Section 2: SARS-CoV-2 Biology and Clinical Implications (from DOI: 10.1007/s11886-020-01293-2)
From publication: "Cardiovascular Risks in Patients with COVID-19: Potential Mechanisms and Areas of Uncertainty" published as Curr Cardiol Rep; 2020 04 29 ; 22 (5) 34. DOI: https://doi.org/10.1007/s11886-020-01293-2
Section 2: SARS-CoV-2 Biology and Clinical Implications
Coronaviridae, a family of positive strand RNA viruses causing human respiratory infections, was named for the crown-shaped outer coat seen on the electron-microscopy. First discovered in the 1960s, it received great attention during the 2003 SARS coronavirus (SARS-CoV) outbreak. There is approximately an 80% nucleotide sequence similarity between SARS-CoV and SARS-CoV-2, the pathogen of COVID-19. Hence, most of our understanding of the biology of SARS-CoV-2 has been extrapolated from prior research on the original SARS virus.
The "crown" seen on electron microscopy are protruding proteins called "spike proteins" which are essential to viral entry into human cells (Fig. 1a). Studies in mice and human cells demonstrated that the SARS virus enters into the cell via contact between the spike protein and angiotensin-converting enzyme 2 (ACE2), a regulator of the renin/angiotensin pathway expressed on a subset of cell surfaces. The contact of these two proteins triggers cleavage of the viral spike protein via an enzyme transmembrane protease, serine 2 (TMPRSS2), which then activates a cascade of molecular events leading to the fusion of the viral membrane envelope with the plasma membrane of the host cells and subsequent entry of viral contents into the cytoplasm. The spike protein of SARS-CoV and SARS-CoV-2 shares 76% of amino acid sequence and an overall conservation of structure. In vitro studies suggest SARS-CoV-2 may have an even higher affinity towards binding of ACE2, which may partially explain its higher transmission rate compared to SARS-CoV. As in SARS-CoV, in vitro studies showed SARS-CoV-2 enters the cell through ACE2, and inhibitors of the protease TMPRSS2 impairs viral entry . It is most likely that ACE2 is the primary receptor by which viral entry occurs, but whether additional receptors exist for SARS-CoV-2 remains unknown.
Given the likely importance of ACE2 in pathogenesis of COVID19 and the respiratory tract being the primary site of viral entry into the body, investigators have focused on type 2 pneumocytes in alveoli as the presumed target cells of SARS-CoV-2, given that these cells express the highest level of ACE2 and TMPRSS2 in the human lung. The viral infection and injury of these pneumocytes are thought to be central to the prominent diffuse alveolar damage seen on pathology of patients with COVID19. Interestingly, ACE2 expression is low in the lower airways, but more elevated in nasal ciliated and goblet cells, which may explain the symptom of anosmia which has been recently reported by Brann et al.. At the organ level, however, respiratory tissue carries significantly less ACE2 (by 10-100-fold) than the digestive organs, kidneys, and heart (Fig. 1b). The high expression of ACE2 in the GI tract was thought to explain the frequent occurrence of GI symptoms with SARS. However, while GI symptoms are present in COVID-19 patients, they do not appear to be as frequent compared to SARS, suggesting key vector-specific differences in tissue tropism. There are reports, however, of detection of viral RNA in the stool of asymptomatic patients, which raises the possibility of additional routes of asymptomatic spread. The relatively elevated expression of ACE2 levels in the heart compared to the lungs also lends biological plausibility for the perceived elevated incidence of cardiac injuries seen in COVID-19 patients.
The central role of ACE2 in viral entry in combination with reported worse outcomes seen in patients with hypertension and diabetes fueled much of the speculation that ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), both commonly used by hypertensive or diabetic patients, may play a role in the observed increased risk. The evidence was mostly based on studies that have demonstrated a moderate increase in Ace2 expression in the mouse heart treated with ACEIs. However, there is no such report of ACE2 level alterations in the lungs thus far. While theoretically, increased ACE2 expression in the lungs may lead to worsened viral entry, the potential worsening of respiratory status and progression to ARDS in hypertensive and diabetic patients taking ACE inhibitors remains speculative. In addition, ACE2 is thought to be potentially protective in acute lung injury and ARDS, as the genetic knockout of Ace2 in rodents results in worsened lung injury, and overexpression of Ace2 in the lung is protective. This protective role of ACE2 is hypothesized to be due to modulation of the angiotensin response to lung, immune, and vascular cells within the pulmonary system. To address the role of angiotensin in lung injury, there is an ongoing clinical trial to examine whether losartan treatment affects outcomes in COVID-19 associated ARDS (NCT04312009). Given the known benefit of ACEI/ARB treatment in patients with diabetes mellitus, heart failure, and hypertension, many societies including the American College of Cardiology, American Heart Association, Heart Failure Society of American, and the European Society of Cardiology have released statements to advise against discontinuation of these medications in COVID-19 patients until more data are available.
