**6. Entry of SARS-CoV-2 into the brain**

There are different ways that are the possible pathway for the entry of SARS-CoV-2 into the brain. Some of the ways include olfactory transmucosal invasion, hematogenous dissemination, and neuronal retrograde dissemination [5]. The olfactory sensory neurons of the olfactory mucosa are bipolar neurons. The axons of the olfactory sensory neurons along the apical side project into the nasal cavity while that on the basal side merge into filia and protrudes into the olfactory bulb through the cribriform plate. Thus, the olfactory sensory neurons are in direct contact with the cerebrospinal fluid [60]. In the olfactory mucosa, ACE2 receptors are mainly found in the non-neuronal cells, sustentacular cells while their expression in the olfactory sensory neurons is less [30]. The blood vessels lining the olfactory mucosa express both ACE2 and TMPRSS2 protease receptors which help in the invasion of the SARS-CoV-2 virus and facilitate binding, replication, and accumulation of the virus [61, 62]. Studies have found that SARS-CoV-2 enters CNS through this neural-mucosal interface by infection of the olfactory neurons or by diffusion through channels formed by olfactory ensheathing cells in the olfactory mucosa [60, 63]. Following the olfactory transmucosal invasion, the virus passes along the olfactory tract via axonal transport, trans-synaptic transport, or microfusion to different areas of the brain linked with the olfactory tract [60, 64].

Recent studies have observed that SARS-CoV-2 RNA was found in brain regions that are not directly connected to olfactory mucosa like the cerebellum which shows that other forms/routes of viral entry into the brain are at play. Neuronal retrograde dissemination is the one where the virus may breach peripheral nerve terminals and take a trans-synaptic route to reach CNS. For instance, SARS-CoV-2 may invade peripheral chemoreceptors and may reach the cardiorespiratory centre in the brain stem [65] or through the gut-brain axis where the virus may enter the brain through enteric nerves [66]. In case of hematogenous dissemination, the virus after infecting the airways may breach the epithelial barrier and enter the bloodstream. Through systemic circulation, the virus may reach the cerebral circulation and could infect endothelial cells of blood–brain barrier or epithelial cells of the blood CSF barrier to reach the brain or via circumventricular organs which lack the blood–brain barrier [5]. Trojan horse mechanism is another way by which SARS-CoV-2 could reach the brain parenchyma. It is the process in which the virus infects leucocytes which get activated and disseminate to other tissues and cross blood– brain barrier [67].

Once SARS-CoV-2 enters the brain, it enters and infects the neurons, glial cells, and endothelial cells through ACE2 and replicates which leads to cell death. It causes damage to the blood–brain barrier which will increase its permeability and cause oedema, intracerebral bleeding, and neuronal death. The infected neurons can release inflammatory mediators that can activate other immune cells like mast cells, neurons, microglia, astrocytes, endothelial cells, and pericytes [68, 69].
