Introduction:
From the beginning of the COVID-19 outbreak, simultaneously with treatment measures, health and preventive measures such as strict quarantine, social distancing, hand washing, disinfection of various surfaces, and wearing a mask among others, as health protocols to reduce and cut off the transmission chain were on the agenda of governments and health organizations [1, 2]. SARS-CoV-2 infects target cells primarily via interaction of the receptor-binding domain of the S protein with the cellular angiotensin-converting enzyme 2 (ACE2) receptor after activation of the S protein by transmembrane serine protease 2 (TMPRSS2) [3]. The S protein is composed of two functional subunits, S1 and S2; S1 is responsible for receptor binding, whereas S2 (the C-terminal domain) is specifically responsible for viral-cellular membrane fusion [4,5]. Although SARS-CoV-2 primarily targets the respiratory tract, causing fever, dry cough, sore throat, fatigue, and dyspnoea [6], the virus also results in dysfunction of multiple organ systems outside the lung, including the kidneys, liver, brain, heart, gastrointestinal tract and other organ, as ACE2 and other candidate receptors are also expressed in these tissues [7].
In fact, the central nervous system (CNS) complications have been observed in more than 30% of individuals with COVID-19 presenting with a higher infection severity. Emerging studies have revealed the neuroinvasive potential of SARS-CoV-2, with neurological manifestations ranging from lethargy, headache, loss of smell and taste, delirium, insomnia, brain inflammation, stroke, brain haemorrhage to cognitive impairment [8].
Various studies using cultured cells, animal models, and brain tissues from patients who died of COVID-19, have independently revealed the capacity of SARS-CoV-2 to invade the CNS [9]. Supporting evidence from a postmortem study indicated the presence of viral RNA and proteins in the brains of more than half (21 of 40) of German patients who died of COVID-19 [10]. In addition, the presence of SARS-CoV-2 in the cerebrospinal fluid (CSF) of infected individuals also confirms CNS infection. Notably, by employing well-characterized human brain organoids, researchers have visualized widespread infectivity of SARS-CoV-2 and extensive death of virus-infected and nearby neuronal cells, and found that the viral infection can be abrogated by pretreatment with an ACE2 antibody or administration of CSF obtained from patients with COVID-19 [11]. Moreover, brain imaging studies have revealed the presence of multiple haemorrhagic lesions and changes in the brain structure of patients infected with SARS-CoV-2, even in milder cases [12]. Together, this evidence implies that SARS-CoV-2 has the ability to enter the CNS and cause neurological conditions.
In a recent study, diffuse neural inflammatory markers were found in >80% of COVID-19 patient brains, processes which could contribute to the observed neurological symptoms [13]. Furthermore, another pair of frequent symptoms of infection by SARS-CoV-2 are hyposmia and hypogeusia, the loss of the ability to smell and taste, respectively. Interestingly, hyposmia has been reported in early-stage Alzheimer’s disease (AD), and AD type II astrocytosis has been observed in neuropathology studies of COVID-19 patients [14].