Q&A’s: “We are willing to discuss, knowledge grows by sharing”
Our hypothesis received a lot of comments, all from experts in the field. Here is a mixture of questions and answers. It is important to get the details right.
This is a just a start, we will update regularly.
Q1) “Angiotensin receptors such as AT1R are related to the angiotensin converting enzyme in the same way as Acetylcholine-esterase is related to muscarinic receptors. It is a physiological chain of events, not an interaction one. Even if COVID-binding to ACE is the infection pathway, there is no reason to expect that this would be blocked by AT1R blockers.”
A: There is, and this is the chain of events: ACE2 regulates the concentrations of AngII as inflammatory compound and Ang(1-7) as anti-inflammatory compound. At low NO concentrations the AT1R receptor binds to ACE2 and activates its endocytosis for destruction. AT1R then returns to the cell membrane to repeat its task. SARS-CoV-2 binds to ACE2. This means that AT1R induces endocytosis of the virus. Inhibiting AT1R prevents endocytosis of ACE2-bound virus and preserves ACE2 functions at the cell membrane.
Q2) “Another unwanted effect is that the ATR1 antagonist could inhibit proteasome degradation (reduced IkBa degradation), thus preventing the NFkB activation which is crucial for mounting an antiviral response.”
A: NFKB is activated by TLR4 outside the cell, MyD88-dependent. IkBa is activated by TLR4 inside the cell, after endocytosis of TLR4 by DJ-1, TRAF2 dependent, MyD88 independent. When AngII is downregulated, according to this mechanism, activation of NFKB and IkBa should be equally downgraded.
Q3) “… ANGII seems crucial for T cell activation, especially Th1 anti-viral cytotoxicity. Moreover ANGII stimulation of ACE2 would support viral uptake and endosomal clearance. Hypothesis is that this overreactive adaptive immune activation (TH1?) would contribute to morbidity by respiratory distress and excessive lung tissue inflammation. Question remains this theoretic modelling should be proven in vivo, what is balance between effective anti-viral T cell cytotoxicity and excessive inflammation.”
A: The theory is that AngII, in the absence of NO, induces migration of T cells to the place of inflammation, while Ang(1-7), in the presence of NO, induces T cell specification.
Q4) “… ANGII reduces NO production which is instrumental in adaptive immunity while at the same time ANGII stimulates Th1 (anti-viral cytotoxicity?) development and differentiation. In the proposed mechanisms this seems to be a sequential mechanisms switching from innate to adaptive immune response and viral clearance. Thus a delicate balance between ATR1 and ATR2 activity!”
A: This surely needs more exploration. T cell migration and T cell specialization depend on polarized NO expression. Nitric oxide is necessary for a switch from stationary to locomoting phenotype in epithelial cells. [“Migrating cells showed the polarized expression of NOS, suggesting a head-to-rear NO gradient.” E. Niori et al, Am J Physiol. 1996
Q5) “… ACE2 protects against lung injury induced by RSV infection. And ACE2 deficiency worsens RSV pathogenesis through AT1R. Recombinant ACE2 protein alleviated RSV-induced lung injury (promising potential therapeutic target in RSV-induced lung disease).”
A: I am afraid the latter will not turn out to be safe since it disrupts site-specific RAS regulation.
Q6) Pharmacokinetics! ATR1 dissociation curves for the compound? What are the dynamic effects of ATR1 antagonists on ACE2 expression as target for viral binding and endocytosis?
A: Important research! It is suggested that AT1R antagonists not only prevent endocytosis if ACE2-SARS-CoV-2 complex, but might even prevent binding of SARS-CoV-2 to ACE2. A worrisome scenario would be if ACE2-bound SARS-CoV-2 remains dormant (if so, for how long?) at the cell membrane to be endocytosed and activated/replicated with another event, eg a common flue. One our research questions too.
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