| Summary: | In Part One of this exploration of the pathogenesis of coronavirus disease (COVID-19), the author will evaluate the viral and cellular immunological basis for the condition. The virus demonstrates a remarkable capability not just to evade, but to exploit host immune characteristics to perpetuate viral replication. In this regard, severe acute respiratory syndrome (SARS)/severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disables most antiviral mechanisms, including the early interferon response, and avoids detection to permit unimpeded viral multiplication. Consequently, antigen-presenting cells fail to adequately stimulate the T-cell receptor. As a consequence, T-cell p53 remains highly expressed, which in turn disables an adequate effector T-cell response. Replicating SARS-CoV-2 double-strand RNA robustly activates protein kinase R (PKR)/PKRlike endoplasmic reticulum kinase (PERK). While the virus is grossly invulnerable to its antiviral effects, PKR is crucial for effecting the cytokine milieu in COVID-19. PERK is a component of the unfolded protein response, which eventuates in autophagy. SARS virions use double-membrane vesicles and adapt PERK signalling not only to avoid autophagy, but to facilitate replication. Viral activation of PKR/PERK is mutually exclusive to NLRP3 stimulation. The NLRP3 pathway elaborates IL-1β. This is chiefly a feature of paediatric SARS/SARS-CoV-2 cases. The difficulties encountered
in predicting outcome and forging effective therapeutics speaks to the breadth of complexity of the immunopathogenesis of this virus.
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