COVID-19 and Respiratory System Disorders: Current Knowledge, Future Clinical and Translational Research Questions

Abstract

The severe acute respiratory syndrome coronavirus-2 emerged as a serious human pathogen in late 2019, causing the disease coronavirus disease 2019 (COVID-19). The most common clinical presentation of severe COVID-19 is acute respiratory failure consistent with the acute respiratory distress syndrome. Airway, lung parenchymal, pulmonary vascular, and respiratory neuromuscular disorders all feature in COVID-19. This article reviews what is known about the effects of severe acute respiratory syndrome coronavirus-2 infection on different parts of the respiratory system, clues to understanding the underlying biology of respiratory disease, and highlights current and future translation and clinical research questions.

Keywords: COVID-19; acute respiratory distress syndrome; diaphragm; infection; respiratory system; thromboembolism.

Figure 1.

Pathobiological consequences of alveolar epithelial injury by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) infection. SARS-CoV2 host entry through alveolar epithelium critically depends on expression of ACE2 (angiotensin-converting enzyme-2) and TMPRSS2 (transmembrane serine protease 2). First, coronavirus binds through one of its 4 structural proteins, glycoprotein S (spike) to ACE2 on alveolar type II (AT2) cells, initiating fusion of virus, and host cell membranes. Second, TMPRSS2 simultaneously cleaves ACE2, promoting cell surface clearance of ACE2, and the viral glycoprotein S into subunits S₁ and S₂, resulting in viral uncoating and release of viral genome into the cytoplasm. The virus is then replicated using both viral and host cell machinery, translation of the viral core proteins S, M, N, and E in the endoplasmatic reticulum (ER), assembly of virus particles in the ER-Golgi-intermediate compartment, and packaging into small wallet vesicles routed to the plasma membrane for exocytosis. SARS-CoV2 infection-induced AT2 dysfunction or loss is deleterious to the injured lung for several reasons: (1) decrease in surfactant increases the risk for alveolar collapse and atelectasis. (2) Decrease in AT2 progenitor cells causes impaired alveolar type I (AT1) cell replacement, affecting alveolar repair and likely promote fibrosis. (3) ACE2 downregulation drives geographically restricted overactivity of the ACE/Angiotensin II/AT1 receptor axis, worsening the tissue destructive effect of the inflammatory response. (4) Viral-induced cytokine release by AT1/AT2 cells results in capillary leak and alveolar interstitial immune cell infiltration.

Figure 2.

Pathobiological consequences of vascular endothelial injury by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) infection. SARS-CoV2 infection of endothelial cells, which might occur from luminal or alveolar interstitial side, triggers endothelial release of cytokines, which cause increased capillary permeability, thereby allowing adhesion and extravasation of neutrophils and monocytes into the alveolar interstitial space. Stimulated by PAMPs and DAMPs (pathogen-associated and damage-associated molecular patterns), neutrophils, and macrophages secret a multitude of cytokines, procoagulants, and complement, which promote viral attack and clearance but which induces further vascular injury enhancing the risk for thrombosis. Several factors might contribute to the prothrombotic environment, thereby promoting intravascular thrombus formation: (1) Neutrophil-mediated secretion of NETs (neutrophil extracellular traps) and complement enhances platelet aggregation. (2) Cytokine-triggered secretion of TF (tissue factor) by endothelial cells and macrophages stimulates the coagulation cascade and increases fibrin clot formation. (3) Endothelial damage decreases secretion of anticothrombotic mediators, such as AT (antithrombin) and TFPI (TF pathway inhibitor). (4) Lung residential megakaryocytes produce locally available platelets for aggregation. (5) Overactivation of the ACE (angiotensin-converting enzyme)/Ang II (angiotensin II)/AT₁ receptor axis due to virus-induced ACE2 downregulation increases production of PAI1 (plasminogen activator inhibitor 1), reducing plasmin activation and fibrinolysis. AT indicates antithrombin; ATR, angiotensin receptor; and IL, interleukin.