SARS-CoV-2 Infectivity and Neurological Targets in the Brain

Abstract

The gateway for invasion by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into human host cells is via the angiotensin-converting enzyme 2 (ACE2) transmembrane receptor expressed in multiple immune and nonimmune cell types. SARS-CoV-2, that causes coronavirus disease 2019 (COVID-19; CoV-19) has the unusual capacity to attack many different types of human host cells simultaneously via novel clathrin-and caveolae-independent endocytic pathways, becoming injurious to diverse cells, tissues and organ systems and exploiting any immune weakness in the host. The elicitation of this multipronged attack explains in part the severity and extensive variety of signs and symptoms observed in CoV-19 patients. To further our understanding of the mechanism and pathways of SARS-CoV-2 infection and susceptibility of specific cell-and tissue-types and organ systems to SARS-CoV-2 attack in this communication we analyzed ACE2 expression in 85 human tissues including 21 different brain regions, 7 fetal tissues and 8 controls. Besides strong ACE2 expression in respiratory, digestive, renal-excretory and reproductive cells, high ACE2 expression was also found in the amygdala, cerebral cortex and brainstem. The highest ACE2 expression level was found in the pons and medulla oblongata in the human brainstem, containing the medullary respiratory centers of the brain, and may in part explain the susceptibility of many CoV-19 patients to severe respiratory distress.

Cognitive impact of COVID-19: looking beyond the short term

“…ACE-2 is expressed in stem cell-derived neurons [121] and in neuronal and glial cells within the brain [33,42], potentially enabling virus entry and spread through the cribriform plate by retrograde axonal transport along olfactory nerves [33], or from sensory fibres that pass from the lungs to the brain stem via the vagal nerve and nodose ganglion [4]. ACE-2 is also expressed in the temporal lobe and hippocampus-brain regions that are involved in cognition and memory and are affected in AD [122]. Neuronal uptake and spread within the brain were demonstrated in human ACE-2 transgenic mice infected with SARS-CoV-1 [123] and SARS-CoV-2 [124].…”

Multiple Neuroinvasive Pathways in COVID-19

“…However, since SARS-CoV-2 has a higher ACE2 binding affinity than SARS-COV, it may have a higher potential for attacking the brain directly [8]. It should be noted, however, that the level of ACE2 expression in the brain is lower than in other organs, and additional receptors may play a role in SARS-CoV-2 invasion of the brain [25]. CD147 (also known as basigin) has been implicated as another receptor to which the SAR-CoV-2 spike protein is capable of binding, thus serving as an additional route of brain infection [26].…”

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders

“…Gene expression analysis of human post-mortem brain samples by DNA arrays-A guanidine isothiocyanate-and silica gel-based membrane total RNA purification system and miRNA isolation kit (PureLink™ Invitrogen, Carlsbad, CA) were used to isolate total RNA for DNA array-based analysis; total RNA concentrations were quantified using RNA 6000 Nano LabChips and a 2100 Bioanalyzer (Caliper Technologies, Mountainview, CA; Agilent Technologies, Palo Alto, CA). Ch25h, Lcn2, Saa3, S100a and β-actin cytoskeletal RNA abundances were analyzed and quantified using GeneCHip arrays (LC Sciences, Houston TX, USA) or Northern dot blot arrays as previously described [92][93][94][95][96]. Altered RNA levels of interest were further verified using a quantitative Northern dot blot focusing assay that utilizes a T4 PNK kinase radiolabel system employing [α-32P]-dATP (6000 Ci/m mol; Invitrogen, Carlsbad, CA) that significantly interrogates the abundance of RNA and miRNA signals [94,96].…”

“…Ch25h, Lcn2, Saa3, S100a and β-actin cytoskeletal RNA abundances were analyzed and quantified using GeneCHip arrays (LC Sciences, Houston TX, USA) or Northern dot blot arrays as previously described [92][93][94][95][96]. Altered RNA levels of interest were further verified using a quantitative Northern dot blot focusing assay that utilizes a T4 PNK kinase radiolabel system employing [α-32P]-dATP (6000 Ci/m mol; Invitrogen, Carlsbad, CA) that significantly interrogates the abundance of RNA and miRNA signals [94,96].…”