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a)
Initial attack of the spike protein at the host cell membrane; the latter is physiologically charged negatively and with a variable potential (around 40mV +/- 30 mV); the level of the negative charge depends on the number and on the type of the receptors. The main involved receptors are: SA on the membrane glycoproteins, ACE2 and CD147; SA molecules are expressed at the outer surface of ACE2 and CD147, which favor viral attack;
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b)
Morphologic changes of the whole cell may occur: this phenomenon depends upon the
milieu pH, the membrane potential charge, the concentration and configuration of the receptors, which also influence the osmotic gradient;
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c)
Formation of fusion nuclei between the spike proteins and the host cell membrane by means of electrostatic bonds and hydrogen bridges;
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d)
Release from the host cell of hydrolases (TMPRSS2) which cleave the spike protein separating the S1 subunit from S2, probably at the level of the aminoacidic interval 681-684; on the other hand, furins simultaneously unveil the RBD in S1;
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e)
Fusion of S2 to the lipid layer of the plasma side of the cell membrane;
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f)
Transmembrane attack of the positively charged [N(+) terminal] S1 RBD to the [C(-) terminal] receptors (ACE2, CD147, sialylated glycoproteins), with numerous dipole (S1 positive-SA negative) formation;
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g)
Additionally, hyper-concentrated plasma hepcidin molecules bind the extracellular portion of the transmembrane ferroportin, thus blocking iron extracellular transport;
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h)
As consequence of these synergistic events a change of the membrane electrical potential occurs, which leads to an opening of the cation channels, especially of the VGCC; cations, primarily calcium and iron, enter the cell and concentrate in the cytoplasm and in the organelles;
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i)
Subsequent rapid closure of the VGCC occurs, due to cell homeostasis and re-balancing of the protonic gradient, while a simultaneous intracellular viral replication leads to the production of viroporins; these viral hydrophobic proteins exert a membrane channeling action, thus facilitating new entry of cations from the extracellular space against the gradient, also favoring replication and external release of viruses;
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j)
Re-increase of calcium/iron influx and their intracellular accumulation, which leads to an extremely high oxidative stress, mitochondria degeneration, membrane lipoperoxidation, glutathione peroxidase 4 (GPX4) depletion, all of this configuring the terminal ferroptosis.
