ACE2 and COVID-19 and the resulting ARDS.

This article reviews the correlation between ACE2 and COVID-19 and the resulting acute respiratory distress syndrome (ARDS). ACE2 is a crucial component of the renin-angiotensin system (RAS). The classical ACE-angiotensin Ⅱ (Ang II)-angiotensin type 1 receptor (AT1R) axis and the ACE2-Ang(1-7)-Mas counter-regulatory axis play an essential role in RAS system. ACE2 antagonises the activation of the classical RAS ACE-Ang II-AT1R axis and protects against lung injury. Similar to severe acute respiratory syndrome-related coronavirus, 2019 novel coronavirus (2019-nCoV) also uses ACE2 for cell entry. ARDS is a clinical high-mortality disease which is probably due to the excessive activation of RAS caused by 2019-nCoV infection, and ACE2 has a protective effect on ARDS caused by COVID-19. Because of these protective effects of ACE2 on ARDS, the development of drugs enhancing ACE2 activity may become one of the most promising approaches for the treatment of COVID-19 in the near future. In the meantime, however, the use of RAS blockers such as ACE inhibitors and angiotensin II receptor blockers that inhibit the damaging (ACE-Ang II) arm of the RAS cascade in the lung may also be promising. Trial registration number: NCT04287686.

Synergistic effect of elevated glucose levels with SARS-CoV-2 spike protein induced NOX-dependent ROS production in endothelial cells.

BACKGROUND: Diabetic patients infected with coronavirus disease 2019 (COVID-19) often have a higher probability of organ failure and mortality. The potential cellular mechanisms through which blood glucose exacerbates tissue damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still unclear. METHODS AND RESULTS: We cultured endothelial cells within differing glucose mediums with an increasing concentration gradient of SARS-CoV-2 Spike protein (S protein). S protein can cause the reduction of ACE2 and TMPRSS2, and activation of NOX2 and NOX4. A high glucose medium was shown to aggravate the decrease of ACE2 and activation of NOX2 and NOX4 in cultured cells, but had no effect on TMPRSS2. S protein mediated activation of the ACE2-NOX axis induced oxidative stress and apoptosis within endothelial cells, leading to cellular dysfunction via the reduction of NO and tight junction proteins which may collectively be exacerbated by elevated glucose. In addition, the glucose variability model demonstrated activation of the ACE2-NOX axis in a similar manner observed in the high glucose model in vitro. CONCLUSIONS: Our present study provides evidence for a mechanism through which hyperglycemia aggravates endothelial cell injury resulting from S protein mediated activation of the ACE2-NOX axis. Our research thus highlights the importance of strict monitoring and control of blood glucose levels within the context of COVID-19 treatment to potentially improve clinical outcomes.

Do adipocytes serve as a reservoir for severe acute respiratory symptom coronavirus-2?

Obesity is associated with a higher risk of severe coronavirus disease 2019 (COVID-19) and increased mortality. In the current study, we have investigated the expression of ACE2, NRP1, and HMGB1, known to facilitate severe acute respiratory symptom coronavirus-2 (SARS-CoV-2) cell entry, in adipose tissue from non-COVID-19 control patients with normal weight, overweight, and obesity. All factors were expressed, but no significant differences between the groups were observed. Furthermore, diabetes status and medications did not affect the expression of ACE2. Only in obese men, the expression of ACE2 in adipose tissue was higher than in obese women. In the adipose tissue from patients who died from COVID-19, SARS-CoV-2 was detected in the adipocytes even though the patients died more than 3 weeks after the acute infection. This suggests that adipocytes may act as reservoirs for the virus. In COVID-19 patients, the expression of NRP1 was increased in COVID-19 patients with overweight and obesity. Furthermore, we observed an increased infiltration with macrophages in the COVID-19 adipose tissues compared to control adipose tissue. In addition, crown-like structures of dying adipocytes surrounded by macrophages were observed in the adipose tissue from COVID-19 patients. These data suggest that in obese individuals, in addition to an increased mass of adipose tissue that could potentially be infected, increased macrophage infiltration due to direct infection with SARS-CoV-2 and sustained viral shedding, rather than preinfection ACE2 receptor expression, may be responsible for the increased severity and mortality of COVID-19 in patients with obesity.

Molecular Mimicry of the Viral Spike in the SARS-CoV-2 Vaccine Possibly Triggers Transient Dysregulation of ACE2, Leading to Vascular and Coagulation Dysfunction Similar to SARS-CoV-2 Infection.

The benefits of SARS-CoV-2 spike mRNA vaccines are well known, including a significant decline in COVID-19 morbidity and a decrease in the mortality rate of SARS-CoV-2 infected persons. However, pharmacovigilance studies have revealed the existence of rare cases of cardiovascular complications after mass vaccination using such formulations. Cases of high blood pressure have also been reported but were rarely documented under perfectly controlled medical supervision. The press release of these warning signals triggered a huge debate over COVID-19 vaccines' safety. Thereby, our attention was quickly focused on issues involving the risk of myocarditis, acute coronary syndrome, hypertension and thrombosis. Rare cases of undesirable post-vaccine pathophysiological phenomena should question us, especially when they occur in young subjects. They are more likely to occur with inappropriate use of mRNA vaccine (e.g., at the time when the immune response is already very active during a low-noise infection in the process of healing), leading to angiotensin II (Ang II) induced inflammation triggering tissue damage. Such harmful effects observed after the COVID-19 vaccine evoke a possible molecular mimicry of the viral spike transiently dysregulating angiotensin converting enzyme 2 (ACE2) function. Although the benefit/risk ratio of SARS-CoV-2 spike mRNA vaccine is very favorable, it seems reasonable to suggest medical surveillance to patients with a history of cardiovascular diseases who receive the COVID-19 vaccine.

Angiotensin converting enzyme 2 gene expression and markers of oxidative stress are correlated with disease severity in patients with COVID-19.

BACKGROUND: Oxidative stress is thought to play a significant role in the pathogenesis and severity of COVID-19. Additionally, angiotensin converting enzyme 2 (ACE2) expression may predict the severity and clinical course of COVID-19. Accordingly, the aim of the present study was to evaluate the association of oxidative stress and ACE2 expression with the clinical severity in patients with COVID-19. METHODS AND RESULTS: The present study comprised 40 patients with COVID-19 and 40 matched healthy controls, recruited between September 2021 and March 2022. ACE 2 expression levels were measured using Hera plus SYBR Green qPCR kits with GAPDH used as an internal control. Serum melatonin (MLT) levels, serum malondialdehyde (MDA) levels, and total antioxidant capacity (TAC) were estimated using ELISA. The correlations between the levels of the studied markers and clinical indicators of disease severity were evaluated. Significantly, lower expression of ACE2 was observed in COVID-19 patients compared to controls. Patients with COVID-19 had lower serum levels of TAC and MLT but higher serum levels of MDA compared to normal controls. Serum MDA levels were correlated with diastolic blood pressure (DBP), Glasgow coma scale (GCS) scores, and serum potassium levels. Serum MLT levels were positively correlated with DBP, mean arterial pressure (MAP), respiratory rate, and serum potassium levels. TAC was correlated with GCS, mean platelet volume, and serum creatinine levels. Serum MLT levels were significantly lower in patients treated with remdesivir and inotropes. Receiver operating characteristic curve analysis demonstrates that all markers had utility in discriminating COVID-19 patients from healthy controls. CONCLUSIONS: Increased oxidative stress and increased ACE2 expression were correlated with disease severity and poor outcomes in hospitalized patients with COVID-19 in the present study. Melatonin supplementation may provide a utility as an adjuvant therapy in decreasing disease severity and death in COVID-19 patients.

Cigarette smoke increases susceptibility of alveolar macrophages to SARS-CoV-2 infection through inducing reactive oxygen species-upregulated angiotensin-converting enzyme 2 expression.

Alveolar macrophages (AMs) are the drivers of pulmonary cytokine storm in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to investigate clinical-regulatory factors for the entrance protein of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) in AMs. Human AMs were collected from 56 patients using bronchoalveolar lavage. ACE2 expression in AMs was positively correlated with smoking pack-year (Spearman's r = 0.347, P = 0.038). In multivariate analysis, current smoking was associated with increased ACE2 in AMs (ß-coefficient: 0.791, 95% CI 0.019-1.562, P = 0.045). In vitro study, ex-vivo human AMs with higher ACE2 were more susceptible to SARS-CoV-2 pseudovirus (CoV-2 PsV). Treating human AMs using cigarette smoking extract (CSE) increases the ACE2 and susceptibility to CoV-2 PsV. CSE did not significantly increase the ACE2 in AMs of reactive oxygen species (ROS) deficient Cybb-/- mice; however, exogenous ROS increased the ACE2 in Cybb-/- AMs. N-acetylcysteine (NAC) decreases ACE2 by suppressing intracellular ROS in human AMs. In conclusion, cigarette smoking increases the susceptibility to SARS-CoV-2 by increasing ROS-induced ACE2 expression of AMs. Further investigation into the preventive effect of NAC on the pulmonary complications of COVID-19 is required.

Highly conserved binding region of ACE2 as a receptor for SARS-CoV-2 between humans and mammals.

Several cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection transmitted from human owners to their dogs have recently been reported. The first ever case of SARS-CoV-2 transmission from a human owner to a domestic cat was confirmed on March 27, 2020. A tiger from a zoo in New York, USA, was also reportedly infected with SARS-CoV-2. It is believed that SARS-CoV-2 was transmitted to tigers from their caretakers, who were previously infected with this virus. On May 25, 2020, the Dutch Minister of Agriculture, Nature and Food Quality reported that two employees were infected with SARS-CoV-2 transmitted from minks. These reports have influenced us to perform a comparative analysis among angiotensin-converting enzyme 2 (ACE2) homologous proteins for verifying the conservation of specific protein regions. One of the most conserved peptides is represented by the peptide "353-KGDFR-357 (H. sapiens ACE2 residue numbering), which is located on the surface of the ACE2 molecule and participates in the binding of SARS-CoV-2 spike receptor binding domain (RBD). Multiple sequence alignments of the ACE2 proteins by ClustalW, whereas the three-dimensional structure of its binding region for the spike glycoprotein of SARS-CoV-2 was assessed by means of Spanner, a structural homology modeling pipeline method. In addition, evolutionary phylogenetic tree analysis by ETE3 was used. ACE2 works as a receptor for the SARS-CoV-2 spike glycoprotein between humans, dogs, cats, tigers, minks, and other animals, except for snakes. The three-dimensional structure of the KGDFR hosting protein region involved in direct interactions with SARS-CoV-2 spike RBD of the mink ACE2 appears to form a loop structurally related to the human ACE2 corresponding protein loop, despite of the reduced available protein length (401 residues of the mink ACE2 available sequence vs 805 residues of the human ACE2). The multiple sequence alignments of the ACE2 proteins shows high homology and complete conservation of the five amino acid residues: 353-KGDFR-357 with humans, dogs, cats, tigers, minks, and other animals, except for snakes. Where the information revealed from our examinations can support precision vaccine design and the discovery of antiviral therapeutics, which will accelerate the development of medical countermeasures, the World Health Organization recently reported on the possible risks of reciprocal infections regarding SARS-CoV-2 transmission from animals to humans.

The influence of SARS-CoV-2 infection on expression of drug-metabolizing enzymes and transporters in a hACE2 murine model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting Coronavirus disease 2019 emerged in late 2019 and is responsible for significant morbidity and mortality worldwide. A hallmark of severe COVID-19 is exaggerated systemic inflammation, regarded as a "cytokine storm," which contributes to the damage of various organs, primarily the lungs. The inflammation associated with some viral illnesses is known to alter the expression of drug-metabolizing enzymes and transporters. These alterations can lead to modifications in drug exposure and the processing of various endogenous compounds. Here, we provide evidence to support changes in the mitochondrial ribonucleic acid expression of a subset of drug transporters (84 transporters) in the liver, kidneys, and lungs and metabolizing enzymes (84 enzymes) in the liver in a humanized angiotensin-converting enzyme 2 receptor mouse model. Specifically, three drug transporters (Abca3, Slc7a8, Tap1) and the pro-inflammatory cytokine IL-6 were upregulated in the lungs of SARS-CoV-2 infected mice. We also found significant downregulation of drug transporters responsible for the movement of xenobiotics in the liver and kidney. Additionally, expression of cytochrome P-450 2f2 which is known to metabolize some pulmonary toxicants, was significantly decreased in the liver of infected mice. The significance of these findings requires further exploration. Our results suggest that further research should emphasize altered drug disposition when investigating therapeutic compounds, whether re-purposed or new chemical entities, in other animal models and ultimately in individuals infected with SARS-CoV-2. Moreover, the influence and impact of these changes on the processing of endogenous compounds also require further investigation.

Structural and non-structural proteins in SARS-CoV-2: potential aspects to COVID-19 treatment or prevention of progression of related diseases.

Coronavirus disease 2019 (COVID-19) is caused by a new member of the Coronaviridae family known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are structural and non-structural proteins (NSPs) in the genome of this virus. S, M, H, and E proteins are structural proteins, and NSPs include accessory and replicase proteins. The structural and NSP components of SARS-CoV-2 play an important role in its infectivity, and some of them may be important in the pathogenesis of chronic diseases, including cancer, coagulation disorders, neurodegenerative disorders, and cardiovascular diseases. The SARS-CoV-2 proteins interact with targets such as angiotensin-converting enzyme 2 (ACE2) receptor. In addition, SARS-CoV-2 can stimulate pathological intracellular signaling pathways by triggering transcription factor hypoxia-inducible factor-1 (HIF-1), neuropilin-1 (NRP-1), CD147, and Eph receptors, which play important roles in the progression of neurodegenerative diseases like Alzheimer's disease, epilepsy, and multiple sclerosis, and multiple cancers such as glioblastoma, lung malignancies, and leukemias. Several compounds such as polyphenols, doxazosin, baricitinib, and ruxolitinib could inhibit these interactions. It has been demonstrated that the SARS-CoV-2 spike protein has a stronger affinity for human ACE2 than the spike protein of SARS-CoV, leading the current study to hypothesize that the newly produced variant Omicron receptor-binding domain (RBD) binds to human ACE2 more strongly than the primary strain. SARS and Middle East respiratory syndrome (MERS) viruses against structural and NSPs have become resistant to previous vaccines. Therefore, the review of recent studies and the performance of current vaccines and their effects on COVID-19 and related diseases has become a vital need to deal with the current conditions. This review examines the potential role of these SARS-CoV-2 proteins in the initiation of chronic diseases, and it is anticipated that these proteins could serve as components of an effective vaccine or treatment for COVID-19 and related diseases. Video Abstract.

Novel Therapeutic Target Critical for SARS-CoV-2 Infectivity and Induction of the Cytokine Release Syndrome.

We discovered a novel therapeutic target critical for SARS-CoV-2, cellular infectivity and the induction of the cytokine release syndrome. Here, we show that the mammalian enzyme neuraminidase-1 (Neu-1) is part of a highly conserved signaling platform that regulates the dimerization and activation of the ACE2 receptors and the Toll-like receptors (TLRs) implicated in the cytokine release syndrome (CRS). Activated Neu-1 cleaves glycosylated residues that provide a steric hindrance to both ACE2 and TLR dimerization, a process critical to both viral attachment to the receptor and entry into the cell and TLR activation. Blocking Neu-1 inhibited ACE2 receptor dimerization and internalization, TLR dimerization and activation, and the expression of several key inflammatory molecules implicated in the CRS and death from ARDS. Treatments that target Neu-1 are predicted to be highly effective against infection with SARS-CoV-2, given the central role played by this enzyme in viral cellular entry and the induction of the CRS.

From Cell to Symptoms: The Role of SARS-CoV-2 Cytopathic Effects in the Pathogenesis of COVID-19 and Long COVID.

Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection triggers various events from molecular to tissue level, which in turn is given by the intrinsic characteristics of each patient. Given the molecular diversity characteristic of each cellular phenotype, the possible cytopathic, tissue and clinical effects are difficult to predict, which determines the heterogeneity of COVID-19 symptoms. The purpose of this article is to provide a comprehensive review of the cytopathic effects of SARS-CoV-2 on various cell types, focusing on the development of COVID-19, which in turn may lead, in some patients, to a persistence of symptoms after recovery from the disease, a condition known as long COVID. We describe the molecular mechanisms underlying virus-host interactions, including alterations in protein expression, intracellular signaling pathways, and immune responses. In particular, the article highlights the potential impact of these cytopathies on cellular function and clinical outcomes, such as immune dysregulation, neuropsychiatric disorders, and organ damage. The article concludes by discussing future directions for research and implications for the management and treatment of COVID-19 and long COVID.

Tissue-specific pathway activities: A retrospective analysis in COVID-19 patients.

The ACE2 receptors essential for SARS-CoV-2 infections are expressed not only in the lung but also in many other tissues in the human body. To better understand the disease mechanisms and progression, it is essential to understand how the virus affects and alters molecular pathways in the different affected tissues. In this study, we mapped the proteomics data obtained from Nie X. et al. (2021) to the pathway models of the COVID-19 Disease Map project and WikiPathways. The differences in pathway activities between COVID-19 and non-COVID-19 patients were calculated using the Wilcoxon test. As a result, 46% (5,235) of the detected proteins were found to be present in at least one pathway. Only a few pathways were altered in multiple tissues. As an example, the Kinin-Kallikrein pathway, an important inflammation regulatory pathway, was found to be less active in the lung, spleen, testis, and thyroid. We can confirm previously reported changes in COVID-19 patients such as the change in cholesterol, linolenic acid, and arachidonic acid metabolism, complement, and coagulation pathways in most tissues. Of all the tissues, we found the thyroid to be the organ with the most changed pathways. In this tissue, lipid pathways, energy pathways, and many COVID-19 specific pathways such as RAS and bradykinin pathways, thrombosis, and anticoagulation have altered activities in COVID-19 patients. Concluding, our results highlight the systemic nature of COVID-19 and the effect on other tissues besides the lung.

Murine Coronavirus Disease 2019 Lethality Is Characterized by Lymphoid Depletion Associated with Suppressed Antigen-Presenting Cell Functionality.

The disease severity of coronavirus disease 2019 (COVID-19) varies considerably from asymptomatic to serious, with fatal complications associated with dysregulation of innate and adaptive immunity. Lymphoid depletion in lymphoid tissues and lymphocytopenia have both been associated with poor disease outcomes in patients with COVID-19, but the mechanisms involved remain elusive. In this study, human angiotensin-converting enzyme 2 (hACE2) transgenic mouse models susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were used to investigate the characteristics and determinants of lethality associated with the lymphoid depletion observed in SARS-CoV-2 infection. The lethality of Wuhan SARS-CoV-2 infection in K18-hACE2 mice was characterized by severe lymphoid depletion and apoptosis in lymphoid tissues related to fatal neuroinvasion. The lymphoid depletion was associated with a decreased number of antigen-presenting cells (APCs) and their suppressed functionality below basal levels. Lymphoid depletion with reduced APC function was a specific feature observed in SARS-CoV-2 infection but not in influenza A infection and had the greatest prognostic value for disease severity in murine COVID-19. Comparison of transgenic mouse models resistant and susceptible to SARS-CoV-2 infection revealed that suppressed APC function could be determined by the hACE2 expression pattern and interferon-related signaling. Thus, we demonstrated that lymphoid depletion associated with suppressed APC function characterizes the lethality of COVID-19 mouse models. Our data also suggest a potential therapeutic approach to prevent the severe progression of COVID-19 by enhancing APC functionality.

COVID-19: Time for a clinical classification?

COVID-19 pandemic caused by SARS-CoV-2 virus has been around for 2 years causing significant health-care catastrophes in most parts of the world. The understanding of COVID-19 continues to expand, with multiple newer developments such as the presence of asymptomatic cases, feco-oral transmission, and endothelial dysfunction. The existing classification was developed before this current understanding. With the availability of recent literature evidences, we have attempted a classification encompassing pathogenesis and clinical features for better understanding of the disease process. The pathogenesis of COVID-19 continues to evolve. The spiked protein of the SARS-CoV-2 virus binds to ACE2 receptors causes direct cytopathic damage and hyperinflammatory injury. In addition to alveolar cells, ACE2 is also distributed in gastrointestinal tract and vascular endothelium. ACE2-SARS-CoV-2 interaction engulfs the receptors leading to depletion. Accumulation of Ang2 via AT1 receptor (AT1R) binding causes upregulation of macrophage activity leading to pro-inflammatory cytokine release. Interleukin-6 (IL-6) has been attributed to cause hyperinflammatory syndrome in COVID-19. In addition, it also causes severe widespread endothelial injury through soluble IL-6 receptors. Thrombotic complications occur following the cleavage and activation of von Willebrand factor. Based on the above understanding, clinical features, organ involvement, risk stratification, and disease severity, we have classified COVID-19 patients into asymptomatic, pulmonary, GI, and systemic COVID-19 (S-COVID-19). Studies show that the infectivity and prognosis are different and distinct amongst these groups. Systemic-COVID-19 patients are more likely to be critically ill with multi-organ dysfunction and thrombo-embolic complications.

Impact of COVID-19 on the cardiovascular health of women: a review by the Italian Society of Cardiology Working Group on 'gender cardiovascular diseases'.

The coronavirus disease 19 (COVID-19), due to coronavirus 2 (SARS-CoV-2) infection, presents with an extremely heterogeneous spectrum of symptoms and signs. COVID-19 susceptibility and mortality show a significant sex imbalance, with men being more prone to infection and showing a higher rate of hospitalization and mortality than women. In particular, cardiovascular diseases (preexistent or arising upon infection) play a central role in COVID-19 outcomes, differently in men and women. This review will discuss the potential mechanisms accounting for sex/gender influence in vulnerability to COVID-19. Such variability can be ascribed to both sex-related biological factors and sex-related behavioural traits. Sex differences in cardiovascular disease and COVID-19 involve the endothelial dysfunction, the innate immune system and the renin-angiotensin system (RAS). Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19 and it shows hormone-dependent actions. The incidence of myocardial injury during COVID-19 is sex-dependent, predominantly in association with a greater degree of inflammation and coagulation disorders among men. Its pathogenesis is not fully elucidated, but the main theories foresee a direct role for the ACE2 receptor, the hyperimmune response and the RAS imbalance, which may also lead to isolated presentation of COVID-19-mediated myopericarditis. Moreover, the latest evidence on cardiovascular diseases and their relationship with COVID-19 during pregnancy will be discussed. Finally, authors will analyse the prevalence of the long-covid syndrome between the two sexes and its impact on the quality of life and cardiovascular health.

SARS-CoV-2 Enters Human Leydig Cells and Affects Testosterone Production In Vitro.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a SARS-like coronavirus, continues to produce mounting infections and fatalities all over the world. Recent data point to SARS-CoV-2 viral infections in the human testis. As low testosterone levels are associated with SARS-CoV-2 viral infections in males and human Leydig cells are the main source of testosterone, we hypothesized that SARS-CoV-2 could infect human Leydig cells and impair their function. We successfully detected SARS-CoV-2 nucleocapsid in testicular Leydig cells of SARS-CoV-2-infected hamsters, providing evidence that Leydig cells can be infected with SARS-CoV-2. We then employed human Leydig-like cells (hLLCs) to show that the SARS-CoV-2 receptor angiotensin-converting enzyme 2 is highly expressed in hLLCs. Using a cell binding assay and a SARS-CoV-2 spike-pseudotyped viral vector (SARS-CoV-2 spike pseudovector), we showed that SARS-CoV-2 could enter hLLCs and increase testosterone production by hLLCs. We further combined the SARS-CoV-2 spike pseudovector system with pseudovector-based inhibition assays to show that SARS-CoV-2 enters hLLCs through pathways distinct from those of monkey kidney Vero E6 cells, a typical model used to study SARS-CoV-2 entry mechanisms. We finally revealed that neuropilin-1 and cathepsin B/L are expressed in hLLCs and human testes, raising the possibility that SARS-CoV-2 may enter hLLCs through these receptors or proteases. In conclusion, our study shows that SARS-CoV-2 can enter hLLCs through a distinct pathway and alter testosterone production.

Macrophage ACE2 is necessary for SARS-CoV-2 replication and subsequent cytokine responses that restrict continued virion release.

Macrophages are key cellular contributors to the pathogenesis of COVID-19, the disease caused by the virus SARS-CoV-2. The SARS-CoV-2 entry receptor ACE2 is present only on a subset of macrophages at sites of SARS-CoV-2 infection in humans. Here, we investigated whether SARS-CoV-2 can enter macrophages, replicate, and release new viral progeny; whether macrophages need to sense a replicating virus to drive cytokine release; and, if so, whether ACE2 is involved in these mechanisms. We found that SARS-CoV-2 could enter, but did not replicate within, ACE2-deficient human primary macrophages and did not induce proinflammatory cytokine expression. By contrast, ACE2 overexpression in human THP-1-derived macrophages permitted SARS-CoV-2 entry, processing and replication, and virion release. ACE2-overexpressing THP-1 macrophages sensed active viral replication and triggered proinflammatory, antiviral programs mediated by the kinase TBK-1 that limited prolonged viral replication and release. These findings help elucidate the role of ACE2 and its absence in macrophage responses to SARS-CoV-2 infection.

Repurposing of RAS-Pathway Mediated Drugs for Intestinal Inflammation Related Diseases for Treating SARS-CoV-2 Infection.

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is an emerging zoonotic virus, which causes Coronavirus Disease 2019 (COVID-19). Entry of coronaviruses into the cell depends on binding of the viral spike (S) proteins to cellular receptors Angiotensin-converting enzyme 2 (ACE2). The virus-mediated reduction of ACE2/Ang1-7 causes flooding of inflammatory cytokines. A similar scenario of hyper immunologic reaction has been witnessed in the context of Intestinal Inflammatory Diseases (IIDs) with the deregulation of ACE2. This review summarizes several IIDs that lead to such susceptible conditions. It discusses suitable mechanisms of how ACE2, being a crucial regulator of the Renin-Angiotensin System (RAS) signaling pathway, can affect the physiology of intestine as well as lungs, the primary site of SARS-CoV-2 infection. ACE2, as a SARS-CoV-2 receptor, establishes a critical link between COVID-19 and IIDs. Intercessional studies targeting the RAS signaling pathway in patients may provide a novel strategy for addressing the COVID-19 crisis. Hence, the modulation of these key RAS pathway members can be beneficial in both instances. However, it's difficult to say how beneficial are the ACE inhibitors (ACEI)/ Angiotensin II type-1 receptor blockers (ARBs) during COVID-19. As a result, much more research is needed to better understand the relationship between the RAS and SARS-CoV-2 infection.

Spatial Distribution of SARS-CoV-2 Receptors and Proteases in Testicular Cells.

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 RNA has been found in the human testis on occasion, but subgenomic SARS-CoV-2 and infectious SARS-CoV-2 virions have not been found. There is no direct evidence of SARS-CoV-2 infection of testicular cells. To better understand this, it is necessary to determine whether SARS-CoV-2 receptors and proteases are present in testicular cells. To overcome this limitation, we focused on elucidating with immunohistochemistry the spatial distribution of the SARS-CoV-2 receptors angiotensin-converting enzyme 2 (ACE2) and cluster of differentiation 147 (CD147), as well as their viral spike protein priming proteases, transmembrane protease serine 2 (TMPRSS2) and cathepsin L (CTSL), required for viral fusion with host cells. At the protein level, human testicular tissue expressed both receptors and proteases studied. Both ACE2 and TMPRSS2 were found in interstitial cells (endothelium, Leydig, and myoid peritubular cells) and in the seminiferous epithelium (Sertoli cells, spermatogonia, spermatocytes, and spermatids). The presence of CD147 was observed in all cell types except endothelium and peritubular cells, while CTSL was exclusively observed in Leydig, peritubular, and Sertoli cells. These findings show that the ACE2 receptor and its protease TMPRSS2 are coexpressed in all testicular cells, as well as the CD147 receptor and its protease CTSL in Leydig and Sertoli cells, indicating that testicular SARS-CoV-2 infection cannot be ruled out without further investigation.