Angiotensin-converting Enzyme 2 Function Research Articles

Density functional theory and enzyme studies support interactions between angiotensin receptor blockers and angiotensin converting enzyme-2: Relevance to coronavirus 2019

The binding affinities and interactions between eight drug candidates, both commercially available (candesartan; losartan; losartan carboxylic acid; nirmatrelvir; telmisartan) and newly synthesized benzimidazole-N-biphenyltetrazole (ACC519T), benzimidazole bis-N,Nʹ-biphenyltetrazole (ACC519T(2) and 4-butyl-N,N-bis([2-(2H-tetrazol-5-yl)biphenyl-4-yl]) methyl (BV6), and the active site of angiotensin-converting enzyme-2 (ACE2) were evaluated for their potential as inhibitors against SARS-CoV-2 and regulators of ACE2 function through Density Functional Theory methodology and enzyme activity assays, respectively. Notably, telmisartan and ACC519T(2) exhibited pronounced binding affinities, forming strong interactions with ACE2′s active center, favorably accepting proton from the guanidinium group of arginine273. The ordering of candidates by binding affinity and reactivity descriptors, emerged as telmisartan > ACC519T(2) > candesartan > ACC519T > losartan carboxylic acid > BV6 > losartan > nirmatrelvir. Proton transfers among the active center amino acids revealed their interconnectedness, highlighting a chain-like proton transfer involving tyrosine, phenylalanine, and histidine. Furthermore, these candidates revealed their potential antiviral abilities by influencing proton transfer within the ACE2 active site. Furthermore, through an in vitro pharmacological assays we determined that candesartan and the BV6 derivative, 4-butyl-N,N0-bis[20-2Htetrazol-5-yl)bipheyl-4-yl]methyl)imidazolium bromide (BV6(K+)2) also contain the capacity to increase ACE2 functional activity. This comprehensive analysis collectively underscores the promise of these compounds as potential therapeutic agents against SARS-CoV-2 by targeting crucial protein interactions.

Angiotensin-Converting Enzyme 2 Posttranslational Modifications and Implications for Hypertension and SARS-CoV-2: 2023 Lewis K. Dahl Memorial Lecture.

ACE2 (angiotensin-converting enzyme 2), a multifunctional transmembrane protein, is well recognized as an important member of the (RAS) renin-angiotensin system with important roles in the regulation of cardiovascular function by opposing the harmful effects of Ang-II (angiotensin II) and AT1R (Ang-II type 1 receptor) activation. More recently, ACE2 was found to be the entry point for the SARS-CoV-2 virus into cells, causing COVID-19. This finding has led to an exponential rise in the number of publications focused on ACE2, albeit these studies often have opposite objectives to the preservation of ACE2 in cardiovascular regulation. However, notwithstanding accumulating data of the role of ACE2 in the generation of angiotensin-(1-7) and SARS-CoV-2 internalization, numerous other putative roles of this enzyme remain less investigated and not yet characterized. Currently, no drug modulating ACE2 function or expression is available in the clinic, and the development of new pharmacological tools should attempt targeting each step of the lifespan of the protein from synthesis to degradation. The present review expands on our presentation during the 2023 Lewis K. Dahl Memorial Lecture Sponsored by the American Heart Association Council on Hypertension. We provide a critical summary of the current knowledge of the mechanisms controlling ACE2 internalization and intracellular trafficking, the mutual regulation with GPCRs (G-protein-coupled receptors) and other proteins, and posttranslational modifications. A major focus is on ubiquitination which has become a critical step in the modulation of ACE2 cellular levels.

ACE2 Receptor: A Potential Pharmacological Target in COVID-19.

Studies have shown that injection of recombinant angiotensin-converting enzyme 2 (ACE2) significantly increased circulatory levels of ACE2 activity, reduced cardiac hypertrophy and fibrosis, and effectively lowered blood pressure. In addition, recombinant ACE2 ameliorated albuminuria and might contribute to renal protection. Meanwhile, potential pharmacological treatments based on ACE2 are attracting increasing attention from scientists following a growing understanding of the role of the ACE2 receptor in the pathogenesis of coronavirus disease 2019 (COVID-19). In this article, we comprehensively summarized the literature on the structure, distribution, and function of ACE2. More importantly, we draw a conclusion that ACE2 decoys such as sACE2, hrsACE2 and ACE2-derived peptides, drugs down-regulating the ACE2 or TMPRSS2 gene expression, and the application of epigenetic modifiers and Traditional Chinese Medicine might represent promising approaches for the future of COVID-19 treatment.

SARS‐CoV‐2 virus associated angiotensin converting enzyme 2 expression modulation in colorectal cancer: Insights from mRNA and protein analysis COVID-19 associated (ACE2) expression in colorectal cancer

The SARS‐CoV‐2 virus gains entry into human cells by exploiting the angiotensin‐converting enzyme 2 (ACE2), a key component known as the spike protein (S), as a point of entry. Initially, SARS‐CoV‐2 suppresses the natural function of ACE2, leading to a gradual decline in cell health. Additionally, individuals with cancer are considered more susceptible to COVID-19. This study investigates the expression patterns of ACE2 in colorectal cancer (CRC) patients with and without a history of COVID-19 infection. RT-PCR was used to analyze samples from both cancerous and adjacent non-affected colorectal tissues of 47 CRC patients, comprising two groups: 24 CRC patients with no history of COVID-19 and 23 CRC patients with a recent history of COVID-19 infection. Epithelial CR cells were isolated from both types of tissues and cultured to evaluate cell adhesion. Immunohistochemistry analyses were conducted to examine ACE2 protein expression using various ACE2 antibodies for both cell types. The study revealed ACE2 mRNA expression in all CRC tissues of patients with and without a history of COVID-19. ACE2 expression was significantly higher in CRC patients without a history of COVID-19. Notably, the non-affected colorectal cancer (NACRC) tissues of patients without a history of COVID-19 also showed ACE2 expression, whereas no ACE2 expression was detected in the biopsies of CRC patients with a positive COVID-19 history. ACE2 antibodies were employed to validate ACE2 protein expression at the mRNA level. COVID-19 appears to downregulate ACE2 expression in both CRC and NACRC tissues of CRC patients with a positive history of COVID-19 infection.

Structure-Guided Chemical Optimization of Bicyclic Peptide (Bicycle) Inhibitors of Angiotensin-Converting Enzyme 2.

Angiotensin-converting enzyme 2 (ACE2) is a metalloprotease that cleaves angiotensin II, a peptide substrate involved in the regulation of hypertension. Here, we identified a series of constrained bicyclic peptides, Bicycle, inhibitors of human ACE2 by panning highly diverse bacteriophage display libraries. These were used to generate X-ray crystal structures which were used to inform the design of additional Bicycles with increased affinity and inhibition of ACE2 enzymatic activity. This novel structural class of ACE2 inhibitors is among the most potent ACE2 inhibitors yet described in vitro, representing a valuable tool to further probe ACE2 function and for potential therapeutic utility.

Artificial Lipid Biomembranes for Full-Length SARS-CoV-2 Receptor.

The angiotensin-converting enzyme 2 (ACE2), as a functional receptor for SARS-CoV-2, is essential for preliminary assessment of potential hosts and treatment strategies. However, many studies are based on its truncated version but not full-length structure. Compared to the truncated version, a single-transmembrane helix presents in the full-length structure of ACE2, influencing its interaction and binding with SARS-CoV-2. Therefore, synthesis of the full-length ACE2 is an urgent requirement. Here, cell-free membrane protein synthesis systems (CFMPSs) are constructed for full-length membrane proteins. The transmembrane protein MscL is screened as a model among 10 membrane proteins based on their expression and solubility. Next, CFMPSs are constructed and optimized based on natural vesicles, vesicles with outer 4 membrane proteins removed or 2 chaperonins added, and 37 types of nanodiscs. They all increase membrane protein solubility to more than 50%. Finally, the full-length ACE2 of 21 species are successfully expressed with yields between 0.4-0.9mg/mL using the constructed CFMPS. Their functions show definite differences from the truncated versions, suggesting that the transmembrane region of ACE2 affects its structure and function. CFMPSs can be further extended to a broader range of membrane proteins, paving the way for their use in basic and applied research. This article is protected by copyright. All rights reserved.

Telmisartan and losartan: The marked differences between their chemical and pharmacological properties may explain the difference in therapeutic efficacy in hospitalized patients with COVID‐19

Telmisartan and losartan: The marked differences between their chemical and pharmacological properties may explain the difference in therapeutic efficacy in hospitalized patients with COVID‐19

Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2.

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a significant public health burden with limited treatment options. Many β-coronaviruses, including SARS-CoV-2, gain entry to host cells through the interaction of SARS-CoV-2 spike protein with membrane-bound ACE2 (angiotensin-converting enzyme 2). Given its necessity for SARS-CoV-2 infection, ACE2 represents a potential therapeutic target in COVID-19. However, early attempts focusing on ACE2 in COVID-19 have not validated it as a druggable target nor identified other ACE2-related novel proteins for therapeutic intervention. Here, we identify a mechanism for ACE2 protein modulation by the deubiquitinase (DUB) enzyme UCHL1 (ubiquitin carboxyl-terminal hydrolase isozyme L1). ACE2 is constitutively ubiquitinated and degraded by the proteasome in lung epithelia. SARS-CoV-2 spike protein cellular internalization increased ACE2 protein abundance by decreasing its degradation. Using an siRNA library targeting 96 human DUBs, we identified UCHL1 as a putative regulator of ACE2 function as a viral receptor. Overexpressed UCHL1 preserved ACE2 protein abundance, whereas silencing of the DUB in cells destabilized ACE2 through increased polyubiquitination. A commercially available small molecule inhibitor of UCHL1 DUB activity decreased ACE2 protein concentrations coupled with inhibition of SARS-CoV-2 infection in epithelial cells. These findings describe a unique pathway of ACE2 regulation uncovering UCHL1 as a potential therapeutic target to modulate COVID-19 viral entry as a platform for future small molecule design and testing.

Angiotensin-converting enzyme 2 in human plasma and lung tissue

Purpose We investigated plasma angiotensin-converting enzyme 2 (ACE2) concentration in a population sample and the ACE2 expression quantitated with the diaminobenzidine mean intensity in the lung tissue in patients who underwent lung surgery. Materials and methods The study participants were recruited from a residential area in the suburb of Shanghai for the plasma ACE2 concentration study (n = 503) and the lung tissue samples were randomly selected from the storage in Ruijin Hospital (80 men and 78 age-matched women). Results In analyses adjusted for covariables, men had a significantly higher plasma ACE2 concentration (1.21 vs. 0.98 ng/mL, p = 0.027) and the mean intensity of ACE2 in the lung tissue (55.1 vs. 53.9 a.u., p = 0.037) than women. With age increasing, plasma ACE2 concentration decreased (p = 0.001), while the mean intensity of ACE2 in the lung tissue tended to increase (p = 0.087). Plasma ACE2 concentration was higher in hypertension than normotension, especially treated hypertension (1.23 vs. 0.98 ng/mL, p = 0.029 vs. normotension), with no significant difference between users of RAS inhibitors and other classes of antihypertensive drugs (p = 0.64). There was no significance of the mean intensity of ACE2 in the lung tissue between patients taking and those not taking RAS inhibitors (p = 0.14). Neither plasma ACE2 concentration nor the mean intensity of ACE2 in the lung tissue differed between normoglycemia and diabetes (p ≥ 0.20). Conclusion ACE2 in the plasma and lung tissue showed divergent changes according to several major characteristics of patients.

Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels.

COVID-19 is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. Invasion of the brain by SARS-CoV-2 has been observed in humans and is postulated to be involved in post-COVID state. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Prevention of brain infection in the acute phase of the disease might thus be of therapeutic relevance to prevent long-lasting symptoms of COVID-19. We previously showed that melatonin or two prescribed structural analogs, agomelatine and ramelteon delay the onset of severe clinical symptoms and improve survival of SARS-CoV-2-infected K18-hACE2 mice. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevents SARS-CoV-2 entry in the brain, thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Molecular modeling analyses complemented by experimental studies in cells showed that SARS-CoV-2 entry in endothelial cells is prevented by melatonin binding to an allosteric-binding site on human angiotensin-converting enzyme 2 (ACE2), thus interfering with ACE2 function as an entry receptor for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs and its clinically used analogs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00018-022-04390-3.

The activation status of integrin β1 determines the ACE‐2 expression and functions in renal epithelial and cancer cells

BackgroundIntegrins are heterodimeric cell surface receptors that participate in intracellular signaling and regulate multiple cellular functions. These membrane receptors are also crucial for the organ development, structural maintenance, and disease pathologies of the kidney. Integrin β1 is the major integrin subunit present in the kidney. Alteration of integrin β1 expression is a characteristic of many kidney diseases such as kidney cancer and chronic kidney disease. The purpose of this study is to find the importance of integrin β1 in the expression and function of angiotensin‐converting enzyme 2 (ACE‐2) in the kidney. We hypothesized that the expression and function of ACE‐2 depend on the activation status of integrin β1 in the renal epithelial and cancer cells.MethodKidney epithelial‐specific integrin β1 KO mice were generated by crossing between ITGBfl/fland γGT‐Cre mice. PCR‐based analysis of genomic DNA was used to confirm the gene deletion. Expression of integrin β1 in the kidney cortex was monitored by qRT‐PCR. Immunoblotting and qRT‐PCR were performed to observe protein expression and mRNA level of ACE‐2 in mouse kidneys. The pharmacological compound, BTT 3033, was used to inhibit integrin β1 in HK‐2 and Caki‐1 cells. Integrin β1 activation status was monitored by immunocytochemistry using a conformation‐specific antibody. SARS‐CoV‐2 spike protein was used to find out the functional importance of the integrin β1‐ACE‐2 complex. Statistical significance of the observed data was carried out using a two‐tail t‐test.ResultsDeletion of integrin β1 from the renal epithelial cells reduced expression of ACE‐2 in the mice kidneys (n=3; p<0.05). Immunoblotting and qRT‐PCR showed, expression of integrin β1 (n=3; p<0.05) and ACE‐2 (n=3; p<0.05) were higher in renal cancer cells than renal epithelial cells indicating a positive correlation in their expression patterns. With the treatment of BTT 3033, there was a significant decrease in the activation status of integrin β1 in kidney epithelial (HK‐) and cancer (Caki‐1) cells (n=30; p<0.05). ACE‐2 mRNA levels decreased in HK‐2 and Caki‐1 cells when treated with an integrin β1 antagonist, BTT 3033 (n=3; p<0.05). Treatment of HK‐2 and Caki‐1 with BTT 3033 also decreased the internalization of the SARS‐CoV‐2 spike protein.ConclusionResults from this study demonstrate the importance of matrix proteins receptor integrin β1 in maintaining the ACE‐2 expression and function in the kidney. This study will have implications in various chronic diseases where significant changes in the composition of matrix proteins and integrin expressions are observed. Further studies are needed to understand the role of altered matrix composition in ACE‐2 mediated physiological functions.

ACE2, Circumventricular Organs and the Hypothalamus, and COVID-19.

The SARS-CoV-2 virus gains entry to cells by binding to angiotensin-converting enzyme 2 (ACE2). Since circumventricular organs and parts of the hypothalamus lack a blood–brain barrier, and immunohistochemical studies demonstrate that ACE2 is highly expressed in circumventricular organs which are intimately connected to the hypothalamus, and the hypothalamus itself, these might be easy entry points for SARS-CoV-2 into the brain via the circulation. High ACE2 protein expression is found in the subfornical organ, area postrema, and the paraventricular nucleus of the hypothalamus (PVH). The subfornical organ and PVH are parts of a circuit to regulate osmolarity in the blood, through the secretion of anti-diuretic hormone into the posterior pituitary. The PVH is also the stress response centre in the brain. It controls not only pre-ganglionic sympathetic neurons, but is also a source of corticotropin-releasing hormone, that induces the secretion of adrenocorticotropic hormone from the anterior pituitary. It is proposed that the function of ACE2 in the circumventricular organs and the PVH could be diminished by binding with SARS-CoV-2, thus leading to a reduction in the ACE2/Ang (1–7)/Mas receptor (MasR) signalling axis, that modulates ACE/Ang II/AT1R signalling. This could result in increased presympathetic activity/neuroendocrine secretion from the PVH, and effects on the hypothalamic–pituitary–adrenal axis activity. Besides the bloodstream, the hypothalamus might also be affected by SARS-CoV-2 via transneuronal spread along the olfactory/limbic pathways. Exploring potential therapeutic pathways to prevent or attenuate neurological symptoms of COVID-19, including drugs which modulate ACE signalling, remains an important area of unmet medical need.

Angiotensin-converting enzyme 2 inhibits inflammation and apoptosis in high glucose-stimulated microvascular endothelial cell damage by regulating the JAK2/STAT3 signaling pathway

ABSTRACT Mounting evidence supports that angiotensin-converting enzyme 2 (ACE2) may exert a vital function in multiple complications induced by diabetes. The aim of this research was to verify the function of ACE2 in diabetic angiopathy (DA). In our study, it was revealed that high glucose (HG) treatment impeded cell proliferation and induced cell apoptosis. Moreover, ACE2 level was reduced in HG-stimulated HMEC-1 cells. Functional assays demonstrated that ACE2 addition promoted cell viability, suppressed apoptosis, oxidative stress, ROS generation, and inflammation in HG-stimulated HMEC-1 cells. Furthermore, the activation of the JAK2/STAT3 pathway induced by HG was impeded by overexpression of ACE2. Besides, JAK2/STAT3 pathway inhibitor AG490 reversed the changes of cell viability, apoptosis, oxidative stress, and inflammation caused by ACE2 deletion in HG-treated HMEC-1 cells. In sum, our findings highlighted that ACE2 promoted the viability and restrained the oxidative stress, inflammation, and apoptosis in HG-induced microvascular endothelial cells (VECs) injury via regulating the JAK2/STAT3 pathway, suggesting ACE2 might be a potential therapeutic target for DA treatment.

Patients with severe COVID-19 have reduced circulating levels of angiotensin-(1-7): A cohort study.

Background and AimsAngiotensin‐converting enzyme 2 (ACE2) acts as a functional receptor for the entry of severe acute respiratory syndrome coronavirus 2 into host cells. Angiotensin (1–7) (Ang (1–7)) obtained from the function of ACE2 improves heart and lung function. We investigated the relationship between Ang (1–7) level and disease severity in patients with coronavirus disease 2019 (COVID‐19).MethodsThis cohort study was carried out at Masih Daneshvari Hospital in Tehran, Iran from September 2020 to October 2020. To do so, the Ang (1–7) levels of 331 hospitalized COVID‐19 patients with and without underlying disease were measured by ELISA kit. The need for oxygen, intubation, and mechanical ventilation were recorded for all the patients.ResultsResults showed a significant inverse relationship between the levels of Ang 1–7 and the severity of the disease (needed oxygen, intubation, and mechanical ventilation). According to the results, median (interquartile range) of Ang (1–7) levels was significantly lower in patients who needed oxygen versus those who needed no oxygen (44.50 (91) vs. 82.25 (68), p = 0.002), patients who needed intubation and mechanical ventilation versus those who did not (9.80 (62) vs. 68.70 (102), p < 0.000) and patients hospitalized in an intensive care unit (ICU) than people hospitalized in other wards. We also found that the older patients were more in need of ICU and mechanical ventilation than younger patients.ConclusionsHigher levels of Ang (1–7) have been associated with decreased disease severity. Besides this, we perceived that synthetic Ang 1–7 peptides may be useful to treat and reduce the complications of COVID‐19.

Allosteric control of ACE2 peptidase domain dynamics.

The Angiotensin Converting Enzyme 2 (ACE2) assists the regulation of blood pressure and is the main target of the coronaviruses responsible for SARS and COVID19. The catalytic function of ACE2 relies on the opening and closing motion of its peptidase domain (PD). In this study, we investigated the possibility of allosterically controlling the ACE2 PD functional dynamics. After confirming that ACE2 PD binding site opening-closing motion is dominant in characterizing its conformational landscape, we observed that few mutations in the viral receptor binding domain fragments were able to impart different effects on the binding site opening of ACE2 PD. This showed that binding to the solvent exposed area of ACE2 PD can effectively alter the conformational profile of the protein, and thus likely its catalytic function. Using a targeted machine learning model and relative entropy-based statistical analysis, we proposed the mechanism for the allosteric perturbation that regulates the ACE2 PD binding site dynamics at atomistic level. The key residues and the source of the allosteric regulation of ACE PD dynamics are also presented.

The role of angiotensin-converting enzyme 2 (ACE2) in SARS-CoV-2 (severe acute respiratory syndrome Coronavirus-2) infection process

SARS-CoV-2 can cause severe acute respiratory illness and multi-organ injury. Angiotensin-converting enzyme 2 (ACE2) is an important enzyme of the renin-angiotensin system (RAS), which is the main receptor for entry of SARS-CoV-2 into host cells. Both cell surface ACE2 and soluble ACE2 (sACE2) can interact with the receptor binding domain (RBD) in SARS-CoV-2 S protein. After binding to cell surface ACE2, SARS-CoV-2 enters host cells by direct fusion of the viral with host cell membranes with the support of host’s TMPRSS2 (transmembrane serine protease 2) and furin. In contrast, sACE2-bound SARS-CoV-2 enters host cells through AT1 (Angiotensin type 1 receptor) and AVPR1B (arginine vasopressin receptor 1B). The entery process strongly down regulates membrane-bound ACE2, promoting an activation of the canonical pathway of RAS (ACE-Ang II-AT1 receptor axis). Consequently, this promotes an intense activity of NF-kB (nuclear factor kappa B), which in turn increases the transcription of IL-6, and triggers the cytokine storm. Moreover, the decreasing of ACE2 function in lung leed to the activation of DABK/BKB1R axis signaling, contributing to the pathogenesis of acute lung inflammation. This review summarizes information about the role of ACE2 in SARS-CoV-2 infection and Covid-19, also the research directions for prevention and treatment of Covid-19 which based on ACE2.

ACE2 function in the pancreatic islet: Implications for relationship between SARS-CoV-2 and diabetes.

The molecular link between SARS‐CoV‐2 infection and susceptibility is not well understood. Nonetheless, a bi‐directional relationship between SARS‐CoV‐2 and diabetes has been proposed. The angiotensin‐converting enzyme 2 (ACE2) is considered as the primary protein facilitating SARS‐CoV and SARS‐CoV‐2 attachment and entry into the host cells. Studies suggested that ACE2 is expressed in the endocrine cells of the pancreas including beta cells, in addition to the lungs and other organs; however, its expression in the islets, particularly beta cells, has been met with some contradiction. Importantly, ACE2 plays a crucial role in glucose homoeostasis and insulin secretion by regulating beta cell physiology. Given the ability of SARS‐CoV‐2 to infect human pluripotent stem cell‐derived pancreatic cells in vitro and the presence of SARS‐CoV‐2 in pancreatic samples from COVID‐19 patients strongly hints that SARS‐CoV‐2 can invade the pancreas and directly cause pancreatic injury and diabetes. However, more studies are required to dissect the underpinning molecular mechanisms triggered in SARS‐CoV‐2‐infected islets that lead to aggravation of diabetes. Regardless, it is important to understand the function of ACE2 in the pancreatic islets to design relevant therapeutic interventions in combatting the effects of SARS‐CoV‐2 on diabetes pathophysiology. Herein, we detail the function of ACE2 in pancreatic beta cells crucial for regulating insulin sensitivity, secretion, and glucose metabolism. Also, we discuss the potential role played by ACE2 in aiding SARS‐COV‐2 entry into the pancreas and the possibility of ACE2 cooperation with alternative entry factors as well as how that may be linked to diabetes pathogenesis.

Microbiota and Its Impact on the Immune System in COVID-19-A Narrative Review.

The microbiota is of interest for the development of a therapeutic strategy against SARS-CoV-2 coronavirus disease 2019 (COVID-19) due to its impact on the host immune system. Proven communications of the gut microbiota with the pulmonary microbiota (gut–lung axis) and the pathway of neural connections between the gut and brain (gut–brain axis) may be important in the face of the pandemic. SARS-CoV-2 was shown to affect almost all organs because of the presence of a host receptor known as angiotensin converting enzyme 2 (ACE2). The ACE2 receptor is mainly present in the brush border of intestinal enterocytes, ciliary cells, and type II alveolar epithelial cells in the lungs. The transport function of ACE2 has been linked to the ecology of gut microbes in the digestive tract, suggesting that COVID-19 may be related to the gut microbiota. The severity of COVID-19 may be associated with a number of comorbidities, such as hypertension, diabetes, obesity, and/or old age; therefore, attention is also paid to multiple morbidities and the modulation of microbiota through comorbidities and medications. This paper reviews the research in the context of the state of the intestinal microbiota and its impact on the cells of the immune system during the SARS-CoV-2 pandemic.

SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients.

Angiotensin converting enzyme 2 (ACE2) is a host ectopeptidase and the receptor for the SARS-CoV-2 virus, albeit virus-ACE2 interaction goes far beyond viral entry into target cells. Controversial data exists linking viral infection to changes in ACE2 expression and function, which might influence the subsequent induction of an inflammatory response. Here, we tested the significance of soluble ACE2 enzymatic activity longitudinally in nasopharyngeal swabs and plasma samples of SARS-CoV-2 infected patients, along with the induction of inflammatory cytokines. Release of soluble functional ACE2 increases upon SARS-CoV-2 infection in swabs and plasma of infected patients, albeit rapidly decreasing during infection course in parallel with ACE2 gene expression. Similarly, SARS-CoV-2 infection also induced the expression of inflammatory cytokines. These changes positively correlated with the viral load. Overall, our results demonstrate the existence of mechanisms by which SARS-CoV-2 modulates ACE2 expression and function, intracellular viral sensing and subsequent inflammatory response, offering new insights into ACE2 dynamics in the human upper respiratory tract and pointing towards soluble ACE2 levels as a putative early biomarker of infection severity.

Angiotensin-Converting Enzyme 2 (ACE2) in the Context of Respiratory Diseases and Its Importance in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

Angiotensin-Converting Enzyme 2 (ACE2) is an 805 amino acid protein encoded by the ACE2 gene expressed in various human cells, especially in those located in the epithelia. The primary function of ACE2 is to produce angiotensin (1–7) from angiotensin II (Ang II). The current research has described the importance of ACE2 and Ang (1–7) in alternative routes of the renin-angiotensin system (RAS) that promote the downregulation of fibrosis, inflammation, and oxidative stress processes in a great variety of diseases, such as hypertension, acute lung injury, liver cirrhosis, and kidney abnormalities. Investigations into the recent outbreak of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have revealed the importance of ACE2 during infection and its role in recognizing viral binding proteins through interactions with specific amino acids of this enzyme. Additionally, the ACE2 expression in several organs has allowed us to understand the clinical picture related to the infection caused by SARS-CoV-2. This review aims to provide context for the functions and importance of ACE2 with regards to SARS-CoV-2 in the general clinical aspect and its impact on other diseases, especially respiratory diseases.