**4. Relationship and effects of COVID-19 on neurological systems**

In the past, viruses such as arbovirus, measles virus, enterovirus, herpes simplex virus (HSV), Varicella-Zoster virus (VZV), Cytomegalovirus (CMV), Epstein -Barr virus (EBV), and Human JC virus (JCV) have been reported to invade the nervous systems of hosts with severe neurological effects [41]. Now, SARS CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19 has joined that list with recently reported neurological manifestations of the disease. The mode of entry of these viruses including SARS CoV-2 has been thoroughly studied and classified into the several major routes: endocytosis (direct fusion with neurons), sensory nerve endings, synapses, and axons, circulating leukocytes, lymph nodes, the blood–brain barrier (BBB), the Central Nervous System (CNS) and the Peripheral Nervous System (PNS) [42].

#### **4.1 SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2)**

ACE2 has a high affinity for SARS-CoV-2 (**Figures 1** and **2**). SARS-CoV-2 interacts with ACE2 receptors to invade the cells in the body [45, 46] by receiving the spike (peplomer) glycoprotein of the virus. mRNA expression profile of ACE2 shows that the enzyme is organ-specific but expressed in almost every tissue in the body [46, 47]. ACE2 receptor is usually found in the pulmonary type II alveolar cells and respiratory epithelial at high levels because COVID-19 is primarily a respiratory disease [48, 49]. ACE2 is also found in other body tissues and cells such as myocardial and endothelial cells [50], kidney, stomach, colon, and ileum cells [51], oral mucosa cells [52], astrocytes, neuron and glial cells of the brain and spinal cord tissues (**Figure 1**) [14].

The ACE2 gene is located on chromosome Xp22.22 and contains 18 exons and 20 introns [53]. It produces an 805 amino acid, type I transmembrane glycoprotein which contains a 17-amino-acid N-terminal signal peptide and a 22-amino acid C-terminal membrane hydrophobic transmembrane region anchoring it in the cell membrane [46]. It also has a HEXXH zinc-binding metalloprotease motif, a C-terminal collecting domain, and an insulin-like domain [53]. ACE2 gene expression is also found in other respiratory disorders such as SARS, Middle East respiratory syndrome (MERS), and H1N1 influenza [54].

#### **4.2 Relationship of COVID-19 with neurological systems**

SARS-CoV-2 directly attacks neural cells and infects cerebrovascular endothelium and brain parenchyma (medial temporal lobe) causing early apoptosis and necrosis

*COVID-19 Pandemic, Mental Health and Neuroscience - New Scenarios for Understanding…*

#### **Figure 1.**

*Distribution of ACE 2 in the human body. (image adapted from [43]).*

(**Figure 3**) [4, 44, 48]. This attack occurs through a series of mechanisms such as proteolysis, viral fusion with membrane, and entry mediated by ACE2 and transmembrane serine protease 2 (TMPRSS2) in some parts of the brain, CNS, PNS, and cerebrospinal fluid described through animal studies [see 55–58 for more details]. *Neurological Effects of COVID-19 and Its Treatment/Management DOI: http://dx.doi.org/10.5772/intechopen.105730*

**Figure 2.** *SARS-CoV life cycle (image adapted from [44]).*

**Figure 3.**

*Neurotropism of SARS-CoV-2. SARS-CoV-2 (image and description text and Servier medical art, https://smart. servier.com).*
