Brigitte A. Wevers, Lia van der Hoek, two researchers from the Netherlands, did a good job in describing how common coronaviruses penetrate host cells and some possible mechanisms of their pathological action (1). Scientific clarity is valuable and not very common. As a form of note-taking on SARS-CoV-2, COVID-19 and on viruses in general, we reproduce an extended passage from the paper by Brigitte A. Wevers, Lia van der Hoek, 2009 (1), here.
Wevers, van der Hoek, 2009 (1):
Viral receptors, components that actively promote host cell entry, differ greatly from one virus to the next and constitute a wide variety of proteins and carbohydrates, each with distinct physiologic functions. 68 Although cellular receptors for HCoVOC43 and HCoV-HKU1 remain to be elucidated, the family of membrane-associated proteases seems to be favored by HCoVs, because both neutral aminopeptidase (APN), the receptor for HCoV-229E, 69 and angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV and HCoV-NL63, 70–72 exist as prominent zinc-dependent peptidases on host cell plasma membranes. 73,74 In fact, several structural features of zinc metallopeptidases probably facilitate targeting of APN and ACE2 and govern cellular entry of HCoVs. Zinc peptidases are expressed abundantly on various cell types, because these proteases modulate activity of many proteins including membrane proteins and circulating regulatory peptides.75 Furthermore, both APN and ACE2 appear as heavy glycosylated ectoenzymes, with most of the protein, including catalytic domain, protruding into the extracellular space. 73 During establishment of an infection, interaction of HCoV-229E and SARS-CoV spike proteins with APN or ACE2, respectively, causes a substantial modulation of these cellular entry receptors. 76–78 SARS-CoV has been proven to induce a rapid down-regulation of ACE2 cell surface expression, preferably by means of internalization of the receptor–ligand complex. 78,79 Alternatively, SARS-CoV possesses the capacity to abrogate ACE2 cell surface expression by means of activation of tumor necrosis factor-alpha converting enzyme (TACE). This enzyme mediates ectodomain shedding of ACE2. 80,81 Whether HCoV-NL63 induces a similar down-regulation of ACE2 during infection is at present unknown. It is assumed that cellular APN expression is altered during establishment of an HCoV-229E infection. Following HCoV-229E binding to the target cell, APN molecules aggregate and translocate to caveolin-enriched membrane domains, to activate a specialized endocytic route of virus particle internalization. 77 Most importantly, these processes of receptor-mediated endocytosis often involve simultaneous internalization of the cellular entry molecule itself. 82,83 Likewise, sequestration of porcine APN molecules into intracellular vesicles has been visualized during endocytosis of CoV strain porcine-transmissible gastroenteritis virus (TGEV). 84 Thus, HCoV-229E-induced abrogation of APN expression is highly plausible to occur, although direct evidence is unavailable. Viral targeting of APN and its subsequent down-regulation is definitely a known phenomenon, as this cellular peptidase possibly is implicated in infection with human cytomegalovirus (CMV) also. 85–87 Notwithstanding the fact that human APN is most likely not the primary receptor of the virus, 88 CMV induces abrogation of APN expression.
The phenomenon of entry receptor suppression has been reported for several additional viruses, including HIV, measles virus (MV), influenza virus, and human herpes virus (HHV) type 6. 89–92 Although it may seem contradictory, viruses strongly benefit from down-regulation of their own receptors, and this process correlates with an enhanced pathogenesis also. 93 Abrogation of receptor expression prevents infection of cells by additional virus particles in which viral replication is already progressing. 94 In addition to limiting superinfection, receptor down-regulation can facilitate efficient virion release, leading to a controlled and productive infection. 95 At the same time, abrogation of receptor expression hampers natural physiologic activity of these cellular molecules and therefore may contribute to viral disease pathogenesis also. Internalization of CD4 after HIV-gp120 binding, for example, leads to specific impairment of immune cell functions. 96 Moreover, MV hemagglutinin (HA)-induced CD46 receptor abrogation induces serious dysregulation of complement pathways and mechanisms of immunosuppression.
Down-regulation of APN and ACE2 during HCoV-229E, HCoV-NL63, and SARS-CoV infection may impair the normal physiologic function of the host cells severely and contribute to the development of clinical manifestations. Besides their classification as zinc-dependent peptidases, APN and ACE2 share important functional enzymatic characteristics. Both proteins are integral components of the renin–angiotensin system (RAS). This endocrine system is one of the most important regulators of human physiology, with a key role in maintenance of arterial pressure, fluid hemostatis, salt balances, cardiac function, cell proliferation and hypertrophy, angiogenesis, and apoptosis. Therefore, impaired expression of APN and ACE2 also might alter crucial normal physiologic functionalities of the RAS. Most intriguingly, suppression of ACE2 protein expression during SARS-CoV infection actually causes severe imbalances within the enzymatic RAS cascade, which is proposed to be the main cause of severe acute pneumonia and acute lung failure observed during SARS-CoV infection. 71,76,99 These findings raise the possibility that CoV-induced dysregulation of the RAS might be important for the clinical outcome of HCoV-229E and HCoV-NL63 infections also.
Selected references:
1. Brigitte A. Wevers, Lia van der Hoek. Clin Lab Med 29 (2009) 715–724.
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