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.

Keywords: Alzheimer’s disease; Angiotensin-converting enzyme 2 (ACE2) receptor; COVID-19; CoV-19; Coronavirus; Hartnup's disease; SARS-CoV-2; miRNA-5197; microRNA; single stranded RNA (ssRNA).

Fig. 1

Organization of human MTE blot for Northern blot analysis; ACE2 signals were compared to G3PDH signals in the same sample and expressed as ‘relative signal intensity’; these are shown bar graph format in Figs. 2 and 3; a minimum of N = 6 MTE arrays (3 for ACE2 and 3 for G3PDH) were used in each type-of-tissue determination

Fig. 2

Tissue-specific patterns of ACE2 expression are a strong indicator of gene function and susceptibility to SARS-CoV-2 invasion and the development of CoV-19. High ACE2 expression in vascular, gastrointestinal (GI) tract, respiratory, excretory and reproductive tissues and some relevant cancers and controls; the highest values of expression were found in the heart (both adult and fetal), ileum, kidney, lung (both adult and fetal), testes, ovary and mammary gland; ACE2 is a member of the angiotensin-converting enzyme family of dipeptidyl carboxydipeptidases and has considerable homology to human angiotensin 1 converting enzyme (ACE1), however the ACE2 DNA probe here was unique showing no homology with ACE1; ACE2, expressed as both a secreted protein and trans-membrane form catalyzes the cleavage of angiotensin I (ANG) into ANG_1–9, and ANG II into the vasodilator ANG_1–7; ACE-2 is also a receptor to the spike (S1) glycoprotein of the human coronavirus HCoV-NL63 and the human SARS-CoV and SARS-CoV-2 virus that causes CoV-19 (see: https://www.youtube.com/watch?v=W1k1sUoLPlA; https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=59,272; last accessed 29 July 2020); at least N = 6 MTE arrays (at minimum 3 for ACE2 and 3 for G3PDH) were used in each tissue determination; *p < 0.01 (ANOVA); error bars represent one standard deviation of the mean

Fig. 3

ACE2 expression in 21 anatomical regions of the human brain. The highest expression of the SARS-CoV-2 receptor ACE-2 was found in the amygdala, pons and medulla oblongata; the later two regions contain the respiratory control centers of the brain; considerable expression of ACE2 in the brain, temporal lobe and hippocampus may in part explain neurological disruption and cognitive dysfunction associated with SARS-CoV-2 infection; note difference of scale in the Y-axis (ordinate) compared to Fig. 2; to obtain maximal signal quantitation hybridized and washed membranes were overlaid on the MTE template (Fig. 1) excised and counted in liquid scintillation fluid as previously described; relative signal intensities (Figs. 2, 3) were expressed by comparing the ACE2 hybridization signal to the G3PDH signal for each polyA + mRNA on the same MTE array sector (see Lukiw et al. , ; Zhao et al. ; Jaber et al. 2017); at least N = 6 MTE arrays (3 for ACE2 and 3 for G3PDH) were used in each brain tissue determination; *p < 0.01 (ANOVA); error bars represent one standard deviation of the mean