Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications

Abstract

Background: Gaining further insights into SARS-CoV-2 routes of infection and the underlying pathobiology of COVID-19 will support the design of rational treatments targeting the life cycle of the virus and/or the adverse effects (e.g., multi-organ collapse) that are triggered by COVID-19-mediated adult respiratory distress syndrome (ARDS) and/or other pathologies.

Main body: COVID-19 is a two-phase disease being marked by (phase 1) increased virus transmission and infection rates due to the wide expression of the main infection-related ACE2, TMPRSS2 and CTSB/L human genes in tissues of the respiratory and gastrointestinal tract, as well as by (phase 2) host- and probably sex- and/or age-specific uncontrolled inflammatory immune responses which drive hyper-cytokinemia, aggressive inflammation and (due to broad organotropism of SARS-CoV-2) collateral tissue damage and systemic failure likely because of imbalanced ACE/ANGII/AT1R and ACE2/ANG(1-7)/MASR axes signaling.

Conclusion: Here we discuss SARS-CoV-2 life cycle and a number of approaches aiming to suppress viral infection rates or propagation; increase virus antigen presentation in order to activate a robust and durable adaptive immune response from the host, and/or mitigate the ARDS-related "cytokine storm" and collateral tissue damage that triggers the severe life-threatening complications of COVID-19.

Keywords: ACE2; ARDS; COVID-19; SARS-CoV-2; TMPRSS2.

Fig. 1

Illustration of the main cell signaling axes [i.e., ACE/ANGII/AT1R and ACE2/ANG(1–7)/MASR] and of other cellular components being involved in SARS-CoV-2 infection (i.e., TMPRSS2 or furin), endocytosis and replication. 1. SARS-CoV-2 (extracellular); 2. binding to ACE2; 3. TMPRSS2 (or FURIN) priming; 4. clathrin-mediated endocytosis (entry to early and acidic late -microtubule bound- endosomes) - 4* denotes endosomal compartments during exocytosis; 5, 6. uncoating, genomic RNA release and viral-protein synthesis in free and endoplasmic reticulum-attached ribosomes; 7. vesicle-mediated exocytosis; 8. antigen presentation by endocytic compartments (MHC II) and proteasomes (MHC I); 9. immune cell attraction and development of immunity or elimination of infected cells. MHC II/MHC I, Major Histocompatibility Complex class II, I. ┤inhibition, → induction

Fig. 2

Major severe COVID-19 pathologies and infection routes. a The modules involved in, 10. acute phase of SARS-CoV-2 infection in the lung (ARDS); 11. vasodilation, increased capillary permeability, apoptosis/necrosis of endothelial cells as well as 12. ARDS-induced “cytokine storm” and likely virus entry to the circulation which may then cause systemic failure due to broad organotropism in tissues expressing high levels of ACE2 (e.g., heart and kidneys) or the “cytokine storm”-related excessive inflammation, are indicated. b Sites of potentially SARS-CoV-2 infected organs in the alimentary tract of the digestive system and in accessory organs i.e., salivary glands, liver, gallbladder, and pancreas. ACE2 is expressed in relatively high levels in duodenum, small and large intestines, rectum, as well as in gallbladder. Thus, following the consumption of contaminated food the virus likely reaches the stomach passively; the reported adverse effects in other accessory organs like liver or pancreas are probably the result of excessive inflammation during severe COVID-19. c Central (brain, spinal cord) and peripheral nervous system as an infection route of SARS-CoV-2; ACE2, neuropilin-1 (NRP1) and CD147 that reportedly potentiate virus infectivity into the central nervous system are shown. The molecular pathways involved in SARS-CoV-2 infection in human (e.g., lung) cells are depicted in Fig. 1