Expression Of TMPRSS2 Research Articles

Abstract 710: Androgen-deprivation therapy boosts MX1 expression, a silent effector against COVID-19

Abstract Cancer is a risk factor for SARS-CoV-2 infection. Recent reports have shown that prostate cancer (PCa) patients undergoing androgen-deprivation therapies (ADT) were partially protected from COVID-19. The human myxovirus resistance gene 1 (MX1) is expressed in many tissues, including prostate, and we have previously demonstrated its antitumoral activity in PCa. This protein participates in the antiviral response and it is an IFN-stimulated gene (ISGs), especially during influenza virus infection. There are ongoing clinical trials for COVID-19 prevention and/or treatment using type I or III interferons. However, IFN administration could enhance a "cytokine-storm" causing a hyper-inflammatory response and contributing to organ failure. In this work, we performed bioinformatics analyses in a case-control study from SARS-CoV-2 positive (n=403) and negative (n=50) patients. We analyzed the response to infection assessing gene expression profiles in nasopharyngeal swabs of key host cell receptors (ACE2, TMPRSS2, BSG/CD147, CTSB, CTSL, ADAM17) and antiviral proteins (MX1, MX2, NRF2, IRF3, HIF1A, HMOX1).SARS-CoV-2 positive cases had higher ACE2, but lower TMPRSS2, BSG/CD147 and CTSB expression. Patient age negatively affected ACE2 expression. MX1 and MX2 were higher in SARS-CoV-2 positive individuals, and negative trends were observed as patients' age increased. Principal Component Analysis determined that ACE2, MX1, MX2 and BSG/CD147 expressions were able to cluster non-COVID-19 and COVID-19 individuals. Multivariable regression showed that MX1 expression significantly increased for each unit of viral load increment.Given that MX1 was differentially expressed between COVID-19 and non-COVID-19 patients, we evaluated MX1 expression in A549 and Calu3 lung cell lines. MX1 was significantly up-regulated upon infection with SARS-CoV-2.Since ADT reduces SARS-CoV-2 infection incidence, we aim to study MX1 regulation by dihydrotestosterone (DHT). We browsed publicly available ChIP-seq experiments evaluating androgen receptor (AR) binding sites in different PCa cell lines under DHT stimulation. Results indicated enriched AR binding sites on the MX1 sequence. Therefore, we treated LNCaP cells with DHT, observing a significant decrease in MX1 mRNA levels. Accordingly, we observed a significant increase of MX1 gene expression in PCa patients after ADT treatment.In summary, our study findings support differences in ACE2, MX1, MX2 and BSG/CD147 expression between COVID-19 and non-COVID-19 patients; and point out to MX1 as a critical responder in SARS-CoV-2 infection. Furthermore, we demonstrated MX1 modulation by ADT. Taking into consideration the fact that PCa patients that underwent ADT were less prone to present the infection, we propose this gene as an alternative druggable target for COVID-19 patients, especially those with PCa as a previous condition. Citation Format: Juan Antonio Bizzotto, Pablo Sanchis, Sofia Lage-Vickers, Rosario Lavignolle, Agustina Sabater, Mercedes Abbate, Ayelen Toro, Florencia Cascardo, Santiago Olszevicki, Nicolas Anselmino, Estefania Labanca, Emiliano Ortiz, Elba Vazquez, Javier Cotignola, Geraldine Gueron. Androgen-deprivation therapy boosts MX1 expression, a silent effector against COVID-19 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 710.

Вплив якості слізної плівки на захисні властивості проти SARS-COV-2 і на подальші ризики зараження COVID-19 при хворобі сухого ока

SARS-CoV-2 is a new coronavirus causing global pandemic COVID-19 throughout the world, the clinical manifestations of which may include not only respiratory syndrome and systemic manifestations, but also eye symptoms. The purpose of the study. This study processed and presented to the scientific community the latest scientific evidence from the world literature regarding the effect of tear film quality on protective properties against SARS-CoV-2 and on further risks of COVID-19 infection in dry eye disease. Many studies have proven the presence of ACE2 as well as TMPRSS2 expression in the conjunctival and corneal epithelium and detection of SARS-CoV-2 RNA in the tear fluid of infected patients, which indicates the ocular tissue tropism to the virus and its possible transmission through the ocular surface. The detection of SARS-CoV-2 in conjunctival or tear samples may depend on viral load and secretion, as well as on sampling time during the course of the disease. It has been suggested that SARS-CoV-2 is prone to exist on the surface of the eye in the early stages of conjunctivitis, and the viral load decreases after a few days. However, cases of virus detection without conjunctivitis may indicate that SARS-CoV-2 can cause latent and asymptomatic infection. With the introduction of protective anti-epidemic measures such as protective masks, the rapid increase and progression of dry eye disease has begun, which leads to decreased ocular surface immune mechanisms, and could potentially increase the risks of SARS-CoV-2 virus transmission. The mechanisms of protection of the healthy ocular surface and possible ways to combat SARS-CoV-2 were reviewed. And the potential causes of increased ocular surface infections during a pandemic were also shown. Through wearing of protective masks, there is additional dispersion of air around the eyes and accelerated evaporation of tear fluid with its thinning and rupture, which contributes to the progression of the prevalence of dry eye disease. The information confirmed by research has already appeared in the literature. This ocular surface condition has been defined by the term "MADE" – dry eye associated with wearing a mask. Dry eye disease, in turn, is a multifactorial ocular surface disease that results in tear film instability, hyperosmolar stress, and a cascade of inflammatory responses. This initiates ocular surface damage, impaired immune status, pathological apoptosis of conjunctival and corneal cells, and loss of basic protective function. Conclusion. Thus, given the obvious decrease in the immune defense mechanisms of the ocular surface in dry eye disease, which is a vulnerable place for virus penetration, this area deserves further in-depth study

A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry

SARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identify small molecules that reduce surface expression of TMPRSS2 using a library of 2,560 FDA-approved or current clinical trial compounds. We identify homoharringtonine and halofuginone as the most attractive agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrate marked resistance to SARS-CoV-2 infection in both live and pseudoviral in vitro models. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat active COVID-19 infection.

Altered expression of SARS-CoV-2 entry and processing genes by Porphyromonas gingivalis-derived lipopolysaccharide, inflammatory cytokines and prostaglandin E2 in human gingival fibroblasts

ObjectiveThe aim of this in vitro study was to investigate the expression of SARS-CoV-2 entry and processing genes in human gingival fibroblasts (HGnF) following treatment with Porphyromonas gingivalis-derived lipopolysaccharide (PgLPS) or inflammatory cytokines/mediators. DesignWe assessed the expression of SARS-CoV-2 entry and processing genes; angiotensin-converting enzyme 2 (ACE2), cellular serine proteases transmembrane serine protease 2 (TMPRSS2), Furin, and basigin (BSG) in HGnF by real-time PCR. To further asses the contribution of PgLPS and inflammatory cytokines/mediators to proliferation and SARS-CoV-2 entry and processing gene expression, HGnF were treated with PgLPS, IL1β, TNFα, and PGE2. ResultsThe expression for ACE2 in HGnF was significantly elevated after PgLPS or IL1β, TNFα, PGE2 treatment. The expression of TMPRSS2 was increased by PgLPS, IL1β, or PGE2 while BSG was elevated by PgLPS and IL1β. The expression of BSG and FURIN decreased after TNFα treatment. ConclusionSARS-CoV-2 entry and processing genes are expressed in human gingival fibroblasts and their expressions are altered by PgLPS, IL1β, TNFα and PGE2 treatment.

Stress Decreases Host Viral Resistance and Increases Covid Susceptibility in Embryonic Stem Cells.

Stress-induced changes in viral receptor and susceptibility gene expression were measured in embryonic stem cells (ESC) and differentiated progeny. Rex1 promoter-Red Fluorescence Protein reporter ESC were tested by RNAseq after 72hr exposures to control stress hyperosmotic sorbitol under stemness culture (NS) to quantify stress-forced differentiation (SFD) transcriptomic programs. Control ESC cultured with stemness factor removal produced normal differentiation (ND). Bulk RNAseq transcriptomic analysis showed significant upregulation of two genes involved in Covid-19 cell uptake, Vimentin (VIM) and Transmembrane Serine Protease 2 (TMPRSS2). SFD increased the hepatitis A virus receptor (Havcr1) and the transplacental Herpes simplex 1 (HSV1) virus receptor (Pvrl1) compared with ESC undergoing ND. Several other coronavirus receptors, Glutamyl Aminopeptidase (ENPEP) and Dipeptidyl Peptidase 4 (DPP4) were upregulated significantly in SFD>ND. Although stressed ESC are more susceptible to infection due to increased expression of viral receptors and decreased resistance, the necessary Covid-19 receptor, angiotensin converting enzyme (ACE)2, was not expressed in our experiments. TMPRSS2, ENPEP, and DPP4 mediate Coronavirus uptake, but are also markers of extra-embryonic endoderm (XEN), which arise from ESC undergoing ND or SFD. Mouse and human ESCs differentiated to XEN increase TMPRSS2 and other Covid-19 uptake-mediating gene expression, but only some lines express ACE2. Covid-19 susceptibility appears to be genotype-specific and not ubiquitous. Of the 30 gene ontology (GO) groups for viral susceptibility, 15 underwent significant stress-forced changes. Of these, 4 GO groups mediated negative viral regulation and most genes in these increase in ND and decrease with SFD, thus suggesting that stress increases ESC viral susceptibility. Taken together, the data suggest that a control hyperosmotic stress can increase Covid-19 susceptibility and decrease viral host resistance in mouse ESC. However, this limited pilot study should be followed with studies in human ESC, tests of environmental, hormonal, and pharmaceutical stressors and direct tests for infection of stressed, cultured ESC and embryos by Covid-19.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s12015-021-10188-w.

COVID-19 and celiac disease: A pathogenetic hypothesis for a celiac outbreak.

BackgroundA growing body of evidence supports the intestinal trophism of SARS‐CoV‐2, with ciliated cells and intestinal enterocytes being target cells because of the high expression of ACE2 and TMPRSS2. Indeed, COVID‐19 promotes a “cytokine storm” in the intestinal mucosa: the resulting epithelial damage leads to increased barrier permeability, allowing the passage of gliadin in the intestinal lamina.MethodsBased on current literature, we hypothesize the role of COVID‐19 as a potential trigger factor for celiac disease in predisposed patients.ConclusionsGenetically predisposed patients could be more likely to develop celiac disease following SARS‐CoV‐2 infection, making COVID‐19 a candidate culprit for a potential outbreak of celiac disease in the forthcoming future.

Firefighters and COVID-19: An Occupational Health Perspective.

Firefighters and COVID-19: An Occupational Health Perspective.

In Silico Identification of miRNA-lncRNA Interactions in Male Reproductive Disorder Associated with COVID-19 Infection.

Coronavirus disease 2019 (COVID-19), a global pandemic, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and transmembrane serine protease 2 (TMPRSS2) facilitates ACE2-mediated virus entry. Moreover, the expression of ACE2 in the testes of infertile men is higher than normal, which indicates that infertile men may be susceptible to be infected and SARS-CoV-2 may cause reproductive disorder through the pathway induced by ACE2 and TMPRSS2. Little is known about the pathway regulation of ACE2 and TMPRSS2 expression in male reproductive disorder. Since the regulation of gene expression is mediated by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) at the post-transcriptional level, the aim of this study was to analyze the dysregulated miRNA–lncRNA interactions of ACE2 and TMPRSS2 in male reproductive disorder. Using bioinformatics analysis, we speculate that the predicted miRNAs including miR-125a-5p, miR-125b-5p, miR-574-5p, and miR-936 as regulators of ACE2 and miR-204-5p as a modulator of TMPRSS2 are associated with male infertility. The lncRNAs with a tissue-specific expression for testis including GRM7-AS3, ARHGAP26-AS1, BSN-AS1, KRBOX1-AS1, CACNA1C-IT3, AC012361.1, FGF14-IT1, AC012494.1, and GS1-24F4.2 were predicted. The identified miRNAs and lncRNAs are proposed as potential biomarkers to study the possible association between COVID-19 and male infertility. This study encourages further studies of miRNA–lncRNA interactions to explain the molecular mechanisms of male infertility in COVID-19 patients.

Expression of SARS-CoV2 Infectivity Machinery in the Male Reproductive Tract: Possible Outcomes on Fertility

Emergence of the COVID-19 pandemic continues to rage and rattles the entire world causing multifaceted hardships. Though initially thought to be a disease that primarily affects the lungs, latest evidence suggests its possible Long-term effects on multiple organ systems. SARS-Cov-2, the virus responsible for this disease infects the cells through ACE2 receptor and the serine protease TMPRSS2. In light of the fact that ACE2 expression is very high in the testis and the expression of TMPRSS2 in other reproductive organs, there has been growing interest to determine the effect of SARS-Cov-2 infection on the male reproductive system, especially on fertility. Through bioinformatics analyses, in vitro and cohort studies, the effects on SARS-Cov-2 infection at the molecular to physiological levels are proposed. Perturbations in hormonal levels, damage to the anatomical structure and inflammation in reproductive organs, decline in sperm count and sperm function have been reported. Thus, the significance of COVID-19 on global reproductive health has gained importance. In this article, we summarize the reported facts related to SARS-Cov-2 infectivity on male reproductive system. Such a comprehensive summation herein will help the researchers to have an up to date knowledge in this area of research and to coronavirus newer studies to address the effects of the COVID-19 pandemic on male reproduction, especially fertility.

Current status of the COVID-19 and male reproduction: A review of the literature.

BackgroundCoronavirus disease 2019 (COVID‐19), which causes serious respiratory illnesses such as pneumonia and lung failure, was first reported in mid‐December 2019 in China and has spread around the world. In addition to causing serious respiratory illnesses such as pneumonia and lung failure, there have been conflicting reports about the presence of SARS‐CoV‐2 in the semen of patients who were previously diagnosed with COVID‐19 and possible implications for the male reproductive tract.ObjectiveThe goal for the present study was to review the current status of the literature concerning COVID‐19 and male reproduction.Material and methodsAn electronic literature search was done by using PubMed and Google Scholar databases. Relevant papers, concerning SARS‐COV‐2 and COVID‐19 and male reproduction, published between January 2020 and December 2020 were selected, analyzed and eventually included in the present literature review.ResultsSARS‐CoV‐2 may infect any cell type expressing angiotensin‐converting enzyme 2 (ACE2), including reproductive cells. Besides the presence of the SARS‐CoV‐2 receptor, the expression of host proteases, such as transmembrane serine protease 2 (TMPRSS2), is needed to cleave the viral S protein, allowing permanent fusion of the viral and host cell membranes. Here, we aimed to review the current status of the literature concerning COVID‐19 and male reproduction. The lack of co‐expression of ACE2 and TMPRSS2 in the testis suggests that sperm cells may not be at increased risk of viral entry and spread. However, the presence of orchitis in COVID‐19‐confirmed patients and compromised sex‐related hormonal balance among these patients intrigues reproductive medicine.DiscussionSARS‐CoV‐2 may use alternate receptors to enter certain cell types, or the expression of ACE2 and TMPRSS2 may not be detected in healthy individuals.ConclusionCOVID‐19 challenges all medical areas, including reproductive medicine. It is not yet clear what effects, if any, the COVID‐19 pandemic will have on male reproduction. Further research is needed to understand the long‐term impact of SARS‐CoV‐2 on male reproductive function.

Molecular mechanism of anti-SARS-CoV2 activity of Ashwagandha-derived withanolides

COVID-19 caused by SARS-CoV-2 corona virus has become a global pandemic. In the absence of drugs and vaccine, and premises of time, efforts and cost required for their development, natural resources such as herbs are anticipated to provide some help and may also offer a promising resource for drug development. Here, we have investigated the therapeutic prospective of Ashwagandha for the COVID-19 pandemic. Nine withanolides were tested in silico for their potential to target and inhibit (i) cell surface receptor protein (TMPRSS2) that is required for entry of virus to host cells and (ii) viral protein (the main protease Mpro) that is essential for virus replication. We report that the withanolides possess capacity to inhibit the activity of TMPRSS2 and Mpro. Furthermore, withanolide-treated cells showed downregulation of TMPRSS2 expression and inhibition of SARS-CoV-2 replication in vitro, suggesting that Ashwagandha may provide a useful resource for COVID-19 treatment.

Regression of Castration-Resistant Prostate Cancer by a Novel Compound HG122.

Prostate cancer (PCa) is a common aggressive disease worldwide which usually progresses into incurable castration-resistant prostate cancer (CRPC) in most cases after 18–24 months treatment. Androgen receptor (AR) has been considered as a crucial factor involved in CRPC and the study of AR as a potential therapeutic target in CRPC may be helpful in disease control and life-cycle management. In this study, we identified a potent small molecule compound, HG122, that suppressed CRPC cells proliferation and metastasis, and inhibited tumor growth both in subcutaneous and orthotopic tumor model. In addition, HG122 reduced the mRNA expression of PSA and TMPRSS2 which are target genes of AR, resulting in cell growth inhibition and metastasis suppression of CRPC, without affecting the expression of AR mRNA level. Mechanically, HG122 promoted AR protein degradation through the proteasome pathway impairing the AR signaling pathway. In conclusion, HG122 overcomes enzalutamide (ENZ) resistance in CRPC both in vitro and in vivo, thus suggesting HG122 is a potential candidate for the clinical prevention and treatment of CRPC.

Letter to the Editor re: Baldassarri etal., 2021 "Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males".

We would like to thank Baldassarri et al. for presenting their findings that short androgen receptor (AR) polyQ alleles confer protection against life-threatening COVID-19 infection among European males [[1]Baldassarri M et al.Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.EBioMedicine. 2021; 103246Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. Data previously presented by McCoy et al. suggests that longer AR CAG repeats are associated with more severe COVID-19 disease. In skeletal muscle, for example, long AR CAG repeats confer increased transcriptional activity in response to testosterone. In prostate cancer, short CAG repeats have been associated with a poor prognosis. This difference in skeletal muscle and prostate tissue could be explained by the tissue-dependent expression of co-factors that aid in activation of the androgen response element (ARE) [[2]McCoy J et al.Androgen receptor genetic variant predicts COVID-19 disease severity: a prospective longitudinal study of hospitalized COVID-19 male patients.J Eur Acad Dermatol. Venereol. 2021; 35: e15-e17Crossref PubMed Scopus (23) Google Scholar]. Baldassarri et al. suggested to initiate clinical trials of testosterone therapy in men expressing defective androgen signaling and having serologic evidence of hypoandrogenism [[1]Baldassarri M et al.Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.EBioMedicine. 2021; 103246Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. There is evidence that th lower AR activity caused by the longer CAG repeats is biologically compensated by increased testosterone levels. The response to testosterone therapy may be increased in patients with shorter CAG repeats, who have enhanced AR activity [[3]Tirabassi G Cignarelli A Perrini S et al.Influence of CAG repeat polymorphism on the targets of testosterone action.Int J Endocrinol. 2015; : 1-12Crossref Scopus (45) Google Scholar]. We suggest a more robust discussion in light of already published randomized clinical trials addressing the role of antiandrogen therapy in reducing disease severity by reducing expression of TMPRSS2. Randomized control trials with 5-alpha-reductase inhibitors and antiandrogens have shown accelerated viral clearance at 7 days and improvement in inflammatory markers in males infected with SARS-CoV-2 compared to males treated with a placebo as well as a reduction in COVID-19 symptoms and hospitalization rates among males [[4]Cadegiani FA McCoy J Gustavo Wambier C Goren A Early Antiandrogen Therapy With Dutasteride Reduces Viral Shedding, Inflammatory Responses, and Time-to-Remission in Males With COVID-19: A Randomized, Double-Blind, Placebo-Controlled Interventional Trial (EAT-DUTA AndroCoV Trial –Biochemical).Cureus. 2021; https://doi.org/10.7759/cureus.13047Crossref Google Scholar]. A single case report gives much information about how external androgens seem to exacerbate COVID-19 symptoms, and how blocking the androgen receptor with a strong antiandrogen such as proxalutamide, seems to resolve COVID-19 symptoms within the first 24 hours of therapy [[5]Cadegiani F Lin EM Goren A Wambier CG. Potential risk for developing severe COVID-19 disease among anabolic steroid users.BMJ Case Report. 2021; 14e241572Crossref PubMed Scopus (10) Google Scholar]. We expect the publication of the results of the NCT04728802 (Proxalutamide Treatment for Hospitalized COVID-19 Patients) soon, which may strongly discourage clinical trials with androgens in hospitalized COVID-19 patients. We are thankful to the authors for their contribution to current literature, and we look forward to more studies investigating genetic and hormonal predictors of COVID-19 disease severity, as well as results of ongoing studies of antiandrogen therapy for COVID-19 by other groups. None Declared

MO038SCARF EXPRESSION IN KIDNEY DISEASE

Background and AimsChronic kidney disease (CKD) is the most common risk factor for lethal COVID19 and the risk factor that most increases the risk of death of COVID19 patients. Additionally, acute kidney injury (AKI) is frequent in COVID19 and AKI increases the risk of death. However, the underlying cellular and molecular mechanisms of such increased risk are unclear. SARS-CoV-2 and coronavirus-associated receptors and factors (SCARFs) are required for and/or regulate (in a positive or negative manner) coronary cell entry and/or viral replication. We have now studied changes in the expression of genes encoding for SCARF in the context of acute and chronic kidney disease.MethodData mining of in-house (experimental models of AKI -folic acid nephropathy- and CKD -Unilateral ureteral obstruction- in mice) and publicly available databases (Nephroseq, published single cell transcriptomics studies) of kidney tissue transcriptomics as well as the Protein Atlas database.ResultsOut of 28 SCARF genes identified by Singh et al (Cell Reports 2020), 26 were represented in the experimental AKI database. Of them 7 (27%) were differentially expressed during AKI (FDR <0.05), 4 of them upregulated and 3 downregulated (Figure 1.A). Additionally, 27 were represented in the experimental CKD database. Of them 17 (63%) were differentially expressed during experimental CKD, 6 of them upregulated and 11 downregulated (Figure 1.B). Two genes were consistently upregulated (Ctsl and Ifitm3) and two consistently downregulated (Tmprss2 and Top3b) in both experimental AKI and CKD (Figure 1.A and B). They encode cathepsin L, interferon induced transmembrane protein 3, transmembrane serine protease 2, DNA topoisomerase III beta, respectively. Single cell transcriptomics databases localized Ctsl expression mainly to podocytes and tubular cells while protein atlas showed clear tubular staining. The main site of Ifitm3 was endothelium in both datasets and it was also localized to leukocytes by single cell transcriptomics. Tmprss2 was mainly localized to tubular cells in both datasets while Top3b was widely expressed in parenchymal renal cells, endothelium and leucocytes in single cell transcriptomics. Increased kidney expression of Ifitm3 and decreased expression of Tmprss2 and Top3b were confirmed in diverse CKD datasets in Nephroseq.ConclusionBoth AKI and CKD are associated with differential expression of SCARF genes in kidney tissue, the impact of CKD appearing to be larger. Characterization of these changes and their functional impact in kidney tissue and beyond the kidneys may provide clues to the increased risk of severe or lethal COVID19 in kidney disease patients.Kidney SCARF gene expression

Genome-wide screening of SARS-CoV-2 infection-related genes based on the blood leukocytes sequencing data set of patients with COVID-19.

Coronavirus disease 2019 (COVID‐19) is a global epidemic disease caused by a novel virus, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), causing serious adverse effects on human health. In this study, we obtained a blood leukocytes sequencing data set of COVID‐19 patients from the GEO database and obtained differentially expressed genes (DEGs). We further analyzed these DEGs by protein–protein interaction analysis and Gene Ontology enrichment analysis and identified the DEGs closely related to SARS‐CoV‐2 infection. Then, we constructed a six‐gene model (comprising IFIT3, OASL, USP18, XAF1, IFI27, and EPSTI1) by logistic regression analysis and calculated the area under the ROC curve (AUC) for the diagnosis of COVID‐19. The AUC values of the training group, testing group, and entire group were 0.930, 0.914, and 0.921, respectively. The six genes were highly expressed in patients with COVID‐19 and positively correlated with the expression of SARS‐CoV‐2 invasion‐related genes (ACE2, TMPRSS2, CTSB, and CTSL). The risk score calculated by this model was also positively correlated with the expression of TMPRSS2, CTSB, and CTSL, indicating that the six genes were closely related to SARS‐CoV‐2 infection. In conclusion, we comprehensively analyzed the functions of DEGs in the blood leukocytes of patients with COVID‐19 and constructed a six‐gene model that may contribute to the development of new diagnostic and therapeutic ideas for COVID‐19. Moreover, these six genes may be therapeutic targets for COVID‐19.

Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with implications for sex-discordant COVID-19 outcomes

The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.

Presence of SARS-CoV-2 and Its Entry Factors in Oral Tissues and Cells: A Systematic Review.

Background and Objectives: The aim of this systematic review is to summarize the current data about the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its entry factors in oral tissues and cells. Materials and Methods: This systematic review was carried out based on the Preferred Reporting Items for a Systematic Review and Meta-Analysis (PRISMA). Three databases were analyzed (Pubmed, Web of science and Scopus) by three independent researchers. From the 18 identified studies, 10 of them met the inclusion criteria. The presence of SARS-CoV-2 or its entry factors (angiotensin-converting enzyme II (ACE2), transmembrane serine proteases (TMPRSS), and furin) was analyzed in these 10 studies during the pandemic. Results: ACE2 expression was analyzed in 9 of the 10 studies. ACE2 is expressed mainly in the tongue, oral mucosa, salivary glands and epithelial cells. The expression of the TMPRSS2 gene or protein was analyzed in 6 studies. These studies reported that the expression of TMPRSS2 was mainly in the salivary glands, tongue, sulcular epithelium and oral mucosa; as well as in cells of the salivary glands (ductal, acinar and myoepithelial cells) and the tongue (the spinous-based cell layer, horny layer and the epithelial surface). Other TMPRSS were also reported. The expression of TMPRSS3, TMPRSS4, TMPRSS5, TMPRSS7 and TMPRSS11D was reported mainly in salivary glands and in epithelial-type cells. Furan expression was analyzed in three studies. The expression of furin was detected mainly in epithelial cells of the tongue. A variety of methods were used to carry out the detection of SARS-CoV-2 or its input molecules. Conclusions: These results show that SARS-CoV-2 can infect a wide variety of oral tissues and cells, and that together with the theories dedicated to explaining the oral symptoms present in SARS-CoV-2 positive patients, it provides us with a good scientific basis for understanding the virus infection in the oral cavity and its consequences.

High Expression of ACE2 and TMPRSS2 at the Resection Margin Makes Lung Cancer Survivors Susceptible to SARS-CoV-2 With Unfavorable Prognosis.

BackgroundCoronavirus disease 2019 (COVID-19) has rapidly spread worldwide. Systematic analysis of lung cancer survivors at molecular and clinical levels is warranted to understand the disease course and clinical characteristics.MethodsA single-center, retrospective cohort study was conducted in 65 patients with COVID-19 from Wuhan Huoshenshan Hospital, of which 13 patients were diagnosed with lung cancer. The study was conducted from February 4 to April 11, 2020.ResultsDuring the course of treatment, lung cancer survivors infected with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) had shorter median time from symptom onset to hospitalization (P = 0.016) and longer clinical symptom remission time (P = 0.020) than non-cancer individuals. No differences were observed among indicators such as time from symptom onset to hospitalization and symptom remission time between medium-term and short-term survivors. The expression of ACE2 (P = 0.013) and TMPRSS2 (P <0.001) was elevated in lung cancer survivors as compared with that in non-cancer individuals.Conclusions ACE2 and TMPRSS2 levels were higher at resection margins of lung cancer survivors than those in normal tissues of non-cancerous individuals and may serve as factors responsible for the high susceptibility to COVID-19 among lung cancer survivors. Lung cancer patients diagnosed with COVID-19, including medium-term survivors, have worse outcomes than the general population.

SARS-CoV-2 infects human adult donor eyes and hESC-derived ocular epithelium.

The SARS-CoV-2 pandemic has caused unparalleled disruption of global behavior and significant loss of life. To minimize SARS-CoV-2 spread, understanding the mechanisms of infection from all possible routes of entry is essential. While aerosol transmission is thought to be the primary route of spread, viral particles have been detected in ocular fluid, suggesting that the eye may be a vulnerable point of viral entry. To this end, we confirmed SARS-CoV-2 entry factor and antigen expression in post-mortem COVID-19 patient ocular surface tissue and observed productive viral replication in cadaver samples and eye organoid cultures, most notably in limbal regions. Transcriptional analysis of ex vivo infected ocular surface cells and hESC-derived eye cultures revealed robust induction of NF-κB in infected cells as well as diminished type I/III interferon signaling. Together these data suggest that the eye can be directly infected by SARS-CoV-2 and implicate limbus as a portal for viral entry.

Dysbalance of ACE2 levels - a possible cause for severe COVID-19 outcome in COPD.

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) poses a serious threat to healthcare systems worldwide. Binding of the virus to angiotensin‐converting enzyme 2 (ACE2) is an important step in the infection mechanism. However, it is unknown if ACE2 expression in patients with chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary arterial hypertension (IPAH), or pulmonary fibrosis (PF), is changed as compared to controls. We used lung samples from patients with COPD (n = 28), IPAH (n = 10), and PF (n = 10) as well as healthy control donor (n = 10) tissue samples to investigate the expression of ACE2 and related cofactors that might influence the course of SARS‐CoV‐2 infection. Expression levels of the ACE2 receptor, the putative receptor CD147/BSG, and the viral entry cofactors TMPRSS2 (transmembrane serine protease 2), EZR, and FURIN were determined by quantitative PCR and in open‐access RNA sequencing datasets. Immunohistochemical and single‐cell RNA sequencing (scRNAseq) analyses were used for localization and coexpression, respectively. Soluble ACE2 (sACE2) plasma levels were analyzed by enzyme‐linked immunosorbent assay. In COPD as compared to donor, IPAH, and PF lung tissue, gene expression of ACE2, TMPRSS2, and EZR was significantly elevated, but circulating sACE2 levels were significantly reduced in COPD and PF plasma compared to healthy control and IPAH plasma samples. Lung tissue expressions of FURIN and CD147/BSG were downregulated in COPD. None of these changes were associated with changes in pulmonary hemodynamics. Histological analysis revealed coexpression of ACE2, TMPRSS2, and Ezrin in bronchial regions and epithelial cells. This was confirmed by scRNAseq analysis. There were no significant expression changes of the analyzed molecules in the lung tissue of IPAH and idiopathic PF as compared to control. In conclusion, we reveal increased ACE2 and TMPRSS2 expression in lung tissue with a concomitant decrease of protective sACE2 in COPD patients. These changes represent the possible risk factors for an increased susceptibility of COPD patients to SARS‐CoV‐2 infection.