Epithelial and Endothelial Expressions of ACE2: SARS-CoV-2 Entry Routes.

Angiotensin converting enzyme 2 (ACE2) is a main receptor for SARS-CoV-2 entry to the host cell. ACE2 is one of the key enzymes in renin-angiotensin system and plays a vital role in the maintenance of cardiovascular function. ACE/ACE2 balance is critical in the regulation of blood pressure, electrolyte homeostasis, vascular and cardiac remodeling and inflammation. ACE2 was shown to be abundantly present in human epithelial cells of the lung and enterocytes of the small intestine as well as in endothelial cells of the arterial and venous vessels. ACE2 and TMPRSS2 are colocalized on the cell surface and produced a critical step host cell entry of SARS-CoV-2. TMPRSS2-cleaved ACE2 permits SARS-CoV-2 host cell entry however, ADAM17-cleaved ACE2 produces protective effects in several organs. Differently, basigin (CD147) was suggested as a putative alternate receptor for SARS-CoV-2 entry into endothelial cells. The intestinal ACE2 receptor is associated with the neutral amino acid transporter B0AT1 and ACE2 is necessary for the expression of this transporter on the luminal surface of intestinal epithelial cells. There is a good association between the localization of SARS-CoV-2 binding receptor ACE2 and the disease target organs in respiratory, cardiovascular and gastrointestinal systems. Decreased expression of ACE2, being a receptor for coronavirus, would prevent cellular entry of the virus thereby reducing progression of the infection. However, increased ACE2 expression produces beneficial health effects. Further studies are needed to clarify this conflicting situation. Currently, it is recommended to continue the therapy with ACE2-increasing drugs in patients with COVID-19.

A pressor dose of angiotensin II has no influence on the angiotensin-converting enzyme 2 and other molecules associated with SARS-CoV-2 infection in mice.

In the early phase of the Coronavirus disease 2019 (COVID-19) pandemic, it was postulated that the renin-angiotensin-system inhibitors (RASi) increase the infection risk. This was primarily based on numerous reports, which stated that the RASi could increase the organ Angiotensin-converting enzyme 2 (ACE2), the receptor of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in rodents. RASi can theoretically antagonize the potential influence of angiotensin II (Ang II) on ACE2. However, while Ang II decreases the ACE2 levels in cultured cells, there is little evidence that supports this phenomenon in living animals. In this study, we tested whether Ang II or Ang II combined with its antagonist would alter the ACE2 and other molecules associated with the infection of SARS-CoV-2. Male C57BL6/J mice were administered vehicle, Ang II (400 ng/kg/min), or Ang II with losartan (10 mg/kg/min) for 2 weeks. ACE2 knockout mice were used as a negative control for the ACE2 assay. We found that both Ang II, which elevated blood pressure by 30 mm Hg, and Ang II with losartan, had no effect on the expression or protein activity of ACE2 in the lung, left ventricle, kidney, and ileum. Likewise, these interventions had no effect on the expression of Transmembrane Protease Serine 2 (TMPRSS2) and Furin, proteases that facilitate the virus-cell fusion, and the expression or activity of Tumor Necrosis Factor α-Convertase (TACE) that cleaves cell-surface ACE2. Collectively, physiological concentrations of Ang II do not modulate the molecules associated with SARS-CoV-2 infection. These results support the recent observational studies suggesting that the use of RASi is not a risk factor for COVID-19.

The Spatial and Cell-Type Distribution of SARS-CoV-2 Receptor ACE2 in the Human and Mouse Brains.

By engaging angiotensin-converting enzyme 2 (ACE2 or Ace2), the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades host cells and affects many organs, including the brain. However, the distribution of ACE2 in the brain is still obscure. Here, we investigated the ACE2 expression in the brain by analyzing data from publicly available brain transcriptome databases. According to our spatial distribution analysis, ACE2 was relatively highly expressed in some brain locations, such as the choroid plexus and paraventricular nuclei of the thalamus. According to cell-type distribution analysis, nuclear expression of ACE2 was found in many neurons (both excitatory and inhibitory neurons) and some non-neuron cells (mainly astrocytes, oligodendrocytes, and endothelial cells) in the human middle temporal gyrus and posterior cingulate cortex. A few ACE2-expressing nuclei were found in a hippocampal dataset, and none were detected in the prefrontal cortex. Except for the additional high expression of Ace2 in the olfactory bulb areas for spatial distribution as well as in the pericytes and endothelial cells for cell-type distribution, the distribution of Ace2 in the mouse brain was similar to that in the human brain. Thus, our results reveal an outline of ACE2/Ace2 distribution in the human and mouse brains, which indicates that the brain infection of SARS-CoV-2 may be capable of inducing central nervous system symptoms in coronavirus disease 2019 (COVID-19) patients. Potential species differences should be considered when using mouse models to study the neurological effects of SARS-CoV-2 infection.

Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications.

The widespread occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a pandemic of coronavirus disease 2019 (COVID-19). The S spike protein of SARS-CoV-2 binds with angiotensin-converting enzyme 2 (ACE2) as a functional "receptor" and then enters into host cells to replicate and damage host cells and organs. ACE2 plays a pivotal role in the inflammation, and its downregulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury and involving inflammatory responses. Severe patients of COVID-19 often develop acute respiratory distress syndrome and multiple organ dysfunction/failure with high mortality that may be closely related to the hyper-proinflammatory status called the "cytokine storm." Massive cytokines including interleukin-6, nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) released from SARS-CoV-2-infected macrophages and monocytes lead inflammation-derived injurious cascades causing multi-organ injury/failure. This review summarizes the current evidence and understanding of the underlying mechanisms of SARS-CoV-2, ACE2 and inflammation co-mediated multi-organ injury or failure in COVID-19 patients.

Coronaviruses and Endocrine System: A Systematic Review on Evidence and Shadows.

Coronaviruses are a big family of viruses that can infect mammalians and birds. In humans they mainly cause respiratory tract infections, with a large spectrum of severity, from mild, self-limited infections to highly lethal forms as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and Coronavirus Disease 2019 (COVID-19). Scanty data are reported for the involvement of endocrine glands in human coronaviruses, in particular SARS-CoV-2. In this review, we summarize endocrinological involvement in human coronaviruses, including data on animal coronaviruses. Avians, ferrets and bovine are affected by specific coronavirus syndromes, with variable involvement of endocrine glands. SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as a target receptor, so ACE2 plays a central role in viral transmission and initial organ involvement. Autoptic studies on SARS patients revealed that thyroid, parathyroid, pituitary gland, endocrine pancreas and especially adrenals and testis could be impaired by different mechanisms (direct damage by SARS-CoV, inflammation, vascular derangement and autoimmune reactions) and few clinical studies have evidenced functional endocrine impairment. Only few data are available for COVID-19 and gonads and endocrine pancreas seem to be involved. International endocrinological societies have brought some recommendations for the COVID-19 pandemic, but further studies need to be performed, especially to detect long-term hormonal sequelae.

ACE2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19.

At the end of 2019, the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. Currently, it is breaking out globally and posing a serious threat to public health. The typically clinical characteristics of COVID-19 patients were fever and respiratory symptoms, and a proportion of patients were accompanied by extrapulmonary symptoms including cardiac injury, kidney injury, liver injury, digestive tract injury, and neurological symptoms. Angiotensin converting enzyme 2 (ACE2) has been proven to be a major receptor for SARS-CoV-2 and could mediate virus entry into cells. And transmembrane protease serine 2 (TMPRSS2) could cleave the spike (S) protein of SARS-CoV-2, which facilitates the fusion of SARS-CoV-2 and cellular membranes. The mRNA expressions of both ACE2 and TMPRSS2 were observed in the heart, digestive tract, liver, kidney, brain and other organs. SARS-CoV-2 may have a capacity to infect extrapulmonary organs due to the expressions of ACE2 and TMPRSS2 in the cells and tissues of these organs. It seems that there is a potential involvement of ACE2 and TMPRSS2 expressions in the virus infection of extrapulmonary organs and the manifestation of symptoms related to these organs in patients with COVID-19. Here, we revealed the expressions of ACE2 and TMPRSS2 in extrapulmonary organs, and we also summarized the clinical manifestation and the management of extrapulmonary complications in patients with COVID-19.

Expression of the SAR2-Cov-2 receptor ACE2 reveals the susceptibility of COVID-19 in non-small cell lung cancer.

Recent studies have revealed that cancer patients had a higher risk of having coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), compared to patients without cancer. The expression of angiotensin-converting enzyme 2 (ACE2), the receptor of SARS-CoV-2, was aberrantly expressed in many tumors. In this study, by exploring the TCGA and GTEx public databases, we investigated ACE2 expression and its association with prognosis in non-small cell lung cancer (NSCLC), the most susceptible caner type. We found that lung was one of the major organs with highly expressed ACE2. Furthermore, ACE2 expression was significantly elevated in lung adenocarcioma (LUAD) and lung squamous cell carcinoma (LUSC) compared to normal tissues. DNA methylation might be one possible mechanism leading to ACE2 upregulation. Despite that, the AEC2 expression was not statistically associated with disease-free survival (DFS) and overall survival (OS) for LUAD patients, and higher ACE2 expression was associated with prolonged DFS in LUSC patients. Taken together, we observed ACE2 was highly expressed in LUAD and LUSC despite the controversial role of ACE2 expression in predicting prognosis in these two common lung cancer types.

SARS-CoV-2 pandemic and research gaps: Understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy.

The COVID-19 pandemic is an emerging threat to global public health. While our current understanding of COVID-19 pathogenesis is limited, a better understanding will help us develop efficacious treatment and prevention strategies for COVID-19. One potential therapeutic target is angiotensin converting enzyme 2 (ACE2). ACE2 primarily catalyzes the conversion of angiotensin I (Ang I) to a nonapeptide angiotensin or the conversion of angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and has direct effects on cardiac function and multiple organs via counter-regulation of the renin-angiotensin system (RAS). Significant to COVID-19, ACE2 is postulated to serve as a major entry receptor for SARS-CoV-2 in human cells, as it does for SARS-CoV. Many infected individuals develop COVID-19 with fever, cough, and shortness of breath that can progress to pneumonia. Disease progression promotes the activation of immune cells, platelets, and coagulation pathways that can lead to multiple organ failure and death. ACE2 is expressed by epithelial cells of the lungs at high level, a major target of the disease, as seen in post-mortem lung tissue of patients who died with COVID-19, which reveals diffuse alveolar damage with cellular fibromyxoid exudates bilaterally. Comparatively, ACE2 is expressed at low level by vascular endothelial cells of the heart and kidney but may also be targeted by the virus in severe COVID-19 cases. Interestingly, SARS-CoV-2 infection downregulates ACE2 expression, which may also play a critical pathogenic role in COVID-19. Importantly, targeting ACE2/Ang 1-7 axis and blocking ACE2 interaction with the S protein of SARS-CoV-2 to curtail SARS-CoV-2 infection are becoming very attractive therapeutics potential for treatment and prevention of COVID-19. Here, we will discuss the following subtopics: 1) ACE2 as a receptor of SARS-CoV-2; 2) clinical and pathological features of COVID-19; 3) role of ACE2 in the infection and pathogenesis of SARS; 4) potential pathogenic role of ACE2 in COVID-19; 5) animal models for pathological studies and therapeutics; and 6) therapeutics development for COVID-19.