Downregulation Of Angiotensin-converting Enzyme 2 Research Articles

Differential Ability of Spike Protein of SARS-CoV-2 Variants to Downregulate ACE2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 19 (COVID-19) and employs angiotensin-converting enzyme 2 (ACE2) as the receptor. Although the expression of ACE2 is crucial for cellular entry, we found that the interaction between ACE2 and the Spike (S) protein in the same cells led to its downregulation through degradation in the lysosomal compartment via the endocytic pathway. Interestingly, the ability of the S protein from previous variants of concern (VOCs) to downregulate ACE2 was variant-dependent and correlated with disease severity. The S protein from the Omicron variant, associated with milder disease, exhibited a lower capacity to downregulate ACE2 than that of the Delta variant, which is linked to a higher risk of hospitalization. Chimeric studies between the S proteins from the Delta and Omicron variants revealed that both the receptor-binding domain (RBD) and the S2 subunit played crucial roles in the reduced ACE2 downregulation activity observed in the Omicron variant. In contrast, three mutations (L452R/P681R/D950N) located in the RBD, S1/S2 cleavage site, and HR1 domain were identified as essential for the higher ACE2 downregulation activity observed in the Delta variant compared to that in the other VOCs. Our results suggested that dysregulation of the renin-angiotensin system due to the ACE2 downregulation activity of the S protein of SARS-CoV-2 may play a key role in the pathogenesis of COVID-19.

Sirt1 activation prevents high glucose-induced angiotensin converting enzyme 2 downregulation in renal tubular cells by regulating the TIMP3/ADAM17 pathway.

Angiotensin converting enzyme 2 (ACE2) exerts renoprotective effects in diabetic kidney disease (DKD) by converting angiotensin (Ang) II into Ang(1-7). Previous studies have demonstrated that ACE2 expression in renal tubules is downregulated in DKD, but the mechanism is not fully understood. Sirtuin-1 (Sirt1) is a protein deacetylase that may regulate the activity of the renin-angiotensin system. The present study investigated the effects of Sirt1 on ACE2 expression under high glucose (HG) conditions and the underlying signaling pathway. Rats with DKD and NRK-52E cells cultured with HG were employed in this study. Western blotting, immunohistochemistry detection and qRT-PCR were performed for protein and mRNA expression analyses. Rats subjected to DKD displayed downregulated expression of Sirt1 and ACE2 in kidneys. Resveratrol, an activator of Sirt1, restored ACE2 expression and ameliorated renal injuries. Similarly, pharmacological activation of Sirt1 with SRT1720 markedly upregulated ACE2 in NRK-52E cells cultured with HG, while Sirt1 small interfering RNA (siRNA) further suppressed ACE2 expression. In addition, A disintegrin and metalloproteinase (ADAM) 17 was observed to be upregulated, and its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3), was downregulated in the kidneys of diabetic rats and NRK-52E cells incubated with HG. The TIMP3/ADAM17 pathway was involved in the regulation of ACE2 expression, as evidenced by decreased ACE2 expression levels after TIMP3-siRNA pretreatment. SRT1720 ameliorated the imbalance of TIMP3/ADAM17 induced by HG and consequently enhanced the expression of ACE2. Notably, the above effect of SRT1720 on ACE2 was interrupted by TIMP3-siRNA. Our findings suggest that Sirt1 activation may prevent HG-induced downregulation of renal tubular ACE2 by modulating the TIMP3/ADAM17 pathway. Sirt1 stimulation might be a potential strategy for the treatment of DKD.

SARS-CoV-2 Vaccination and the Multi-Hit Hypothesis of Oncogenesis.

Cancer is a complex and dynamic disease. The "hallmarks of cancer" were proposed by Hanahan and Weinberg (2000) as a group of biological competencies that human cells attain as they progress from normalcy to neoplastic transformation. These competencies include self-sufficiency in proliferative signaling, insensitivity to growth-suppressive signals and immune surveillance, the ability to evade cell death, enabling replicative immortality, reprogramming energy metabolism, inducing angiogenesis, and activating tissue invasion and metastasis. Underlying these competencies are genome instability, which expedites their acquisition, and inflammation, which fosters their function(s). Additionally, cancer exhibits another dimension of complexity: a heterogeneous repertoire of infiltrating and resident host cells, secreted factors, and extracellular matrix, known as the tumor microenvironment, that through a dynamic and reciprocal relationship with cancer cells supports immortality, local invasion, and metastatic dissemination. This staggering intricacy calls for caution when advising all people with cancer (or a previous history of cancer) to receive the COVID-19 primary vaccine series plus additional booster doses. Moreover, because these patients were not included in the pivotal clinical trials, considerable uncertainty remains regarding vaccine efficacy, safety, and the risk of interactions with anticancer therapies, which could reduce the value and innocuity of either medical treatment. After reviewing the available literature, we are particularly concerned that certain COVID-19 vaccines may generate a pro-tumorigenic milieu (i.e., a specific environment that could lead to neoplastic transformation) that predisposes some (stable) oncologic patients and survivors to cancer progression, recurrence, and/or metastasis. This hypothesis is based on biological plausibility and fulfillment of the multi-hit hypothesis of oncogenesis (i.e., induction of lymphopenia and inflammation, downregulation of angiotensin-converting enzyme 2 (ACE2) expression, activation of oncogenic cascades, sequestration of tumor suppressor proteins, dysregulation of the RNA-G quadruplex-protein binding system, alterationof type I interferon responses, unsilencing of retrotransposable elements, etc.) together with growingevidence and safety reports filed to Vaccine Adverse Effects Report System (VAERS) suggesting that some cancer patients experienced disease exacerbation or recurrence following COVID-19 vaccination. In light of the aboveand because some of these concerns (i.e., alteration of oncogenic pathways, promotion of inflammatory cascades, and dysregulation of the renin-angiotensin system) also apply to cancer patients infected with SARS-CoV-2, we encourage the scientific and medical community to urgently evaluate the impact of both COVID-19 and COVID-19 vaccination on cancer biology and tumor registries, adjusting public health recommendations accordingly.

Serum Soluble Angiotensin-Converting Enzyme-2 Level and Its Potential Association With The Renin-Angiotensin-Aldosterone System in Non-Hypertensive Iraqi COVID-19 Patients: An Observational Study

Background: The novel coronavirus disease (COVID-19) is caused by Severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) which utilizes angiotensin converting enzyme2 (ACE2) to invade the host cells. This membrane-bound peptidase is widely distributed in the body; its activity antagonizes the renin-angiotensin-aldosterone system (RAAS). Once SARS-Cov2 enters the cell, it causes downregulation of ACE2, resulting in the unopposed activation of RAAS. The unregulated activity of the RAAS system can deteriorate the prognosis in COVID-19 patients. A soluble form of ACE2 (sACE2) was reported to have a role in the SARS-Cov2 invasion of the susceptible cells.
 Aim of the study: This study aims to investigate the potential association of serum levels of sACE2 and RAAS components in severe COVID-19 patients compared to healthy individuals.
 Methods: Eighty-five participants enrolled in the study were grouped into 45 non-hypertensive severe COVID-19 patients and 40 healthy individuals with comparable age and gender. Serum levels of sACE2, renin, angiotensin 2, and aldosterone by ELISA, and serum potassium level was measured by turbidimetric method.
 Results: The results showed a significant difference in the serum levels of sACE2 (lower), renin, angiotensin 2, and aldosterone (higher) in COVID-19 patients compared to the control subjects (p-value <0.001; for all.
 Conclusion: Non-hypertensive severe COVID-19 patients have lower sACE2 and higher RAAS peptide levels, and they can serve as diagnostic markers of severe COVID-19 patients.
 Recommendations: we recommend a future study with a larger sample size that enrolls COVID-19 patients with different severity levels.
 Keywords: Aldosterone, Angiotensin, COVID-19, Renin, Soluble angiotensin converting enzyme 2

Post-COVID-19 Syndrome vs. Consequences of Vaccination with Special Reference to Cardiovascular Conditions

Consequences of COVID-19 vaccination partly overlap with symptoms of post-COVID-19 syndrome. Putative mechanisms are also overlapping: endothelial damage and hyper coagulation, hypoxia, autoimmunity, inflammation, downregulation of angiotensin-converting enzyme.

Abstract P218: Ubr1 And Nedd4-2 Synergistically Modulate Ace2 Ubiquitination In Hypertensive Male Mice

Angiotensin-converting enzyme 2 (ACE2) is a counter-regulatory player in the renin-angiotensin system (RAS). Downregulation of ACE2 in hypertension results in vasoconstriction, sympathetic over-activation, and hypertension. Recently, we identified UBR1, an E3 ubiquitin-protein ligase, as a potential ubiquitinase modulating ACE2 expression, notably in hypertensive male mice where UBR1 is upregulated in the hypothalamus and peripheral organs. Here, we aim to understand the role of UBR1 in hypertension and its crosstalk with Nedd4-2, another E3 ligase regulating ACE2. C57BI/6J male mice (3 month-old, n=18) were implanted with telemetry probes for weekly 24 h BP recording. One week following baseline BP recording, mice were implanted with subcutaneous osmotic pumps containing Ang-II (600 ng/kg/min). After confirming hypertension, mice were divided into 4 treatment groups (n=6/group); 1) peripheral UBR1 siRNA via osmotic pump (50 μg/day/2 weeks), 2) central UBR1 siRNA via intracerebroventricular infusion (ICV) (50 μg/day/2 weeks) 3) scrambled shRNA + Ang-II, and 4) no treatment. After 6 weeks of BP recording, mice were euthanized, and hypothalami were harvested for protein analysis (Capillary Western). BP was transiently reduced during the resting phase after 3 weeks of ICV UBR1 siRNA infusion compared to the Ang-II group (MAP: 114±7 vs . 135±3 mmHg). Ang-II infusion enhanced UBR1 protein levels versus no treatment (Fold Change:1.6±0.1 vs . 1.0±0.04; p<0.05) which was prevented by peripheral and central UBR1 siRNA infusion, respectively (0.7±0.08, 1.3±0.08 vs. 1.6±0.1, p<0.05). Interestingly, while UBR1 siRNA infusion increased ACE2 expression (1.7±0.1, 2±0.2, p<0.01, respectively), it was also associated with increased Nedd4-2 levels ( 2.9±0.1, 3.5±0.2, p<0.0001, respectively), and pNedd4-2 (4.1±0.4, 3.8±0.5, p<0.001, respectively). Together, these data suggest that while prevention of UBR1 upregulation in hypertension is associated with an increase in ACE2 expression, it is not sufficient to permanently reduce BP as other E3 ligases, like Nedd4-2, appear to compensate for the knockdown.

Meta-Analysis of the Mechanisms Underlying COVID-19 Modulation of Parkinson's Disease.

Coronavirus disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a "cytokine storm", and neuroinflammation. COVID-19's upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by the formation of Lewy bodies made primarily of the α-synuclein protein encoded by the synuclein alpha (SNCA) gene. We hypothesize that COVID-19 may modulate PD progression through neuroinflammation induced by cytokine storms. This study aimed to elucidate the possible mechanisms and signaling pathways involved in COVID-19-triggered pathology associated with neurodegenerative diseases like PD. This study presents the analysis of the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN's Ingenuity Pathway Analysis (IPA), the study identified the NISP as a top-five canonical pathway/signaling pathway and SNCA as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and SNCA to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of SNCA, and subsequently PD, through a dataset of intermediary molecules. Downstream effect analysis was further used to quantify the downregulation of ACE2 on SNCA activation.

Altered renin-angiotensin system gene expression in airways of antigen-challenged mice: ACE2 downregulation and unexpected increase in angiotensin 1–7

ObjectiveEvidence suggest that the renin-angiotensin system (RAS) is activated in people with asthma, although its pathophysiological role is unclear. Angiotensin-converting enzyme 2 (ACE2) is the major enzyme that converts angiotensin II to angiotensin 1–7 (Ang-1–7), and is also known as a receptor of SARS-CoV-2. The current study was conducted to identify the change in RAS-related gene expression in airways of a murine asthma model. MethodsThe ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction. Twenty-four hours after the last antigen challenge, the main bronchial smooth muscle (BSM) tissues were isolated. ResultsThe KEGG pathway analysis of differentially expressed genes in our published microarray data revealed a significant change in the RAS pathway in the antigen-challenged mice. Quantitative RT-PCR analyses showed significant increases in the angiotensin II-generating enzymes (Klk1, Klk1b3 and Klk1b8) and a significant decrease in Ace2. Surprisingly, ELISA analyses revealed a significant increase in Ang-1–7 levels in bronchoalveolar lavage (BAL) fluids of the antigen-challenged animals, while no significant change in angiotensin II was observed. Application of Ang-1–7 to the isolated BSMs had no effect on their isometrical tension. ConclusionThe expression of Ace2 was downregulated in the BSMs of OA-challenged mice, while Klk1, Klk1b3 and Klk1b8 were upregulated. Despite the downregulation of ACE2, the level of its enzymatic product, Ang-1–7, was increased in the inflamed airways, suggesting the existence of an unknown ACE2-independent pathway for Ang-1–7 production. The functional role of Ang-1–7 in the airways remains unclear.

Brain Renin-Angiotensin System: From Physiology to Pathology in Neuronal Complications Induced by SARS-CoV-2.

Angiotensin-converting enzyme 2 (ACE2), a key enzyme in the renin-angiotensin system (RAS), is expressed in various tissues and organs, including the central nervous system (CNS). The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease-2019 (COVID-19), binds to ACE2, which raises concerns about the potential for viral infection in the CNS. There are numerous reports suggesting a link between SARS-CoV-2 infection and neurological manifestations. This study aimed to present an updated review of the role of brain RAS components, especially ACE2, in neurological complications induced by SARS-CoV-2 infection. Several routes of SARS-CoV-2 entry into the brain have been proposed. Because an anosmia condition appeared broadly in COVID-19 patients, the olfactory nerve route was suggested as an early pathway for SARS-CoV-2 entry into the brain. In addition, a hematogenous route via disintegrations in the blood-brain barrier following an increase in systemic cytokine and chemokine levels and retrograde axonal transport, especially via the vagus nerve innervating lungs, have been described. Common nonspecific neurological symptoms in COVID-19 patients are myalgia, headache, anosmia, and dysgeusia. However, more severe outcomes include cerebrovascular diseases, cognitive impairment, anxiety, encephalopathy, and stroke. Alterations in brain RAS components such as angiotensin II (Ang II) and ACE2 mediate neurological manifestations of SARS-CoV-2 infection, at least in part. Downregulation of ACE2 due to SARS-CoV-2 infection, followed by an increase in Ang II levels, leads to hyperinflammation and oxidative stress, which in turn accelerates neurodegeneration in the brain. Furthermore, ACE2 downregulation in the hypothalamus induces stress and anxiety responses by increasing corticotropin-releasing hormone. SARS-CoV-2 infection may also dysregulate the CNS neurotransmission, leading to neurological complications observed in severe cases of COVID-19. It can be concluded that the neurological manifestations of COVID-19 may be partially associated with changes in brain RAS components.

Significance of Furin Expression in Thyroid Neoplastic Transformation.

Angiotensin-Converting Enzyme 2 (ACE2), Transmembrane Serine Protease 2 (TMPRSS2), and Furin were known to be key players in the SARS-CoV-2 infection, and the thyroid gland was revealed to be one of the relevant targets of the virus. Regardless of the viral infection, the expression of these molecules in the thyroid gland and their putative role in the neoplastic transformation of the thyrocytes has not been thoroughly explored. In this work, we aimed to characterize the mRNA and protein expression pattern of ACE2, TMPRSS2, and Furin in a series of patients with thyroid lesions. Our main results revealed a significantly decreased expression of ACE2 mRNA in the thyroid neoplasms in comparison to normal adjacent tissue. Furin mRNA was significantly increased in thyroid neoplasms when compared to normal adjacent tissue. In addition, a higher Furin mRNA level in thyroid carcinomas was associated with the presence of lymph node metastasis. Furin mRNA expression revealed a high discriminatory power between adjacent tissue and neoplasms. Protein expression of these molecules did not correlate with mRNA expression. Our study shows the mRNA downregulation of ACE2 and overexpression of Furin in thyroid neoplasms. Further studies are required to clarify if Furin expression can be a potential diagnostic indicator in thyroid neoplasia.

Functional characterisation of the ACE2 orthologues in Drosophila provides insights into the neuromuscular complications of COVID-19

SARS-CoV-2, the virus responsible for the coronavirus disease of 2019 (COVID-19), gains cellular entry via interaction with the angiotensin-converting enzyme 2 (ACE2) receptor of host cells. Although SARS-CoV-2 mainly targets the respiratory system, the neuromuscular system also appears to be affected in a large percentage of patients with acute or chronic COVID-19. The cause of the well-described neuromuscular manifestations resulting from SARS-CoV-2 infection remains unresolved. These may result from the neuromuscular-invasive capacity of the virus leading to direct injury. Alternatively, they may be the consequence of ACE2 inactivation either due to viral infection, ACE2 autoantibodies or both. Here, we made use of the Drosophila model to investigate whether ACE2 downregulation is sufficient to induce neuromuscular phenotypes. We show that moderate gene silencing of ACE2 orthologues Ance or Ance3 diminished survival on exposure to thermal stress only upon induction of neuromuscular fatigue driven by increased physical activity. A strong knockdown of Ance or Ance3 directed to muscle reduced or abolished adult viability and caused obvious motoric deficits including reduced locomotion and impaired flight capacity. Selective knockdown of Ance and Ance3 in neurons caused wing defects and an age-dependent decline in motor behaviour, respectively, in adult flies. Interestingly, RNA sequencing allowed us to discover several differentially spliced genes that are required for synaptic function downstream of Ance or Ance3 depletion. Our findings are therefore supportive of the notion that loss of a RAS-independent function for ACE2 contributes to the neuromuscular manifestations associated with SARS-CoV-2 infection.

Utilization of Marine Seaweeds as a Promising Defense Against COVID-19: a Mini-review.

COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which mainly affects the respiratory system. It has been declared as a "pandemic" in March 2020 by the World Health Organization due to the high spreading rate. SARS-CoV-2 binds with the angiotensin-converting enzyme 2 (ACE2) receptors on the cell surface which leads to the downregulation of ACE2 and upregulation of angiotensin-converting enzyme (ACE) receptors. The elevated level of cytokines and ACE receptors leads to the severity of SARS-CoV-2 infection. Due to the limited availability of vaccines and recurrent attacks of COVID-19 mainly in low-income countries, it is important to search for natural remedies to prevent or treat COVID-19 infection. Marine seaweeds are a rich source of bioactive compounds such as phlorotannins; fucoidan; carotenoids; omega-3 and omega-6 fatty acids; vitamins B12, D, and C; and minerals including zinc and selenium that exhibit antioxidant, antiviral, and anti-inflammatory activities. Furthermore, bioactive compounds present in marine seaweeds have the ability to inhibit ACEs by inducing ACE2 which exhibits anti-inflammatory effects in COVID-19. Correspondingly, soluble dietary fibers present in seaweeds are served as prebiotics by generating short-chain fatty acids through fermentation. Hence, seaweeds can be utilized to reduce the gastrointestinal infections associated with SARS-CoV-2 infection.

SIM imaging resolves endocytosis of SARS-CoV-2 spike RBD in living cells

It is urgent to understand the infection mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for the prevention and treatment of COVID-19. The infection of SARS-CoV-2 starts when the receptor-binding domain (RBD) of viral spike protein binds to angiotensin-converting enzyme 2 (ACE2) of the host cell, but the endocytosis details after this binding are not clear. Here, RBD and ACE2 were genetically coded and labeled with organic dyes to track RBD endocytosis in living cells. The photostable dyes enable long-term structured illumination microscopy (SIM) imaging and to quantify RBD-ACE2 binding (RAB) by the intensity ratio of RBD/ACE2 fluorescence. We resolved RAB endocytosis in living cells, including RBD-ACE2 recognition, cofactor-regulated membrane internalization, RAB-bearing vesicle formation and transport, RAB degradation, and downregulation of ACE2. The RAB was found to activate the RBD internalization. After vesicles were transported and matured within cells, RAB was finally degraded after being taken up by lysosomes. This strategy is a promising tool to understand the infection mechanism of SARS-CoV-2.

Female reproductive health during the COVID-19 pandemic: latest evidence and understanding.

The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has imposed a heavy burden on medical systems. In addition to the respiratory system, the virus also causes injuries to other organs and systems such as the gastroenteric system, kidneys, and reproductive system. Female reproductive health requires more attention in this context. We have performed a thorough review of the relevant literature that addresses the impacts of SARS-CoV-2 infection and COVID-19 vaccination on the female reproductive system. Most evidence shows that SARS-CoV-2 does not infect the female reproductive system. However, the virus may indirectly influence sex hormone concentrations through inflammation associated with cytokine storms and nervous system damage. Menstrual disorders in women infected with SARS-CoV-2 may be caused by down-regulation of angiotensin-converting enzyme 2, abnormal hormone levels, medications, and stress. There is no significant difference in ovarian follicle quality and in vitro fertilization parameters between the pre- and post-COVID-19 vaccination groups. In addition, most symptoms due to side effects of vaccination could recover within a short period of time. SARS-CoV-2 infection affects female reproductive system function through multiple mechanisms. It is recommended that women of childbearing age be vaccinated with COVID-19 vaccine.

ApoE4 associated with severe COVID-19 outcomes via downregulation of ACE2 and imbalanced RAS pathway

BackgroundRecent numerous epidemiology and clinical association studies reported that ApoE polymorphism might be associated with the risk and severity of coronavirus disease 2019 (COVID-19), and yielded inconsistent results. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cell membranes.MethodsA meta-analysis was conducted to clarify the association between ApoE polymorphism and the risk and severity of COVID-19. Multiple protein interaction assays were utilized to investigate the potential molecular link between ApoE and the SARS-CoV-2 primary receptor ACE2, ApoE and spike protein. Immunoblotting and immunofluorescence staining methods were used to access the regulatory effect of different ApoE isoform on ACE2 protein expression.ResultsApoE gene polymorphism (ε4 carrier genotypes VS non-ε4 carrier genotypes) is associated with the increased risk (P = 0.0003, OR = 1.44, 95% CI 1.18–1.76) and progression (P < 0.00001, OR = 1.85, 95% CI 1.50–2.28) of COVID-19. ApoE interacts with both ACE2 and the spike protein but did not show isoform-dependent binding effects. ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1–7.ConclusionsApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Instead, ApoE4 downregulates ACE2 protein expression and subsequently the dysregulation of renin–angiotensin system (RAS) may provide explanation by which ApoE4 exacerbates COVID-19 disease.

SARS-CoV-2 viral entry and replication is impaired in Cystic Fibrosis airways due to ACE2 downregulation

As an inherited disorder characterized by severe pulmonary disease, cystic fibrosis could be considered a comorbidity for coronavirus disease 2019. Instead, current clinical evidence seems to be heading in the opposite direction. To clarify whether host factors expressed by the Cystic Fibrosis epithelia may influence coronavirus disease 2019 progression, here we describe the expression of SARS-CoV-2 receptors in primary airway epithelial cells. We show that angiotensin converting enzyme 2 (ACE2) expression and localization are regulated by Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Consistently, our results indicate that dysfunctional CFTR channels alter susceptibility to SARS-CoV-2 infection, resulting in reduced viral entry and replication in Cystic Fibrosis cells. Depending on the pattern of ACE2 expression, the SARS-CoV-2 spike (S) protein induced high levels of Interleukin 6 in healthy donor-derived primary airway epithelial cells, but a very weak response in primary Cystic Fibrosis cells. Collectively, these data support that Cystic Fibrosis condition may be at least partially protecting from SARS-CoV-2 infection.

Is targeting angiotensin-converting enzyme 2 (ACE2) a prophylactic strategy against COVID-19?

Prophylaxis against COVID-19 is greatly needed for vulnerable populations who have a higher risk of developing severe disease. Vaccines and neutralizing antibodies against SARS-CoV-2 are currently the main approaches to preventing the virus infection. However, the constant mutation of SARS-CoV-2 poses a huge challenge to the effectiveness of these prophylactic strategies. A recent study suggested that downregulation of angiotensin-converting enzyme 2 (ACE2), the receptor of SARS-CoV-2 entry into human cells, can decrease susceptibility to viral infection in vitro, in vivo, and in human lungs and livers perfused ex situ. These findings indicate the potential to use agents to reduce ACE2 expression to prevent COVID-19, but the efficacy and safety should be verified in clinical trials. Considering ACE2 performs physiological functions, risks due to its downregulation and benefits from prophylaxis against SARS-CoV-2 infection should be carefully weighed. In the future, updating vaccines against variants of SARS-CoV-2 might still be an important strategy for prophylaxis against COVID-19. Soluble recombinant human ACE2 that acts as a decoy receptor might be an option to overcome the mutation of SARS-CoV-2.

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

SARS-CoV-2 infection downregulates myocardial ACE2 and potentiates cardiac inflammation in humans and hamsters.

Myocardial pathologies resulting from SARS-CoV-2 infections are consistently rising with mounting case rates and reinfections; however, the precise global burden is largely unknown and will have an unprecedented impact. Understanding the mechanisms of COVID-19-mediated cardiac injury is essential toward the development of cardioprotective agents that are urgently needed. Assessing novel therapeutic strategies to tackle COVID-19 necessitates an animal model that recapitulates human disease. Here, we sought to compare SARS-CoV-2-infected animals with patients with COVID-19 to identify common mechanisms of cardiac injury. Two-month-old hamsters were infected with either the ancestral (D614) or Delta variant (B.1.617.2) of SARS-CoV-2 for 2 days, 7 days, and/or 14 days. We measured viral RNA and cytokine expression at the earlier time points to capture the initial stages of infection in the lung and heart. We assessed myocardial angiotensin-converting enzyme 2 (ACE2), the entry receptor for the SARS-CoV-2 virus, and cardioprotective enzyme, as well as markers for inflammatory cell infiltration in the hamster hearts at days 7 and 14. In parallel, human hearts were stained for ACE2, viral nucleocapsid, and inflammatory cells. Indeed, we identify myocardial ACE2 downregulation and myeloid cell burden as common events in both hamsters and humans infected with SARS-CoV-2, and we propose targeting downstream ACE2 downregulation as a therapeutic avenue that warrants clinical investigation.NEW & NOTEWORTHY Cardiac manifestations of COVID-19 in humans are mirrored in the SARS-CoV-2 hamster model, recapitulating myocardial damage, ACE2 downregulation, and a consistent pattern of immune cell infiltration independent of viral dose and variant. Therefore, the hamster model is a valid approach to study therapeutic strategies for COVID-19-related heart disease.

Correlation between structural heart disease and cardiac SARS-CoV-2 manifestations

Background:The prognosis of COVID-19 patients with cardiac involvement is unfavorable and it remains unknown which patients are at risk. The virus enters cells via its receptor angiotensin-converting enzyme 2 (ACE2). Myocardial ACE2 expression is increased in structural heart disease (SHD). We, therefore, aimed to analyze correlations between structural heart disease and cardiac SARS-CoV-2 manifestation.Methods:The clinical course of COVID-19 in patients with structural heart disease was assessed in a prospective cohort of 152 patients. The primary endpoints consisted of hospitalization and survival. Cardiac tissue of 23 autopsy cases with lethal COVID-19 course was obtained and analyzed for (a) the presence of SHD, (b) myocardial presence of SARS-CoV-2 via RT,-PCR, and (c) levels of ACE2 expression using immunofluorescence staining.Results:Structural heart disease is found in 67 patients, of whom 56 (83.60%) are hospitalized. The myocardium is positive for SARS-CoV-2 in 15 patients (65%) in 23 autopsy cases of lethal COVID-19. Moreover, most hearts with evidence of myocardial SARS-CoV-2 have structural heart disease [11 (91,67%) vs. 1 (8,33%), p = 0.029]. Myocardial presence of SARS-CoV-2 is correlated with a significant downregulation of ACE2 compared to negative control hearts (6.545 ± 1.1818 A.U. vs. 7.764 ± 2.411 A.U., p = 0.003). The clinical course of patients with cardiac SARS-CoV-2 manifestation is unfavorable, resulting in impaired survival (median, 12 days and 4.5 days, respectively, HR 0.30, 95% CI, 0.13 to 0.73, p = 0.0005)Conclusions:We provide evidence for a correlation between SHD, altered ACE2 receptor expression, and cardiac SARS-CoV-2 manifestation. Consequently, structural heart disease may be considered a distinct risk factor for a severe clinical course after infection with SARS-CoV-2.Registration number local IRB:Ethics Committee of Northwestern and Central Switzerland ID 2020-00629; Ethics Committee of the Medical University Innsbruck EK Nr: 1103/2020.ClinicalTrials.gov number:NCT04416100.