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

Abstract

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.

Keywords: ACE2; Acute lung injury; Adult distress respiratory syndrome; COVID-19; Hypercoagulability; Hyperinflammatory state; RAS; SARS-CoV-2.

Fig. 1

The four hurtful feedback loops in the pathophysiology of COVID-19. Schema representing the most remarkable pathophysiological events involved in each of the four vicious feedback loops and the complex interactions established between them. Intersections between circles represent interaction between loops. The central circle colored in red means the final events of the physiopathologic cascade. The vicious viral loop is depicted in green, the hyperinflammatory loop is colored in orange, the ACE2/Ang-(1–7) loop is colored in yellow, and the hypercoagulation loop is colored in purple. IFN = interferon; PAMPs = Pathogen-associated molecular patterns; DAMPs = Damage-associated molecular patterns; SARS-CoV-2 = Severe acute respiratory syndrome Coronavirus 2; AECs = Alveolar epithelial cells; ECs = Endothelial cells; ACE2 = Angiotensin-converting enzyme 2; Ang-(1–7) = Angiotensin 1–7; ACE = Angiotensin-converting enzyme; Ang II = Angiotensin II; NO = Nitric oxide; PGI2 = Prostacyclin; MΦ = Macrophages; PMNs = Polymorphonuclear neutrophils; DAD = Diffuse alveolar damage; ALI = Acute lung injury; ARDS = Adult respiratory distress syndrome; EOD = End-organ disease.

Fig. 2

Physiopathology of acute lung injury in SARS-CoV-2 infection (COVID-19). SARS-CoV-2 infects primarily type II pneumocytes through binding to the ACE2 receptor. The infected and surrounding pneumocytes secret cytokine and chemokines, which attract monocyte-macrophages and neutrophils to the alveolar space, which secrete additional cytokines and chemokines. Ultimately the pneumocytes suffer apoptosis/pyroptosis releasing large amounts of proinflammatory factors. Endothelial cells are infected, overexpress adhesion molecules, and release chemokines and cytokines. Endothelial cells undergo apoptosis, which, together with alveolar cell apoptosis, increases vascular leakage and breaks the alveolar-capillary barrier. The hyperinflammatory milieu and endothelial dysfunction activate coagulation cascades through tissue factor expression, platelet activation, and NETosis all of them promoting microcirculatory thrombi formation. The break of endothelial-alveolar barrier further promotes vascular leakage resulting in interstitial and alveolar space flooding. Downregulation of the ACE2/Ang-(1–7)/Mas1R axis contributes to increasing vasoconstriction, inflammatory signals, endothelial dysfunction, vascular leakage, and prothrombotic state. SARS-CoV-2 = Severe acute respiratory syndrome Coronavirus 2; TNF-α = Tumor necrosis factor alpha; IL-10 = Interleukin 10; MCP-1 = Macrophage chemoattractant protein 1; MIP-1A = Macrophage inhibitory protein 1A; IL-6 = Interleukin 6; IL-1β = Interleukin 1 beta; NF-KB = nuclear factor kappa B.

Fig. 3

Implication of angiotensin-converting enzyme 2 (ACE2)/Angiotensin (Ang-1–7)/Mas1R in the pathogenesis of coronavirus disease 2019. The lung, and other organs, lose the protection of the non-canonical RAS system as a result ACE2 downregulation after SARS-CoV-2-induced endocytosis. Consequently, the canonical ACE/Ang II/AT1R becomes dominant, levels of Ang II increase with the subsequent promotion of fibrosis, myocardial hypertrophy, increased ROS, vasoconstriction, inflammation, and endothelial dysfunction. AT1R mediates most of these actions. Endocytosed SARS-CoV-2 spike proteins mediates ADAM 17-mediated proteolytic cleavage of ACE2. ADAM-17 activity is enhanced through the activated AT1R by increased levels of Ang II. TNF-α is the primary substrate of ADAM17. ADAM17 cleaves TNF-α releasing soluble TNF-α extracellularly where it has autocrine and paracrine functionalities. Activation of TNF-α receptor by TNF-α also enhances ADAM17 activity. ACE2 = Angiotensin-converting enzyme 2; SARS-CoV-2 = Severe acute respiratory syndrome coronavirus 2; Ang II = Angiotensin II; ROS = Reactive oxygen species; AT1R = Angiotensin 1 receptor; ADAM17 = A disintegrin and metalloproteinase domain 17; TNF-α = Tumor necrosis factor alpha; TMPRSS2 = transmembrane protease serine 2.