ACE2 Expression Research Articles

A tool for nuclear imaging of the SARS-CoV-2 entry receptor: molecular model and preclinical development of ACE2-selective radiopeptides

PurposeThe angiotensin converting enzyme-2 (ACE2)—entry receptor of SARS-CoV-2—and its homologue, the angiotensin-converting enzyme (ACE), play a pivotal role in maintaining cardiovascular homeostasis. Potential changes in ACE2 expression levels and dynamics after SARS-CoV-2 infection have been barely investigated. The aim of this study was to develop an ACE2-targeting imaging agent as a noninvasive imaging tool to determine ACE2 regulation.MethodsDOTA-DX600, NODAGA-DX600 and HBED-CC-DX600 were obtained through custom synthesis and labeled with gallium-67 (T1/2 = 3.26 d) as a surrogate radioisotope for gallium-68 (T1/2 = 68 min). ACE2- and ACE-transfected HEK cells were used for the in vitro evaluation of these radiopeptides. The in vivo tissue distribution profiles of the radiopeptides were assessed in HEK-ACE2 and HEK-ACE xenografted mice and imaging studies were performed using SPECT/CT.ResultsThe highest molar activity was obtained for [67Ga]Ga-HBED-CC-DX600 (60 MBq/nmol), whereas the labeling efficiency of the other peptides was considerably lower (20 MBq/nmol). The radiopeptides were stable over 24 h in saline (> 99% intact peptide). All radiopeptides showed uptake in HEK-ACE2 cells (36–43%) with moderate ACE2-binding affinity (KD value: 83–113 nM), but no uptake in HEK-ACE cells (< 0.1%) was observed. Accumulation of the radiopeptides was observed in HEK-ACE2 xenografts (11–16% IA/g) at 3 h after injection, but only background signals were seen in HEK-ACE xenografts (< 0.5% IA/g). Renal retention was still high 3 h after injection of [67Ga]Ga-DOTA-DX600 and [67Ga]Ga-NODAGA-DX600 (~ 24% IA/g), but much lower for [67Ga]Ga-HBED-CC-DX600 (7.2 ± 2.2% IA/g). SPECT/CT imaging studies confirmed the most favorable target-to-nontarget ratio for [67Ga]Ga-HBED-CC-DX600.ConclusionsThis study demonstrated ACE2 selectivity for all radiopeptides. [67Ga]Ga-HBED-CC-DX600 was revealed as the most promising candidate due to its favorable tissue distribution profile. Importantly, the HBED-CC chelator enabled 67Ga-labeling at high molar activity, which would be essential to obtain images with high signal-to-background contrast to detect (patho)physiological ACE2 expression levels in patients.

Integrin β1 is a key determinant of the expression of angiotensin-converting enzyme 2 (ACE2) in the kidney epithelial cells.

The expression of the angiotensin-converting enzyme 2 (ACE2) is altered in multiple chronic kidney diseases like hypertension and renal fibrosis, where the signaling from the basal membrane proteins is critical for the development and progression of the various pathologies. Integrins are heterodimeric cell surface receptors that have important roles in the progression of these chronic kidney diseases by altering various cell signaling pathways in response to changes in the basement membrane proteins. It is unclear whether integrin or integrin-mediated signaling affects the ACE2 expression in the kidney. The current study tests the hypothesis that integrin β1 regulates the expression of ACE2 in kidney epithelial cells. The role of integrin β1 in ACE2 expression in renal epithelial cells was investigated by shRNA-mediated knockdown and pharmacological inhibition. In vivo studies were carried out using epithelial cell-specific deletion of integrin β1 in the kidneys. Deletion of integrin β1 from the mouse renal epithelial cells reduced the expression of ACE2 in the kidney. Furthermore, the downregulation of integrin β1 using shRNA decreased ACE2 expression in human renal epithelial cells. ACE2 expression levels were also decreased in renal epithelial cells and cancer cells when treated with an integrin α2β1 antagonist, BTT 3033. SARS-CoV-2 viral entry to human renal epithelial cells and cancer cells was also inhibited by BTT 3033. This study demonstrates that integrin β1 positively regulates the expression of ACE2, which is required for the entry of SARS-CoV-2 into kidney cells.

Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection.

Endothelial dysfunction and inflammation contribute to the vascular pathology of coronavirus disease (COVID-19). However, emerging evidence does not support direct infection of endothelial or other vascular wall cells, and thus inflammation may be better explained as a secondary response to epithelial cell infection. In this study, we sought to determine whether lung endothelial or other resident vascular cells are susceptible to productive severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection and how local complement activation contributes to endothelial dysfunction and inflammation in response to hypoxia and SARS-CoV-2-infected lung alveolar epithelial cells. We found that ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) mRNA expression in lung vascular cells, including primary human lung microvascular endothelial cells (HLMVECs), pericytes, smooth muscle cells, and fibroblasts, was 20- to 90-fold lower compared with primary human alveolar epithelial type II cells. Consistently, we found that HLMVECs and other resident vascular cells were not susceptible to productive SARS-CoV-2 infection under either normoxic or hypoxic conditions. However, viral uptake without replication (abortive infection) was observed in HLMVECs when exposed to conditioned medium from SARS-CoV-2-infected human ACE2 stably transfected A549 epithelial cells. Furthermore, we demonstrated that exposure of HLMVECs to conditioned medium from SARS-CoV-2-infected human ACE2 stably transfected A549 epithelial cells and hypoxia resulted in upregulation of inflammatory factors such as ICAM-1 (intercellular adhesion molecule 1), VCAM-1 (vascular cell adhesion molecule 1), and IL-6 (interleukin 6) as well as complement components such as C3 (complement C3), C3AR1 (complement C3a receptor 1), C1QA (complement C1q A chain), and CFB (complement factor B). Taken together, our data support a model in which lung endothelial and vascular dysfunction during COVID-19 involves the activation of complement and inflammatory signaling and does not involve productive viral infection of endothelial cells.

Effect of renin angiotensin blockers on angiotensin converting enzyme 2 level in cardiovascular patients

BackgroundRenin–angiotensin–aldosterone system (RAAS) is hypothesized to be in the center of COVID pathophysiology as the angiotensin converting enzyme 2 (ACE2) represents the main entrance of the virus, thus there is a need to address the effect of chronic use of RAAS blockers, as in case of treatment of cardiovascular diseases, on the expression of ACE2. Accordingly, this study aimed to clarify the effect of ACE inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) on ACE2 and to assess the correlation between ACE2 and several anthropometric and clinic-pathological factors.MethodsA total of 40 healthy controls and 60 Egyptian patients suffering from chronic cardiovascular diseases were enrolled in this study. Patients were divided into 40 patients treated with ACEIs and 20 patients treated with ARBs. Serum ACE2 levels were assessed by ELISA.ResultsAssessment of serum ACE2 level in different groups showed a significant difference between ACEIs and healthy groups and ACEIs and ARBs group, while there was no difference between ARBs and healthy. Multivariate analysis using ACE2 level as constant and age, female sex, ACEIs use and myocardial infarction (MI) showed that there was a significant effect of female sex and ACEIs use on ACE2 level with no effect of age, MI and diabetes.ConclusionACE2 levels varied between ACEIs and ARBs. It tends to be lower in ACEIs group and there is a strong positive association between ACE2 level and the female sex. This needs to be considered in Future studies to further understand the relationship between gender, sex hormones and ACE2 level.Trial registrationRetrospectively registered ClinicalTrials.gov ID: NCT05418361 (June 2022).Graphical abstract

Associations of polymorphisms of the &lt;i&gt;ACE&lt;/i&gt; and &lt;i&gt;ACE2&lt;/i&gt; genes with clinical manifestations and cardiovascular complications of the coronavirus infection

A problem of the novel coronavirus infection pandemic is the absence of specific biomarkers, the determination of which would make it possible to assess the likelihood of a severe disease course, development of complications, immediate and long-term consequences, and effective etiotropic (antiviral) therapy. The severity of the novel coronavirus infection depends on various factors such as the initial state of health, immune status, age, smoking status, concomitant cardiovascular diseases, and diabetes mellitus. However, a severe disease course is also observed in patients without the aforementioned risk factors. The development of the disease and its complications depends on sex and geographical identity. Angiotensin-converting enzyme 2 (ACE2), associated by gene-gene interaction with ACE, plays a main role in the pathogenesis of the penetration of severe acute respiratory syndrome-2 coronavirus into the cell. The main body of information on this problem is represented by systematic meta-analyses and results of single-center cohort studies, which offer insufficient information to unequivocally assert the associations of ACE and ACE2 gene polymorphisms with pathological changes in the circulatory system during and after a new coronavirus infection. Differences in the incidence of ACE and ACE2 alleles may explain the differences between susceptible populations and/or response to the severe coronavirus infection. The above studies were carried out on the effect of the coronavirus in the initial period of the pandemic. For a more complete molecular genetic picture of the influence of polymorphism, persons with different strains of the coronavirus must be considered. In addition, no data are available regarding the expressions of ACE and ACE2 genes in response to a coronavirus infection. Moreover, the identification of the polymorphic variants of the genes of the reninangiotensinaldosterone system and ACE2 associated with a high risk of developing and worsening cardiovascular diseases may be one of the promising areas for the early diagnosis and prevention of post-COVID-19 changes. Therefore, all scientific interest research is aimed at studying genetic factors, such as single nucleotide polymorphisms that affect susceptibility to infection, severity of the disease course, and development of circulatory system consequences. In general, polymorphic variants of ACE and ACE2 and their interaction will help us understand this problem and systematize knowledge for further research in this area.

Changes in intestinal morphology, number of mucus-producing cells and expression of coronavirus receptors APN, DPP4, ACE2 and TMPRSS2 in pigs with aging

Porcine enteric viral infections cause high morbidity and mortality in young piglets (<3 weeks). Later, these rates decrease with age. This age-dependent infectivity remains largely unexplored. This study investigated the changes in intestinal morphology, number of mucus-producing cells and expression level of coronavirus receptors in three age groups of pigs. Villus height and crypt depth increased with age from 3 days to 3 months in duodenum and ileum but not in mid-jejunum, where the villus height decreased from 580 µm at 3 days to 430 µm at 3 months. Enterocyte length-to-width ratio increased from 3 days to 3 months in all intestinal regions. The number of mucus-producing cells increased with age in the intestinal villi and crypts. The Brunner’s glands of the duodenum contained the highest concentration of mucus-producing cells. The expression of coronavirus receptor APN was highest in the small intestinal villi at all ages. DPP4 expression slightly decreased over time in jejunum and ileum; it was highest in the ileal villi of 3-day-old piglets (70.2% of cells). ACE2 and TMPRSS2 positive cells increased with age in jejunal and ileal crypts and were particularly dominant in the ileal crypts (> 45% of cells). Except for the expression of DPP4 in the jejunum and ileum of young pigs, the expression pattern of the selected coronavirus receptors was very different and not correlated with the age-dependent susceptibility to viral infections. In contrast, the number of mucus-producing cells increased over time and may play an essential role in protecting enteric mucosae against intestinal viruses.

Indian food habit & food ingredients may have a role in lowering the severity & high death rate from COVID-19 in Indians: findings from the first nutrigenomic analysis.

During the COVID-19 pandemic, the death rate was reportedly 5-8 fold lower in India which is densely populated as compared to less populated western countries. The aim of this study was to investigate whether dietary habits were associated with the variations in COVID-19 severity and deaths between western and Indian population at the nutrigenomics level. In this study nutrigenomics approach was applied. Blood transcriptome of severe COVID-19 patients from three western countries (showing high fatality) and two datasets from Indian patients were used. Gene set enrichment analyses were performed for pathways, metabolites, nutrients, etc., and compared for western and Indian samples to identify the food- and nutrient-related factors, which may be associated with COVID-19 severity. Data on the daily consumption of twelve key food components across four countries were collected and a correlation between nutrigenomics analyses and per capita daily dietary intake was investigated. Distinct dietary habits of Indians were observed, which may be associated with low death rate from COVID-19. Increased consumption of red meat, dairy products and processed foods by western populations may increase the severity and death rate by activating cytokine storm-related pathways, intussusceptive angiogenesis, hypercapnia and enhancing blood glucose levels due to high contents of sphingolipids, palmitic acid and byproducts such as CO2 and lipopolysaccharide (LPS). Palmitic acid also induces ACE2 expression and increases the infection rate. Coffee and alcohol that are highly consumed in western countries may increase the severity and death rates from COVID-19 by deregulating blood iron, zinc and triglyceride levels. The components of Indian diets maintain high iron and zinc concentrations in blood and rich fibre in their foods may prevent CO2 and LPS-mediated COVID-19 severity. Regular consumption of tea by Indians maintains high high-density lipoprotein (HDL) and low triglyceride in blood as catechins in tea act as natural atorvastatin. Importantly, regular consumption of turmeric in daily food by Indians maintains strong immunity and curcumin in turmeric may prevent pathways and mechanisms associated with SARS-CoV-2 infection and COVID-19 severity and lowered the death rate. Our results suggest that Indian food components suppress cytokine storm and various other severity related pathways of COVID-19 and may have a role in lowering severity and death rates from COVID-19 in India as compared to western populations. However, large multi-centered case-control studies are required to support our current findings.

Lymphocytes regulate expression of the SARS-CoV-2 cell entry factor ACE2 in the pancreas of T2DM patients.

COVID-19 patients with type 2 diabetes mellitus (T2DM) show both poorer clinical outcomes and have an increased risk of death. SARS-CoV-2 virus infection requires simultaneous expression of the SARS-CoV-2 cell entry factors angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine type 2 (TMPRSS2) in the same cell. The aim of the study was to explore the underlying mechanisms of a COVID-19 infection in patients with T2DM. The distribution and expression of AEC2 and TMPRSS2 in different pancreatic cell types in clinical samples of T2DM patients and diabetic mouse models were analysed by single-cell sequencing, bioinformatics analysis and basic experiments. The results showed that ACE2 and TMPRSS2 are expressed in the ducts of the human pancreas. These findings suggest that SARS-CoV-2 can infect ductal cells in vivo through ACE2 and TMPRSS2. T2DM can promote the co-expression of ACE2 and TMPRSS2 in exocrine ducts, including in the human pancreas. We hypothesize that ACE2 expression levels are associated with increased numbers of lymphocytes in vivo. Increased blood glucose levels are associated with increased ACE2 expression and an increased number of lymphocytes. At the same time, lymphocytes can promote ACE2 expression.

Lung Expression of Macrophage Markers CD68 and CD163, Angiotensin Converting Enzyme 2 (ACE2), and Caspase-3 in COVID-19.

Background and Objectives: The coronavirus (SARS-CoV-2) damages all systems and organs. Yet, to a greater extent, the lungs are particularly involved, due to the formation of diffuse exudative inflammation in the form of acute respiratory distress syndrome (ARDS) with next progression to pulmonary fibrosis. SARS-associated lung damage is accompanied by the pronounced activation of mononuclear cells, damage of the alveoli and microvessels, and the development of organized pneumonia. To study the expression of macrophage markers (CD68 and CD163), angiotensin-converting enzyme-2 (ACE2), and caspase-3 on the results of two fatal clinical observations of COVID-19. Materials and Methods: In both clinical cases, the female patients died from complications of confirmed COVID-19. Conventional morphological and immunohistochemical methods were used. Results: There was an acute exudative hemorrhagic pneumonia with the formation of hyaline membranes, focal organization of fibrin, stromal sclerosis, stasis, and thrombus formation in the lung vessels. Signs such as the formation of hyaline membranes, organization, and fibrosis were more pronounced in severe disease activity. The activation of CD68+/CD163+ macrophages could cause cell damage at an early stage of pneumonia development, and subsequently cause fibrotic changes in lung tissue. ACE2 expression in lung tissue was not detected in severe pneumonia, while in moderate pneumonia, weak expression was noted in individual cells of the alveolar epithelium and vascular endothelium. Conclusions: This finding could show the dependence of ACE2 expression on the severity of the inflammatory process in the lungs. The expression of caspase-3 was more pronounced in severe pneumonia.

Association between RAAS Antagonism and COVID-19-related Mortality in Patients with Overweight/Obesity-related Hypertension: A Retrospective Cohort Study.

Angiotensin receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI) increase the expression of ACE2, which is a receptor for entry of SARS-CoV-2 into cells. Though evidence suggests that ARB/ACEI are safe among the general population with COVID-19, their safety in patients with overweight/obesity-related hypertension deserves further evaluation. We assessed the association between ARB/ACEI use and COVID-19 severity in patients with overweight/obesity-related hypertension. This study included 439 adult patients with overweight/obesity (body mass index ≥ 25 kg/m2) and hypertension, diagnosed with COVID-19 and admitted to University of Iowa Hospitals and Clinic from March 1 to December 7, 2020. Mortality and severity of COVID-19 were evaluated based on length of stay in hospital, intensive care unit admission, use of supplemental oxygen, mechanical ventilation, and vasopressors. Multivariable logistic regression was used to examine the associations of ARB/ACEI use with mortality and other markers of COVID-19 severity, with a two-sided alpha set at 0.05. Exposure to ARB (n = 91) and ACEI (n = 149) before hospitalization was significantly associated with lower mortality (odds ratio [OR] = 0.362, 95% confidence interval [CI] 0.149 to 0.880, p = 0.025) and a shorter length of stay (95% CI -0.217 to -0.025, p = 0.015). Additionally, patients using ARB/ACEI showed a non-significant trend toward lower intensive care unit admission (OR = 0.727, 95% CI 0.485 to 1.090, p = 0.123), use of supplemental oxygen (OR = 0.929, 95% CI 0.608 to 1.421, p = 0.734), mechanical ventilation (OR = 0.728, 95% CI 0.457 to 1.161, p = 0.182), and vasopressors (OR = 0.677, 95% CI 0.430 to 1.067, p = 0.093). Results suggest that hospitalized patients with COVID-19 and overweight/obesity-related hypertension who were prescribed ARB/ACEI before admission to the hospital exhibit lower mortality and less severe COVID-19 than those who were not taking ARB/ACEI. The results also suggest that exposure to ARB/ACEI may protect patients with overweight/obesity-related hypertension from severe COVID-19 and death.

Veklury®(remdesivir) formulations inhibit initial membrane-coupled events of SARS-CoV-2 infection due to their sulfobutylether-β-cyclodextrin content.

Despite its contradictory clinical performance, remdesivir (Veklury®) has a pivotal role in COVID-19 therapy. Possible contributions of the vehicle, sulfobutylether-β-cyclodextrin (SBECD) toVeklury® effects have been overlooked. The powder and solution formulations of Veklury® are treated equivalently despite their different vehicle content. Our objective was to study Veklury® effects on initial membrane-coupled events of SARS-CoV-2 infection focusing on the cholesterol depletion-mediated role of SBECD. Using time-correlated flow cytometry and quantitative three-dimensional confocal microscopy, we studied early molecular events of SARS-CoV-2-host cell membrane interactions. Veklury® and different cholesterol-depleting cyclodextrins (CDs) reduced binding of the spike receptor-binding domain (RBD) to ACE2 and spike trimer internalization for Wuhan-Hu-1, Delta and Omicron variants. Correlations of these effects with cholesterol-dependent changes in membrane structure and decreased lipid raft-dependent ACE2-TMPRSS2 interaction establish that SBECD is not simply a vehicle but also an effector along with remdesivir due to its cholesterol-depleting potential. Veklury® solution inhibited RBD binding more efficiently due to its twice higher SBECD content. The CD-induced inhibitory effects were more prominent at lower RBD concentrations and in cells with lower endogenous ACE2 expression, indicating that the supportive CD actions can be even more pronounced during in vivo infection when viral load and ACE expression are typically low. Our findings call for the differentiation of Veklury® formulations in meta-analyses of clinical trials, potentially revealing neglected benefits of the solution formulation, and also raise the possibility of adjuvant cyclodextrin (CD) therapy, even at higher doses, in COVID-19.

Expression of SARS-CoV-2 receptor angiotensin-converting enzyme 2 by activating protein-1 in human mast cells.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection activates mast cells and induces a cytokine storm, leading to severe Coronavirus disease in 2019 (COVID-19). SARS-CoV-2 employs angiotensin-converting enzyme 2 (ACE2) for cell entry. In the present study, the expression of ACE2 and its mechanism in activated mast cells were studied utilizing the human mast cell line, HMC-1 cells and it was elucidated whether dexamethasone used as a treatment for COVID-19 could regulate ACE2 expression. Here we documented for the first time that levels of ACE2 were increased by stimulation of phorbol 12-myristate 13-acetate and A23187 (PMACI) in HMC-1 cells. Increased levels of ACE2 were significantly diminished by treatment with Wortmannin, SP600125, SB203580, PD98059, or SR11302. The expression of ACE2 was most significantly reduced by the activating protein (AP)-1 inhibitor SR11302. PMACI stimulation enhanced the expression of the transcription factor AP-1 for ACE2. In addition, levels of transmembrane protease/serine subfamily member 2 (TMPRSS2) and tryptase were increased in PMACI-stimulated HMC-1 cells. However, dexamethasone significantly lowered levels of ACE2, TMPRSS2, and tryptase generated by PMACI. Treatment with dexamethasone also reduced activation of signaling molecules linked to ACE2 expression. According to these findings, levels of ACE2 were up-regulated through activation of AP-1 in mast cells, suggesting that suppressing ACE2 levels in mast cells would be a therapeutic approach to lessen the harm caused by COVID-19.

Single-cell RNA sequencing analysis of a COVID-19-associated maculopapular rash in a patient with psoriasis treated with ustekinumab.

Coronavirus disease 2019 (COVID-19) primarily affects the respiratory system but extrapulmonary manifestations, including the skin, have been well documented. However, transcriptomic profiles of skin lesions have not been performed thus far. Here, we present a single-cell RNA sequencing analysis in a patient with COVID-19 infection with a maculopapular skin rash while on treatment with the interleukin (IL)-12/IL-23 blocker ustekinumab for his underlying psoriasis. Results were compared with healthy controls and untreated psoriasis lesions. We found the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry receptors ACE2 and TMPRSS2 in keratinocytes of the patient with COVID-19, while ACE2 expression was low to undetectable in psoriasis lesions and healthy skin. Among all cell types, ACE2+ keratinocyte clusters showed the highest levels of transcriptomic dysregulation in COVID-19, expressing type 1-associated immune markers such as CXCL9 and CXCL10. In line with a generally type 1-skewed immune microenvironment, cytotoxic lymphocytes showed increased expression of the IFNG gene and other T-cell effector genes, while type 2, type 17, or type 22 T-cell activation was largely absent. Conversely, downregulation of several anti-inflammatory mediators was observed. This first transcriptomic description of a COVID-19-associated rash identifies ACE2+ keratinocytes displaying profound transcriptional changes, and inflammatory immune cells that might help to improve the understanding of SARS-CoV-2-associated skin conditions.

Acute kidney injury in a covid-19 patient with Non-ST elevation myocardial infarction: case report

Introduction: Coronavirus disease 2019 (COVID-19) has a variety of manifestations, from asymptomatic to acute illness that can affect several organs, although being primarily associated with the respiratory system. The virus binds to angiotensin-converting enzyme-2 (ACE-2) receptors in humans and the expression of ACE-2 in heart and kidneys explains the association of COVID-19 with the renal and cardiovascular systems. Case description: Male, 62-year-old, was admitted to the emergency room (ER) for presented shortness of breath, angina pain, and gastric pain. He was a smoker and denied having comorbidities. At arrival, an examination of vital signs and physical showed tachypnea, tachycardia, hypertension, and bilateral crackles. The electrocardiography (ECG) showed left ventricular hypertrophy and Non-ST-Elevation in anterolateral. The chest x-ray showed pneumonia and cardiomegaly. Laboratory findings showed that decreased renal function and Polymerase Chain Reaction (PCR) test was positive, and increased in serum Troponin level supported the diagnosis of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-Cov-2) pneumonia with Non-ST elevation myocardial infarct (NSTEMI) and Acute Kidney Injury (AKI). Loading of Aspilet, Clopidogrel, Atorvastatin, and Thrombolysis with Fondaparinux was done. The following day, transthoracic echocardiography was performed anterolateral regional wall motion abnormality with 43% of Left Ventricle Ejection Fraction (LVEF). Two weeks after hospital discharge, the echocardiography evaluation showed no improvement and was diagnosed with Chronic Heart Failure with New York Heart Association (NYHA) Functional Classification II et causa Coronary Artery Disease. Conclusion: Treatment of covid-19 patients with cardiovascular and renal complications is quite challenging since there is no specific guideline for COVID-19 patients with renal and cardiovascular complications.

Cutaneous susceptibility to SARS-CoV-2 infection according to the expression of viral entry factors in the skin

Introduction: Reports of dermatological manifestations in patients with COVID-19 suggest a possible cutaneous tropism of SARS-CoV-2; however, the capacity of this virus to infect the skin is unknown. Objective: To determine the susceptibility of the skin to SARS-CoV-2 infection based on the expression of viral entry factors ACE2 and TMPRSS2 in this organ. Method: A comprehensive analysis of human tissue gene expression databases was carried out looking for the presence of the ACE2 and TMPRSS2 genes in the skin. mRNA expression of these genes in skin-derived human cell lines was also assessed. Results: The analyses showed high co-expression of ACE2 and TMPRSS2 in the gastrointestinal tract and kidney, but not in the skin. Only the human immortalized keratinocyte HaCaT cell line expressed detectable levels of ACE2, and no cell line originating in the skin expressed TMPRSS2. Conclusions: Our results suggest that cutaneous manifestations in patients with COVID-19 cannot be directly attributed to the virus. It is possible that cutaneous blood vessels endothelial damage, as well as the effect of circulating inflammatory mediators produced in response to the virus, are the cause of skin involvement.

The big challenge of SARS-CoV-2 latency: testes as reservoir

In the efforts to explain COVID-19 pathophysiology, studies are being carried out on the correspondence between the expression of SARS-CoV-2 cell receptors and viral sequences. ACE2, CD147 and TMPRSS2 receptors expression could indicate poorly explored potential infection targets. For the genomic analysis of SARS-CoV-2 receptors, using BioGPS information was decided, which is a portal that centralizes genetic annotation resources, in combination with that of The Human Protein Atlas, the largest portal of human transcriptome and proteome data. We also reviewed the most recent articles on the subject. RNA and viral receptor proteins ex-pression was observed in numerous anatomical sites, which partially coincides with the information reported in the literature. High expression in testicular cells markedly stood out, and it would be therefore important ruling out whether this anatomical site is a SARS-CoV-2 reservoir; otherwise, germ cell damage, as it is observed in infections with other RNA viruses, should be determined.

Type 2 inflammation reduces SARS-CoV-2 replication in the airway epithelium in allergic asthma through functional alteration of ciliated epithelial cells

Despite well-known susceptibilities to other respiratory viral infections, individuals with allergic asthma have shown reduced susceptibility to severe coronavirus disease 2019 (COVID-19). We sought to identify mechanisms whereby type 2 inflammation in the airway protects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by using bronchial airway epithelial cells (AECs) from aeroallergen-sensitized children with asthma and healthy nonsensitized children. We measured SARS-CoV-2 replication and ACE2 protein and performed bulk and single-cell RNA sequencing of exvivo infected AEC samples with SARS-CoV-2 infection and with or without IL-13 treatment. We observed that viral replication was lower in AECs from children with allergic asthma than those from in healthy nonsensitized children and that IL-13 treatment reduced viral replication only in children with allergic asthma and not in healthy children. Lower viral transcript levels were associated with a downregulation of functional pathways of the ciliated epithelium related to differentiation as well as cilia and axoneme production and function, rather than lower ACE2 expression or increases in goblet cells or mucus secretion pathways. Moreover, single-cell RNA sequencing identified specific subsets of relatively undifferentiated ciliated epithelium (which are common in allergic asthma and highly responsive to IL-13) that directly accounted for impaired viral replication. Our results identify a novel mechanism of innate protection against SARS-CoV-2 in allergic asthma that providesimportant molecular and clinical insights during the ongoing COVID-19 pandemic.

Shared Neurological and Cognitive Factors in COVID-19 and Alzheimer’s Disease: A Literature Review

Introduction: The neuropathological etiology of COVID-19 suggests infection may increase the risk of neurodegenerative disorders, most notably Alzheimer’s disease (AD). Despite some overlap between COVID-19 and AD, the current research on this relationship is developing and evidence has been mixed. This review aims to assess the literature on how the neurological and cognitive sequalae associated with COVID-19 infection affect risk for AD and its associated symptoms, and vice versa. Methods: Articles were found by searching through the PubMed database with the terms (sensory OR cognitive OR neurological OR neuroimaging) AND (Alzheimer’s disease OR Alzheimer’s OR dementia) AND (COVID-19 OR SARS-CoV-2 OR COVID). Search inclusion criteria required the papers be written in English, be published in 2020 or later, and pertain to COVID-19 and/or AD specifically. This process was supplemented by manual searching. The articles used for this review include meta-analyses, literature reviews, and prospective and retrospective empirical studies. Results: Various well-known AD risk factors and outcomes may be observed in COVID-19 patients, and vice versa. These include amyloid precursor protein (APP) buildup, tau hyperphosphorylation, the apolipoprotein E (APOE) e4e4 genotype, angiotensin converting enzyme 2 (ACE2) gene expression, cholinergic functioning, delirium, cognitive decline, and deleterious effects on brain structure and function. Discussion: COVID-19 may increase AD risk and development by increasing protein build-up and damaging AD-related brain regions, which may underlie sensory and cognitive deficits. Furthermore, COVID-19 and AD may interact in positive feedback loops to worsen the development of both. These interactions may be mediated by demyelination, inflammation, APOE e4e4 genotype, and ACE2 expression. Clinical implications for those with COVID-19 and/or AD include the possibility of treatments aimed at cholinergic functioning, as well as high flow oxygen therapy. Conclusion: COVID-19 may increase the risk for and development of AD. AD, in turn, may also increase risk for COVID-19 infection, acting in a positive feedback loop. Future directives include further research on tau pathology, delirium, and amyloid precursor protein processing. Additionally, studies could benefit from telemedicine. Lastly, assessment of AD risk due to COVID-19 could integrate delirium and subjective reports of “brain fog” as measures for underlying risk factors.

NaHS restores the vascular alterations in the renin-angiotensin system induced by hyperglycemia in rats

Hyperglycemia (HG) impairs the renin-angiotensin system (RAS), which may contribute to vascular dysfunction. Besides, hydrogen sulfide (H2S) exerts beneficial cardiovascular effects in metabolic diseases. Therefore, our study aimed to determine the effects of chronic administration of sodium hydrosulfide (NaHS; inorganic H2S donor) and DL-Propargylglycine [DL-PAG; cystathionine-ץ-lyase (CSE) inhibitor] on the RAS-mediated vascular responses impairments observed in thoracic aortas from male diabetic Wistar rats. For that purpose, neonatal rats were divided into two groups that received: 1) citrate buffer (n = 12) or 2) streptozotocin (STZ, 70 mg/kg; n = 48) on the third postnatal day. After 12 weeks, diabetic animals were divided into 4 subgroups (n = 12 each) that received daily i.p. injections during 4 weeks of: 1) non-treatment; 2) vehicle (PBS, 1 mL/kg); 3) NaHS (5.6 mg/kg); and 4) DL-PAG (10 mg/kg). After treatments (16 weeks), blood glucose, angiotensin-(1−7) [Ang-(1−7)], and angiotensin II (Ang II) levels, vascular responses to Ang-(1−7) and Ang II, and the expression of angiotensin AT1, AT2, and Mas receptors, angiotensin converting enzyme (ACE) and ACE type 2 (ACE2) were determined. HG induced: 1) increased blood glucose levels and expression of angiotensin II AT1 receptor; 2) impaired Ang-(1−7) and Ang II mediated vascular responses; 3) decreased angiotensin levels and expression of angiotensin II AT2 and angiotensin-(1−7) Mas receptors, and ACE2; and 4) no changes in ACE expression. Interestingly, NaHS, but not DL-PAG, reversed HG-induced impairments, except for blood glucose level changes. These results suggest that NaHS restores vascular function in streptozotocin-induced HG through RAS modulation.

Identification of the regulatory mechanism of ACE2 in COVID-19-induced kidney damage with systems genetics approach.

Studies showed that SARS-CoV-2 can directly target the kidney and induce renal damage. As the cell surface receptor for SARS-CoV-2 infection, the angiotensin-converting enzyme 2 (ACE2) plays a pivotal role for renal physiology and function. Thus, it is important to understand ACE2 through which pathway influences the pathogenesis of renal damage induced by COVID-19. In this study, we first performed an eQTL mapping for Ace2 in kidney tissues in 53 BXD mice strains. Results demonstrated that Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney, with six genes (Dnase1, Vasn, Usp7, Abat, Mgrn1, and Rbfox1) dominated as the upstream modulator, as they are highly correlated with Ace2 expression. Gene co-expression analysis showed that Ace2 co-variates are significantly involved in the renin-angiotensin system (RAS) pathway which acts as a reno-protector. Importantly, we also found that Ace2 is positively correlated with Pdgf family members, particularly Pdgfc, which showed the most association among the 76 investigated growth factors. Mammalian Phenotype Ontology enrichment indicated that the cognate transcripts for both Ace2 and Pdgfc were mainly involved in regulating renal physiology and morphology. Among which, Cd44, Egfr, Met, Smad3, and Stat3 were identified as hub genes through protein-protein interaction analysis. Finally, in aligning with our systems genetics findings, we found ACE2, pdgf family members, and RAS genes decreased significantly in the CAKI-1 kidney cancer cells treated with S protein and receptor binding domain structural protein. Collectively, our data suggested that ACE2 work with RAS, PDGFC, as well as their cognate hub genes to regulate renal function, which could guide for future clinical prevention and targeted treatment for COVID-19-induced renal damage outcomes. KEY MESSAGES: • Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney. • Ace2 co-variates are enriched in the RAS pathway. • Ace2 is strongly correlated with the growth factor Pdgfc. • Ace2 and Pdgfc co-expressed genes involved in the regulation of renal physiology and morphology. • SARS-CoV-2spike glycoprotein induces down-regulation of Ace2, RAS, and Pdgfc.