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

Pere Domingo*, Isabel Mur, Virginia Pomar, Héctor Corominas, Jordi Casademont, Natividad de Benito

*Corresponding author for this work

Research output: Contribution to journalReview articleResearchpeer-review

44 Citations (Scopus)


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.

Original languageAmerican English
Article number102887
Publication statusPublished - Aug 2020


  • ACE2
  • Acute lung injury
  • Adult distress respiratory syndrome
  • COVID-19
  • Hypercoagulability
  • Hyperinflammatory state
  • RAS
  • SARS-CoV-2


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