Increased Expression of Chondroitin Sulfotransferases following AngII may Contribute to Pathophysiology Underlying Covid-19 Respiratory Failure: Impact may be Exacerbated by Decline in Arylsulfatase B Activity

Abstract

The spike protein of SARS-CoV-2 binds to respiratory epithelium through the ACE2 receptor, an endogenous receptor for Angiotensin II (AngII). The mechanisms by which this viral infection leads to hypoxia and respiratory failure have not yet been elucidated. Interactions between the sulfated glycosaminoglycans heparin and heparan sulfate and the SARS-CoV-2 spike glycoprotein have been identified as participating in viral adherence and infectivity. In this brief report, we present data indicating that stimulation of vascular smooth muscle cells by AngII leads to increased expression of two chondroitin sulfotransferases (CHST11 and CHST15), which are required for the synthesis of the sulfated glycosaminoglycans chondroitin 4-sulfate (C4S) and chondroitin 4,6-disulfate (CSE). We suggest that increased expression of these chondroitin sulfotransferases and the ensuing production of chondroitin sulfates may contribute to viral adherence to bronchioalveolar cells and to the progression of respiratory disease in Covid-19. The enzyme Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase), which removes 4-sulfate groups from the non-reducing end of chondroitin 4-sulfate residues, is required for degradation of C4S and CSE. In hypoxic conditions or following treatment with chloroquine, ARSB activity is reduced. Decline in ARSB can contribute to ongoing accumulation and airway obstruction by C4S and CSE. Decline in ARSB leads to increased expression of Interleukin(IL)-6 in human bronchial epithelial cells, and IL-6 is associated with cytokine storm in Covid-19. These findings indicate how chondroitin sulfates, chondroitin sulfotransferases, and chondroitin sulfatases may participate in the progression of hypoxic respiratory insufficiency in Covid-19 disease and suggest new therapeutic targets.

Pathogenesis of COVID‐19 described through the lens of an undersulfated and degraded epithelial and endothelial glycocalyx

“…Adjacent to the ACE2-binding site and exposed in the RBD lies a group of positively charged AA residues 129 that represents a potential site that could interact with HS, thus enhancing infectivity. 6,47,130 SARS-CoV-1 SP RBD did not show the same electropositive surface. 40 SARS-CoV-2 has approximately 10-20 times higher affinity for ACE2 than SARS-CoV-1, which could explain the higher infectivity rate of SARS-CoV-2.…”

“…Clausen et al and Kim et al found that the ectodomain of SARS‐CoV‐2 SP interacts with cell surface HS through RBD in the S1 subunit, 6,7 in a length‐ and sequence‐dependent manner 7,8,47 . The binding of HS to SARS‐CoV‐2 SP shifts the structure to favor the RBD open conformation that binds ACE2 receptors, 128 probably due to the release of furin by the GL after HS binding 3 .…”

“…50,59 Clausen et al and Kim et al found that the ectodomain of SARS-CoV-2 SP interacts with cell surface HS through RBD in the S1 subunit, 6,7 in a length-and sequencedependent manner. 7,8,47 The binding of HS to SARS-CoV-2 SP shifts the structure to favor the RBD open conformation that binds ACE2 receptors, 128 probably due to the release of furin by the GL after HS binding. 3 SARS-CoV-2 SP binding to cells, therefore, requires the engagement of both cellular HS and ACE2 receptors, suggesting that HS acts as a co-receptor priming the SP for ACE2 receptor interaction (Figure 2).…”

“…6,7,33,46 Indeed, recent research studies indicate interactions between sulfated HS and SARS-CoV-2 SP, 7,8 which participate in viral adherence and infectivity. 8,47 The GL is the first point of contact for all pathogens that infect animal cells, and it is, therefore, not surprising that many viruses exploit GAGs, such as HS, to facilitate the uptake. 6,12,16,[48][49][50][51][52] Through sequence analysis of SARS-CoV-2 SP, it was found that this virus has additional potential GAG binding domains compared to SARS-CoV-1, 50 leading to increased infectivity.…”

“…Furthermore, for any pathogen to gain access to ACE2 receptors, they need to first penetrate through the GL 6,7,33,46 . Indeed, recent research studies indicate interactions between sulfated HS and SARS‐CoV‐2 SP, 7,8 which participate in viral adherence and infectivity 8,47 . The GL is the first point of contact for all pathogens that infect animal cells, and it is, therefore, not surprising that many viruses exploit GAGs, such as HS, to facilitate the uptake 6,12,16,48–52 .…”