Figures
- FIGURE 1
Life cycle of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Based on the phylogenetic study, transmission of SARS-CoV-2 evolves from the natural reservoir of bats (non-human host) to the current pathogenic state of human outbreak through natural selection or another mammal, probably pangolin [15, 16] served as a host of a non-pathogenic version of the SARS-CoV-2 that later jumped into humans with the acquired capacity to current pandemic outbreak through human-to-human transmission [12, 19]. The viral ability to infect small and large animals under laboratory settings points to animals as an intermediate natural host [17, 18]. Based on a Centers for Disease Control and Prevention report, a very small number of pets, including dogs and cats, outside the USA were reported to be infected with the virus that causes coronavirus disease 2019 (COVID-19) after close contact with people with COVID-19. However, a tiger at a zoo and two pet cats in New York (NY, USA) have also tested positive for SARS-CoV-2 [18].
- FIGURE 2
Angiotensin-converting enzyme 2 (ACE2)-mediated counter regulation of the renin−angiotensin system (RAS). The ACE2-angiotensin (1–7) Mas axis (right side) counterbalances the harmful effects of the ACE1-angiotensin II type 1 receptors (AT1R) axis (left side). Angiotensinogen gets converted into angiotensin-I through enzymatic action of renin. ACE2 degrades angiotensin II and generates angiotensin (1–7) which antagonises the effects of angiotensin II. Moreover, clinical evidence suggests that RAS blockade by ACE inhibitors or AT1R blockers and mineralocorticoid antagonists enhance ACE2 level that is ultimately beneficial to the patients with cardiovascular diseases [23–26] but deleterious for coronavirus disease 2019 (COVID-19) patients [17, 22, 27]. The ACE inhibitor and angiotensin receptor blockers (as shown in red) antagonise the angiotensin II/AT1R axis.
- FIGURE 3
Biological mechanism of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Once the SARS-CoV-2 approaches the cell membrane, basal S1 subunit of viral spike glycoprotein binds to a membrane-bound molecule of angiotensin-converting enzyme 2 (ACE2). As more S1 subunits binds to membrane-bound molecules of ACE2, the membrane starts to form an envelope around the virus (an endosome). A cell membrane-bound serine protease, TMPRSS2, cleaves the S1 subunits of SARS-CoV-2 from its S2 subunits that mediated endosome entry into the cells (endocytosis). Inside the cell, viral genetic material is released by either acidification or by proteolysis (cathepsin). Viral replication and translation forms a new virion that cleaves out from cells by exocytosis. Of note, ACE2-mediated cardiovascular protection is lost following endocytosis of ACE2 with SARS-CoV-2 viral particles. The endocytosis triggers ADAM-17-mediated ectodomain shedding of tissue ACE2 [30, 31], which through the integrin pathway induces pathologic intracellular signalling [32]. Lack of ACE2 availability increases angiotensin II levels that result in detrimental effects due to increased activity of angiotensin-II type 1 receptor (AT1R) at the expense of ACE2/angiotensin (Ang) 1–7 driven protective pathways [34]. Viral infection also results in activation of circulatory inflammatory cytokines, antibody response and immune cells; these may damage airways epithelia. IL: interleukin; MCP: monocyte chemotactic protein 1.
- FIGURE 4
Overall lung pathophysiology, immune cell activation and cytokine production. Severe acute respiratory syndrome-coronavirus-2 infects the upper respiratory tract. Most of the patients (∼80%) recover with mild-to-moderate upper respiratory symptoms. In the remaining patients, the virus reaches the lower respiratory track triggering pathologic immune response. Around 6% of the patients shows very severe symptoms of acute respiratory distress syndrome and require intensive care unit admission. Autopsies of patients with coronavirus disease 2019 (COVID-19) showed clusters of severe respiratory illness, including associated features of diffuse alveolar damage, such as diffuse type II pneumocyte hyperplasia, epithelial necrosis, fibrin deposition and hyaline membrane formation [80, 83, 96]. Most patients who died of severe acute respiratory syndrome-coronavirus developed acute respiratory distress syndrome with interstitial mononuclear inflammatory infiltrates [54, 75, 79, 80, 83, 97]. In addition, several nonspecific histological observations have also been observed that include oedema, fibrinous/proteinaceous exudates, hyperplastic pneumocytes, patchy interstitial chronic inflammation, and multinucleated giant cells with a dysregulated immune system that results in very high amounts of inflammatory cytokines [98]. PD1: programmed cell death protein-1; TIM3: T-cell immunoglobulin domain and mucin domain-3; NKG2A: killer cell lectin-like receptor subfamily C member 1; G-CSF: granulocyte-colony stimulating factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; IP10: interferon inducible protein-10; MCP1: monocyte chemotactic protein 1; TNF: tumour necrosis factor; IL: interleukin; Ig: immunoglobulin; IFN: interferon; IMs: interstitial macrophages.
- FIGURE 5
Schematic summary of the potential therapeutic targets. Recapitulation of coronavirus disease 2019 (COVID-19) pathological conditions in global or cell-specific knockouts in the humanised angiotensin-converting enzyme (hACE2) mouse model will enable investigators to dissect the inflammatory immune cascades that are involved in disease pathology. As shown, the blockade of cell-specific receptors, T-helper (Th)1 and/or Th2 cytokines, complement activation, renin–angiotensin system pathway activity, administration of mesenchymal stem cells, and antithrombotic treatments could all be useful as therapeutic targets in COVID-19.
Tables
- TABLE 1
Key features of mouse models used in studies of coronavirus infections
Mouse line Disease model Key findings [Ref.] Wildtype SARS SARS-CoV infections resulted into shedding of large amounts of infectious virus with the development of lung injury due to lowering of ACE2 expression [64] SARS SARS-CoV-infected C3−/− mice exhibited significantly less weight loss and less respiratory dysfunction with reduced lung pathology and lower cytokine and chemokine levels in both the lungs and the sera [65] Ace2−/− SARS SARS-CoV infections resulted in less shedding infectious virus with mild lung pathological changes due to reduced amount of spike RNA [64] ARDS/SARS ACE2 blockade in mice resulted into enhanced vascular permeability, increased lung oedema, neutrophil accumulation, and worsened lung function [53, 64] Tmprss2−/− SARS SARS-CoV infection in Tmprss2−/− mice showed attenuated inflammatory chemokine and/or cytokine responses [33] COVID-19 Transcriptional downregulation of Tmprss2 inhibits host SARS-CoV-2 entry. [63] Tmprss2−/− hDPP4-Tg MERS Tmprss2−/− murine models infected by MERS-CoV showed improved immunopathology [33] hACE2 COVID-19 Mouse model of COVID-19 showing similar pattern of human interstitial pneumonia with infiltration of significant macrophages and lymphocytes into the alveolar interstitium, and accumulation of macrophages in alveolar cavities following SARS-CoV-2 infection [6, 7, 66] hACE2 COVID-19 This model developed productive SARS-CoV-2 infection and inflammatory pulmonary infiltrates as seen in COVID-19 patients
Evidence of inadequate antiviral activity and potential harms of endogenous type I IFN responses were observed[5] C3−/− SARS SARS-CoV-infected C3−/− mice exhibited significantly less weight loss and less respiratory dysfunction with reduced lung pathology and lower cytokine and chemokine levels in both the lungs and the sera [65] Ace2−/−: angiotensinogen converting enzyme 2 knockout; SARS: severe acute respiratory syndrome; CoV: coronavirus; C3−/−: complement 3 knockout; ARDS: acute respiratory distress syndrome; Tmprss2−/−: transmembrane protease, serine 2 knockout; COVID-19: coronavirus disease 2019; hDPP4-Tg: human dipeptidyl peptidase 4 transgene; MERS: Middle East Respiratory Syndrome; hACE-2: transgenic mice bearing human ACE2; IFN: interferon.
Jump To
- Article
- Abstract
- Abstract
- Introduction
- Origin of SARS-COV-2 and mode of transmission to humans
- ACE2: a portal of entry for SARS-CoV-2
- Role of animal models in elucidating the pathogenesis of COVID-19
- The pulmonary pathophysiology of COVID-19
- Potential molecular and biochemical therapeutic targets in the host
- Footnotes
- References
- Figures & Data
- Info & Metrics