSS2 processing of S protein. Both TMPRSS2 and furin are essential for the entry of SARS-CoV-2 into the cell. The furin cleavage site in the S protein of SARS-CoV-2 is not found in SARS-CoV and other beta coronaviruses [17].
