Issue 6: Understanding ACE2 in COVID-19 (APRIL 10, 2020)

UNDERSTANDING ACE2 IN COVID-19

  • Receptor recognition is an important factor for virus recognition, entry into host cells, and subsequent infection​.
  • Angiotensin converting enzyme 2 (ACE2) is known to be the cellular receptor of SARS-CoV-21,2.
  • ACE2 is a homolog of ACE, and both enzymes have different functions.
  • ACE2 is initially attached to cell membrane. Once activated, the ADAM-17 metalloproteinase cleaves the ACE2 membrane “stalk”, causing ACE2 shedding.
  • The ACE2 enzyme can then cleave angiotensin II (ANG) to form ANG(1–7) or ANG(1-9). These, in turn, bind to MasR on the membrane, exerting protective effects.
  • This ACE2‐Ang 1‐7‐MasR‐based pathway plays a role in negative regulation,  balancing the classical Renin-Angiotensin-System (RAS) axis through antagonistic effect3 (figure 1).

Figure 1. ACE2-Ang 1-7-MasR-based pathway5

  • ACE2 is expressed in the lung, kidney, CNS, and heart. Lung tissue is the leading site of angiotensin II production, and ACE2 has been shown to be protective of vascular and organ functions such as hypertension, cognition, cardiovascular disease (CVD), and diabetes4,5.
  • Researchers have shown that:
    1. ACE2 is expressed in  alveolar epithelial type II cells (AECIIs), suggesting that these cells can serve as a reservoir for viral invasion6,
    2. SARS-CoV-2 can invade AECII, and
    3. COVID‐19 and SARS ARDS  patients have similar and typical ARDS pathology in the lung.
  • When SARS-CoV-2 enters AECIIs in the lung via ACE2 binding, the classical RAS pathway is activated and inflammation is exacerbated, particularly in the lung. This could account for the observed high incidence of pneumonia in COVID-19 cases.

POTENTIAL REASONS FOR  REPORTED DIFFERENCES IN SEVERITY AMONG PATIENTS

  • First, ACE2 mutations at virus-binding “hotspots” could enable structural changes in ACE2 allelic variants, modifying molecular interactions with SARS-CoV-2 spike protein and  potentially reducing resistance to infection7,8.
  • Another reason is potential selection bias in the early data from on Wuhan, where more severely affected patients were admitted to hospitals due to the region’s insufficient healthcare resource. Those studies reported that   adults and those with underlying conditions comprised most of the COVID-19 cases reported,  leading to the assumption that  children were less affected9. However, up to 12% of children tested positive for SARS-CoV-2, similar to the general population.
  • While infection potential in children compared to adults appears to be similar10, differences in severity of disease symptoms between these groups suggest that age  could play a role in COVID-19 progression.5 For instance, increased disease severity in adults could be related to aging of the immune system, where  cells become senescent. Zhao et al. speculated that the young immune system in children, with its efficient T cells in the lungs, could better respond to SARS-CoV-2 than the immune system of older patients11.
  • During aging, the balance between the two main enzymes of the pulmonary RAS, ACE and ACE 2, tends toward a higher ACE/ACE2 ratio, leading to inflammation and lung injury4. Hence, older patients could be at higher risk for  severe lung disease if infected by SARS-CoV-2.
  • Lastly, ACE2 levels  appear to be increased in patients with CVD and comorbid conditions12-14. Chen et al. further reported that cardiac pericytes with high ACE2 expression could act as a target for SARS-CoV-2, leading to cellular damage and capillary  damage endothelial cell dysfunction15. Based on this, patients with CVD or high burden of disease could potentially be and increased risk of SARS-Co-V-2  infection.
  • Current data provides increased understanding of COVID-19 pathogenesis. However, there are still many unknowns as we continue to navigate through this rapidly evolving  landscape.

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