scholarly journals Regulation of the ACE2 locus in human airways cells

2020 ◽  
Author(s):  
Hye Kyung Lee ◽  
Olive Jung ◽  
Lothar Hennighausen
Keyword(s):  
Regulatory Elements ◽  
Janus Kinase ◽  
Cell Tropism ◽  
Jak Inhibitors ◽  
Angiotensin Converting Enzyme 2 ◽  
Strong Inflammatory Response ◽  
Human Airways ◽  
Ace2 Gene ◽  
Insight Into ◽  
Bronchial Cells

AbstractThe angiotensin-converting enzyme 2 (ACE2) receptor is the gateway for SARS-CoV-2 to airway epithelium1,2 and the strong inflammatory response after viral infection is a hallmark in COVID-19 patients. Deciphering the regulation of the ACE2 gene is paramount for understanding the cell tropism of SARS-CoV-2 infection. Here we identify candidate regulatory elements in the ACE2 locus in human primary airway cells and lung tissue. Activating histone and promoter marks and Pol II loading characterize the intronic dACE2 and define novel candidate enhancers distal to the genuine ACE2 promoter and within additional introns. dACE2, and to a lesser extent ACE2, RNA levels increased in primary bronchial cells treated with interferons and this induction was mitigated by Janus kinase (JAK) inhibitors that are used therapeutically in COVID-19 patients. Our analyses provide insight into regulatory elements governing the ACE2 locus and highlight that JAK inhibitors are suitable tools to suppress interferon-activated genetic programs in bronchial cells.

scholarly journals Activation of Interferon-Stimulated Transcriptomes and ACE2 Isoforms in Human Airway Epithelium Is Curbed by Janus Kinase Inhibitors

2020 ◽  
Author(s):  
Hye Kyung Lee ◽  
Olive Jung ◽  
Lothar Hennighausen
Keyword(s):  
Airway Epithelium ◽  
Kinase Inhibitors ◽  
Regulatory Elements ◽  
Janus Kinase ◽  
Cell Tropism ◽  
Jak Inhibitors ◽  
Janus Kinase Inhibitors ◽  
Angiotensin Converting Enzyme 2 ◽  
Human Airway ◽  
Human Airway Epithelium

Abstract SARS-CoV-2 infection of human airway epithelium activates genetic programs that lead to progressive hyperinflammation in COVID-19 patients. Here we report on genetic programs activated by interferons and the suppression by Janus kinase (JAK) inhibitors. The angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and deciphering its regulation is paramount for understanding the cell tropism of SARS-CoV-2 infection. We identified candidate regulatory elements in the ACE2 locus in human primary airway cells and lung tissue. Activating histone and promoter marks and Pol II loading characterize the intronic dACE2 and define novel candidate enhancers distal to the genuine ACE2 promoter and within additional introns. dACE2, and to a lesser extent ACE2, RNA levels increased in primary cells treated with interferons and this induction was mitigated by JAK inhibitors that are used therapeutically in COVID-19 patients. Our analyses provide insight into ACE2 regulatory elements and highlight JAK inhibitors as suitable tools to suppress interferon-activated genetic programs in bronchial cells.

scholarly journals JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hye Kyung Lee ◽  
Olive Jung ◽  
Lothar Hennighausen
Keyword(s):  
Airway Epithelium ◽  
Airway Epithelial Cells ◽  
Janus Kinase ◽  
Cell Tropism ◽  
Airway Epithelial ◽  
Rna Seq ◽  
Jak Inhibitors ◽  
Angiotensin Converting Enzyme 2 ◽  
Human Airway ◽  
Human Airway Epithelium

AbstractSARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE2 and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib, used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells.

scholarly journals Topical Tofacitinib: A Janus Kinase Inhibitor for the Treatment of Vitiligo in an Adolescent Patient

2021 ◽  
pp. 190-194
Author(s):  
Sineida Berbert Ferreira ◽  
Rachel Berbert Ferreira ◽  
Afonso Cesar Neves Neto ◽  
Silvana Martins Caparroz Assef ◽  
Morton Scheinberg
Keyword(s):  
Case Report ◽  
Skin Disease ◽  
Kinase Inhibitor ◽  
Effective Therapy ◽  
Janus Kinase ◽  
Jak Inhibitor ◽  
Adolescent Patient ◽  
Jak Inhibitors ◽  
Janus Kinase Inhibitor ◽  
History Of

Vitiligo is an autoimmune skin disease presenting with areas of depigmentation. Recent reports suggest that Janus kinase (JAK) inhibitors may be an effective therapy. In this case report, we show our experience with an adolescent patient with a long history of generalized and refractory vitiligo, for which treatment with topical tofacitinib, a JAK inhibitor, associated with phototherapy for 9 months, resulted in near complete repigmentation.

scholarly journals Update on the therapeutic management of patients with either psoriatic arthritis or ulcerative colitis: focus on the JAK inhibitor tofacitinib

2021 ◽  
Vol 13 ◽  
pp. 1759720X2097777
Author(s):  
Maria Sole Chimenti ◽  
Paola Conigliaro ◽  
Livia Biancone ◽  
Roberto Perricone
Keyword(s):  
Ulcerative Colitis ◽  
Psoriatic Arthritis ◽  
Janus Kinase ◽  
Phase Iii ◽  
Jak Inhibitors ◽  
Immune Mediated ◽  
Significant Burden ◽  
Phase Iii Trials ◽  
Disease Modifying Agents ◽  
Interleukin Inhibitors

Psoriatic arthritis (PsA) and ulcerative colitis (UC) are immune-mediated diseases that cause significant burden worldwide. Recent advances in their management have improved patient outcomes. However, significant unmet needs still remain as not all patients respond to current treatments, and patients may lose responsiveness over time. An improved understanding of the pathophysiology of these diseases has brought about the development of novel disease-modifying agents, including interleukin inhibitors and, more recently, Janus kinase (JAK) inhibitors. With the approval of tofacitinib for the treatment of adults with active PsA and in adult patients with moderately-to-severely active UC, JAK inhibitors have recently entered the treatment armamentarium for PsA and UC. A number of other JAK inhibitors are also undergoing clinical development and are currently in phase III trials. This review provides an overview of the current therapeutic options for PsA and UC, with a focus on the JAK inhibitors.

scholarly journals Mycoplasma suis infection results endothelial cell damage and activation: new insight into the cell tropism and pathogenicity of hemotrophic mycoplasma

2013 ◽  
Vol 44 (1) ◽  
pp. 6 ◽  
Author(s):  
Albina Sokoli ◽  
Katrin Groebel ◽  
Katharina Hoelzle ◽  
Werner M Amselgruber ◽  
José M Mateos ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Damage ◽  
Cell Tropism ◽  
Endothelial Cell Damage ◽  
Mycoplasma Suis ◽  
Hemotrophic Mycoplasma ◽  
Insight Into

scholarly journals Investigation of the genetic variation in ACE2 on the structural recognition by the novel coronavirus (SARS-CoV-2)

2020 ◽  
Author(s):  
Xingyi Guo ◽  
Zhishan Chen ◽  
Yumin Xia ◽  
Weiqiang Lin ◽  
Hongzhi Li
Keyword(s):  
Genetic Variation ◽  
The Novel ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Missense Variants ◽  
Catalytic Metal ◽  
Using Data ◽  
Novel Coronavirus ◽  
Insight Into

Abstract Background: The outbreak of coronavirus disease (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), through its surface spike glycoprotein (S-protein) recognition on the receptor Angiotensin-converting enzyme 2 (ACE2) in humans. However, it remains unclear how genetic variations in ACE2 may affect its function and structure, and consequently alter the recognition by SARS-CoV-2. Methods: We have systemically characterized missense variants in the gene ACE2 using data from the Genome Aggregation Database (gnomAD; N = 141,456). To investigate the putative deleterious role of missense variants, six existing functional prediction tools were applied to evaluate their impact. We further analyzed the structural flexibility of ACE2 and its protein-protein interface with the S-protein of SARS-CoV-2 using our developed Legion Interfaces Analysis (LiAn) program.Results: Here, we characterized a total of 12 ACE2 putative deleterious missense variants. Of those 12 variants, we further showed that p.His378Arg could directly weaken the binding of catalytic metal atom to decrease ACE2 activity and p.Ser19Pro could distort the most important helix to the S-protein. Another seven missense variants may affect secondary structures (i.e. p.Gly211Arg; p.Asp206Gly; p.Arg219Cys; p.Arg219His, p.Lys341Arg, p.Ile468Val, and p.Ser547Cys), whereas p.Ile468Val with AF = 0.01 is only present in Asian.Conclusions: We provide strong evidence of putative deleterious missense variants in ACE2 that are present in specific populations, which could disrupt the function and structure of ACE2. These findings provide novel insight into the genetic variation in ACE2 which may affect the SARS-CoV-2 recognition and infection, and COVID-19 susceptibility and treatment.

scholarly journals Biologic disease modifying antirheumatic drugs and Janus kinase inhibitors in paediatric rheumatology – what we know and what we do not know from randomized controlled trials

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Tatjana Welzel ◽  
Carolyn Winskill ◽  
Nancy Zhang ◽  
Andreas Woerner ◽  
Marc Pfister
Keyword(s):  
Certolizumab Pegol ◽  
Paediatric Rheumatology ◽  
Janus Kinase ◽  
Pharmacokinetic Data ◽  
Disease Course ◽  
Jak Inhibitors ◽  
Disease Modifying Antirheumatic Drugs ◽  
Antirheumatic Drugs ◽  
Age Dependent ◽  
Disease Modifying

Abstract Background Biologic disease modifying antirheumatic drugs (bDMARDs) and Janus Kinase (JAK) inhibitors are prescribed in adult and paediatric rheumatology. Due to age-dependent changes, disease course, and pharmacokinetic processes paediatric patients with inflammatory rheumatic diseases (PiRD) differ from adult rheumatology patients. Methods A systematic literature search for randomized clinical trials (RCTs) in PiRD treated with bDMARDs/JAK inhibitors was conducted on Medline, clinicaltrials.gov, clinicaltrialsregister.eu and conference abstracts as of July 2020. RCTs were included if (i) patients were aged ≤20 years, (ii) patients had a predefined rheumatic diagnosis and (iii) RCT reported predefined outcomes. Selected studies were excluded in case of (i) observational or single arm study or (ii) sample size ≤5 patients. Study characteristics were extracted. Results Out of 608 screened references, 65 references were selected, reporting 35 unique RCTs. All 35 RCTs reported efficacy while 34/3 provided safety outcomes and 16/35 provided pharmacokinetic data. The most common investigated treatments were TNF inhibitors (60%), IL-1 inhibitors (17%) and IL-6 inhibitors (9%). No RCTs with published results were identified for baricitinib, brodalumab, certolizumab pegol, guselkumab, risankizumab, rituximab, sarilumab, secukinumab, tildrakizumab, or upadacitinib. In patients with juvenile idiopathic arthritis (JIA) 25/35 RCTs were conducted. The remaining 10 RCTs were performed in non-JIA patients including plaque psoriasis, Kawasaki Disease, systemic lupus erythematosus and non-infectious uveitis. In JIA-RCTs, the control arm was mainly placebo and the concomitant treatments were either methotrexate, non-steroidal anti-inflammatory drugs (NSAID) or corticosteroids. Non-JIA patients mostly received NSAID. There are ongoing trials investigating abatacept, adalimumab, baricitinib, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, risankizumab, secukinumab, tofacitinib and tildrakizumab. Conclusion Despite the FDA Modernization Act and support of major paediatric rheumatology networks, such as the Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organization (PRINTO), which resulted in drug approval for PiRD indications, there are limited RCTs in PiRD patients. As therapy response is influenced by age-dependent changes, pharmacokinetic processes and disease course it is important to consider developmental changes in bDMARDs/JAK inhibitor use in PiRD patients. As such it is critical to collaborate and conduct international RCTs to appropriately investigate and characterize efficacy, safety and pharmacokinetics of bDMARDs/JAK inhibitors in paediatric rheumatology.

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