The four horsemen of a viral Apocalypse : The pathogenesis of SARS-CoV-2 infection (COVID-19)

The concept of the manuscript was devised by PD who also performed the overall literature searches. IM, VP, HC, and JC designed the search strategy with inputs from PD and NdB. IM, VP, HC, and JC carried out the literature searches and screening, and any discrepancies were discussed with PD and NdB. PD wrote the first draft of the review with inputs from all the authors. This work was partially supported by grant COV20/00070. Instituto de Salud Carlos III, Madrid, Spain. The funding source was not involved in the design of the study or in writing the report. All authors had access to the data used in the analyses, and the lead author reviewed the full report. The full study data were available to all authors. PD, NdB made the decision to submit the paper for publication. We are indebted to Jordi Mancebo and M? Ant?nia Mangues for critical reading of the manuscript, and to Richard Pike for reviewing its writing. The pathogenesis of coronavirus disease 2019 (COVID-19) may be envisaged as the dynamic interaction between four vicious feedback loops chained or happening at once. These are the viral loop, the hyperinflammatory loop, the non-canonical renin-angiotensin system (RAS) axis loop, and the hypercoagulation loop. Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 lights the wick by infecting alveolar epithelial cells (AECs) and downregulating the angiotensin converting enzyme-2 (ACE2)/angiotensin (Ang-1-7)/Mas1R axis. The viral feedback loop includes evading the host's innate response, uncontrolled viral replication, and turning on a hyperactive adaptative immune response. The inflammatory loop is composed of the exuberant inflammatory response feeding back until exploding in an actual cytokine storm. Downregulation of the ACE2/Ang-(1-7)/Mas1R axis leaves the lung without a critical defense mechanism and turns the scale to the inflammatory side of the RAS. The coagulation loop is a hypercoagulable state caused by the interplay between inflammation and coagulation in an endless feedback loop. The result is a hyperinflammatory and hypercoagulable state producing acute immune-mediated lung injury and eventually, adult respiratory distress syndrome.