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

• Published in: EBioMedicine Vol. 58; p. 102887
• Main Authors: Domingo, Pere, Mur, Isabel, Pomar, Virginia, Corominas, Héctor, Casademont, Jordi, de Benito, Natividad
• Format: Journal Article Web Resource
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2020; Elsevier BV; Elsevier
• Subjects: ACE2; Acute lung injury; Adult distress respiratory syndrome; Animals; Betacoronavirus - pathogenicity; Blood Coagulation; Coronavirus Infections - etiology; Coronavirus Infections - metabolism; Coronavirus Infections - pathology; Coronavirus Infections - virology; COVID-19; Cytokines - metabolism; Feedback, Physiological; Humans; Hypercoagulability; Hyperinflammatory state; Pandemics; Pneumonia, Viral - etiology; Pneumonia, Viral - metabolism; Pneumonia, Viral - pathology; Pneumonia, Viral - virology; RAS; Renin-Angiotensin System; Review; SARS-CoV-2; COVID-19; Hypercoagulability; ACE2; Acute lung injury; SARS-CoV-2; Hyperinflammatory state; RAS; Adult distress respiratory syndrome
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2020.102887

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.