scholarly journals Understanding the age divide in COVID-19: why are children overwhelmingly spared?

2020 ◽  
Vol 319 (1) ◽  
pp. L39-L44 ◽  
Author(s):  
K. Lingappan ◽  
H. Karmouty-Quintana ◽  
J. Davies ◽  
B. Akkanti ◽  
M. T. Harting
Keyword(s):  
Immune System ◽  
Lung Injury ◽  
Viral Entry ◽  
Clinical Course ◽  
Neutrophil Infiltration ◽  
Angiotensin Converting Enzyme 2 ◽  
Progression Of Disease ◽  
Adults And Children ◽  
Transmembrane Serine Protease ◽  
Rapid Emergence

The rapid emergence and subsequent global dissemination of SARS-CoV-2 disease (COVID-19) has resulted in over 4 million cases worldwide. The disease has a marked predilection for adults, and children are relatively spared. Understanding the age-based differences in pathophysiological pathways and processes relevant to the onset and progression of disease both in the clinical course and in experimental disease models may hold the key to the identification of therapeutic targets. The differences in the clinical course are highlighted by the lack of progression of the SARS-CoV-2 infection beyond mild symptoms in a majority of children, whereas in adults the disease progresses to acute lung injury and an acute respiratory distress syndrome (ARDS)-like phenotype with high mortality. The pathophysiological mechanisms leading to decreased lung injury in children may involve the decreased expression of the mediators necessary for viral entry into the respiratory epithelium and differences in the immune system responses in children. Specifically, decreased expression of proteins, including angiotensin-converting enzyme 2 ( ACE2) and Transmembrane Serine Protease 2 ( TMPRSS2) in the airway epithelium in children may prevent viral entry. The immune system differences may include a relative preponderance of CD4+ T cells, decreased neutrophil infiltration, decreased production of proinflammatory cytokines, and increased production of immunomodulatory cytokines in children compared with adults. Notably, the developing lung in children may have a greater capacity to recover and repair after viral infection. Understanding the relative contributions of the above processes to the protective phenotype in the developing lung can guide the trial of the appropriate therapies in adults.

scholarly journals COVID-19 and androgen-targeted therapy for prostate cancer patients

2020 ◽  
Vol 27 (9) ◽  
pp. R281-R292 ◽  
Author(s):  
Neil A Bhowmick ◽  
Jillian Oft ◽  
Tanya Dorff ◽  
Sumanta Pal ◽  
Neeraj Agarwal ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Viral Entry ◽  
Host Cells ◽  
Angiotensin Converting Enzyme 2 ◽  
Cancer Management ◽  
Signaling Inhibitors ◽  
Androgen Regulation ◽  
Androgen Suppression ◽  
Transmembrane Serine Protease ◽  
Significant Disease

The current pandemic (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health challenge with active development of antiviral drugs and vaccines seeking to reduce its significant disease burden. Early reports have confirmed that transmembrane serine protease 2 (TMPRSS2) and angiotensin converting enzyme 2 (ACE2) are critical targets of SARS-CoV-2 that facilitate viral entry into host cells. TMPRSS2 and ACE2 are expressed in multiple human tissues beyond the lung including the testes where predisposition to SARS-CoV-2 infection may exist. TMPRSS2 is an androgen-responsive gene and its fusion represents one of the most frequent alterations in prostate cancer. Androgen suppression by androgen deprivation therapy and androgen receptor signaling inhibitors form the foundation of prostate cancer treatment. In this review, we highlight the growing evidence in support of androgen regulation of TMPRSS2 and ACE2 and the potential clinical implications of using androgen suppression to downregulate TMPRSS2 to target SARS-CoV-2. We also discuss the future directions and controversies that need to be addressed in order to establish the viability of targeting TMPRSS2 and/or ACE2 through androgen signaling regulation for COVID-19 treatment, particularly its relevance in the context of prostate cancer management.

scholarly journals Gene of the month: TMPRSS2 (transmembrane serine protease 2)

2020 ◽  
Vol 73 (12) ◽  
pp. 773-776 ◽  
Author(s):  
Michelle Thunders ◽  
Brett Delahunt
Keyword(s):  
Serine Protease ◽  
Viral Entry ◽  
Fusion Gene ◽  
Related Gene ◽  
Diverse Range ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Spread ◽  
Transmembrane Serine Protease ◽  
Oncogenic Transcription Factor

Transmembrane serine protease 2 is encoded by the TMPRSS2 gene. The gene is widely conserved and has two isoforms, both being autocatalytically activated from the inactive zymogen form. A fusion gene between the TMPRSS2 gene and ERG (erythroblast-specific-related gene), an oncogenic transcription factor, is the most common chromosomal aberration detected in prostate cancer, responsible for driving carcinogenesis. The other key role of TMPRSS2 is in priming the viral spike protein which facilitates viral entry essential for viral infectivity. The protease activates a diverse range of viruses. Both SARS-CoV and SARS-CoV-2 (COVID-19) use angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 to facilitate entry to cells, but with SARS-CoV-2 human-to-human transmission is much higher than SARS-CoV. As TMPRSS2 is expressed outside of the lung, and can therefore contribute to extrapulmonary spread of viruses, it warrants further exploration as a potential target for limiting viral spread and infectivity.

scholarly journals Computational drug repurposing study elucidating simultaneous inhibition of entry and replication of novel corona virus by Grazoprevir

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Santosh Kumar Behera ◽  
Nazmina Vhora ◽  
Darshan Contractor ◽  
Amit Shard ◽  
Dinesh Kumar ◽  
...  
Keyword(s):  
Viral Entry ◽  
Clinical Studies ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Angiotensin Converting Enzyme 2 ◽  
Multiple Pathway ◽  
Poisson Boltzmann ◽  
Drug Receptor ◽  
Transmembrane Serine Protease ◽  
Key Residues

AbstractOutcomes of various clinical studies for the coronavirus disease 2019 (COVID-19) treatment indicated that the drug acts via inhibition of multiple pathways (targets) is likely to be more successful and promising. Keeping this hypothesis intact, the present study describes for the first-time, Grazoprevir, an FDA approved anti-viral drug primarily approved for Hepatitis C Virus (HCV), mediated multiple pathway control via synergistic inhibition of viral entry targeting host cell Angiotensin-Converting Enzyme 2 (ACE-2)/transmembrane serine protease 2 (TMPRSS2) and viral replication targeting RNA-dependent RNA polymerase (RdRP). Molecular modeling followed by in-depth structural analysis clearly demonstrated that Grazoprevir interacts with the key residues of these targets. Futher, Molecular Dynamics (MD) simulations showed stability and burial of key residues after the complex formation. Finally, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis identified the governing force of drug-receptor interactions and stability. Thus, we believe that Grazoprevir could be an effective therapeutics for the treatment of the COVID-19 pandemic with a promise of unlikely drug resistance owing to multiple inhibitions of eukaryotic and viral proteins, thus warrants further clinical studies.

scholarly journals TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 384
Author(s):  
Mai Kishimoto ◽  
Kentaro Uemura ◽  
Takao Sanaki ◽  
Akihiko Sato ◽  
William W. Hall ◽  
...  
Keyword(s):  
Viral Entry ◽  
Vaccine Development ◽  
Spike Protein ◽  
Tissue Tropism ◽  
Type Ii ◽  
Angiotensin Converting Enzyme 2 ◽  
Exogenous Expression ◽  
Transmembrane Serine Protease ◽  
The Impact

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) utilizes host proteases, including a plasma membrane-associated transmembrane protease, serine 2 (TMPRSS2) to cleave and activate the virus spike protein to facilitate cellular entry. Although TMPRSS2 is a well-characterized type II transmembrane serine protease (TTSP), the role of other TTSPs on the replication of SARS-CoV-2 remains to be elucidated. Here, we have screened 12 TTSPs using human angiotensin-converting enzyme 2-expressing HEK293T (293T-ACE2) cells and Vero E6 cells and demonstrated that exogenous expression of TMPRSS11D and TMPRSS13 enhanced cellular uptake and subsequent replication of SARS-CoV-2. In addition, SARS-CoV-1 and SARS-CoV-2 share the same TTSPs in the viral entry process. Our study demonstrates the impact of host TTSPs on infection of SARS-CoV-2, which may have implications for cell and tissue tropism, for pathogenicity, and potentially for vaccine development.

scholarly journals Simultaneous Inhibition of Entry and Replication of Novel Corona Virus by Grazoprevir: A Computational Drug Repurposing Study

2020 ◽  
Author(s):  
Santosh Kumar Behera ◽  
Nazmina Vhora ◽  
Darshan Contractor ◽  
Amit Shard ◽  
Dinesh Kumar ◽  
...  
Keyword(s):  
Viral Entry ◽  
Drug Repurposing ◽  
Viral Proteins ◽  
Angiotensin Converting Enzyme 2 ◽  
Synergistic Inhibition ◽  
Single Drug ◽  
Multiple Pathway ◽  
Simultaneous Inhibition ◽  
Transmembrane Serine Protease ◽  
First Time

<div> <div> <div> <p>It is evident from the on-going clinical studies (trials) for coronavirus disease 2019 (COVID-19) that treatment with a single drug is not likely to be sufficient. This, in turn, suggests that the drug acts via inhibition of multiple pathways likely to be more successful and promising. Keeping this hypothesis intact, the present study describes for the first-time, Grazoprevir, an FDA approved anti-viral drug primarily approved for HCV, mediated multiple pathway control via synergistic inhibition of viral entry targeting host cell Angiotensin Converting Enzyme 2 (ACE- 2)/transmembrane serine protease 2 (TMPRSS2) and viral replication targeting RNA-dependent, RNA polymerase (RdRP). We believe that Grazoprevir either alone or given in combination could be effective therapeutics for treatment of COVID-19 pandemic with a promise of unlikely drug resistance owing to multiple inhibition of eukaryotic and viral proteins. </p> </div> </div> </div>

scholarly journals Simultaneous Inhibition of Entry and Replication of Novel Corona Virus by Grazoprevir: A Computational Drug Repurposing Study

2020 ◽  
Author(s):  
Santosh Kumar Behera ◽  
Nazmina Vhora ◽  
Darshan Contractor ◽  
Amit Shard ◽  
Dinesh Kumar ◽  
...  
Keyword(s):  
Viral Entry ◽  
Drug Repurposing ◽  
Viral Proteins ◽  
Angiotensin Converting Enzyme 2 ◽  
Synergistic Inhibition ◽  
Single Drug ◽  
Multiple Pathway ◽  
Simultaneous Inhibition ◽  
Transmembrane Serine Protease ◽  
First Time

<div> <div> <div> <p>It is evident from the on-going clinical studies (trials) for coronavirus disease 2019 (COVID-19) that treatment with a single drug is not likely to be sufficient. This, in turn, suggests that the drug acts via inhibition of multiple pathways likely to be more successful and promising. Keeping this hypothesis intact, the present study describes for the first-time, Grazoprevir, an FDA approved anti-viral drug primarily approved for HCV, mediated multiple pathway control via synergistic inhibition of viral entry targeting host cell Angiotensin Converting Enzyme 2 (ACE- 2)/transmembrane serine protease 2 (TMPRSS2) and viral replication targeting RNA-dependent, RNA polymerase (RdRP). We believe that Grazoprevir either alone or given in combination could be effective therapeutics for treatment of COVID-19 pandemic with a promise of unlikely drug resistance owing to multiple inhibition of eukaryotic and viral proteins. </p> </div> </div> </div>

scholarly journals SARS-CoV-2 Is Not Detected in the Cerebrospinal Fluid of Encephalopathic COVID-19 Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Dimitris G. Placantonakis ◽  
Maria Aguero-Rosenfeld ◽  
Abdallah Flaifel ◽  
John Colavito ◽  
Kenneth Inglima ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Viral Entry ◽  
Cell Types ◽  
Host Cells ◽  
Nasopharyngeal Swab ◽  
Rt Pcr ◽  
Neurologic Sequelae ◽  
Show Evidence ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease

Neurologic manifestations of the novel coronavirus SARS-CoV-2 infection have received wide attention, but the mechanisms remain uncertain. Here, we describe computational data from public domain RNA-seq datasets and cerebrospinal fluid data from adult patients with severe COVID-19 pneumonia that suggest that SARS-CoV-2 infection of the central nervous system is unlikely. We found that the mRNAs encoding the ACE2 receptor and the TMPRSS2 transmembrane serine protease, both of which are required for viral entry into host cells, are minimally expressed in the major cell types of the brain. In addition, CSF samples from 13 adult encephalopathic COVID-19 patients diagnosed with the viral infection via nasopharyngeal swab RT-PCR did not show evidence for the virus. This particular finding is robust for two reasons. First, the RT-PCR diagnostic was validated for CSF studies using stringent criteria; and second, 61% of these patients had CSF testing within 1 week of a positive nasopharyngeal diagnostic test. We propose that neurologic sequelae of COVID-19 are not due to SARS-CoV-2 meningoencephalitis and that other etiologies are more likely mechanisms.

scholarly journals Pediatric COVID-19 and the Factors That May Mitigate Its Clinical Course

2020 ◽  
Vol 10 (01) ◽  
pp. e137-e140
Author(s):  
Mosaad Abdel-Aziz ◽  
Nada M. Abdel-Aziz ◽  
Dina M. Abdel-Aziz ◽  
Noha Azab
Keyword(s):  
Clinical Features ◽  
Clinical Symptoms ◽  
Clinical Course ◽  
Clinical Manifestations ◽  
Gastrointestinal Symptoms ◽  
Angiotensin Converting Enzyme 2 ◽  
Compulsory Vaccination ◽  
Specific Factors ◽  
Novel Coronavirus ◽  
Radiographic Data

AbstractThe clinical manifestations of novel coronavirus disease 2019 (COVID-19) vary from mild flu-like symptoms to severe fatal pneumonia. However, children with COVID-19 may be asymptomatic or may have mild clinical symptoms. The aim of this study was to investigate clinical features of pediatric COVID-19 and to search for the factors that may mitigate the disease course. We reviewed the literature to realize the clinical features, laboratory, and radiographic data that may be diagnostic for COVID-19 among children. Also, we studied the factors that may affect the clinical course of the disease. Fever, dry cough, and fatigue are the main symptoms of pediatric COVID-19, sometimes flu-like symptoms and/or gastrointestinal symptoms may be present. Although some infected children may be asymptomatic, a recent unusual hyperinflammatory reaction with overlapping features of Kawasaki's disease and toxic shock syndrome in pediatric COVID-19 has been occasionally reported. Severe acute respiratory syndrome-coronvirus-2 (SARS-CoV-2) nucleic acid testing is the corner-stone method for the diagnosis of COVID-19. Lymphocyte count and other inflammatory markers are not essentially diagnostic; however, chest computed tomography is highly specific. Factors that may mitigate the severity of pediatric COVID-19 are home confinement with limited children activity, trained immunity caused by compulsory vaccination, the response of the angiotensin-converting enzyme 2 receptors in children is not the same as in adults, and that children are less likely to have comorbidities. As infected children may be asymptomatic or may have only mild respiratory and/or gastrointestinal symptoms that might be missed, all children for families who have a member diagnosed with COVID-19 should be investigated.

scholarly journals Human Immunodeficiency Viruses Pseudotyped with SARS-CoV-2 Spike Proteins Infect a Broad Spectrum of Human Cell Lines through Multiple Entry Mechanisms

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 953
Author(s):  
Chuan Xu ◽  
Annie Wang ◽  
Ke Geng ◽  
William Honnen ◽  
Xuening Wang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Viral Entry ◽  
Broad Spectrum ◽  
A549 Cells ◽  
Cell Types ◽  
Pseudotyped Virus ◽  
Angiotensin Converting Enzyme 2 ◽  
Human Immunodeficiency Viruses ◽  
Tyrosine Protein Kinase ◽  
Overexpressing Cell

Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2), the causative agent of coronavirus disease 19 (COVID-19), enters cells through attachment to the human angiotensin converting enzyme 2 (hACE2) via the receptor-binding domain (RBD) in the surface/spike (S) protein. Several pseudotyped viruses expressing SARS-CoV-2 S proteins are available, but many of these can only infect hACE2-overexpressing cell lines. Here, we report the use of a simple, two-plasmid, pseudotyped virus system comprising a SARS-CoV-2 spike-expressing plasmid and an HIV vector with or without vpr to investigate the SARS-CoV-2 entry event in various cell lines. When an HIV vector without vpr was used, pseudotyped SARS-CoV-2 viruses produced in the presence of fetal bovine serum (FBS) were able to infect only engineered hACE2-overexpressing cell lines, whereas viruses produced under serum-free conditions were able to infect a broader range of cells, including cells without hACE2 overexpression. When an HIV vector containing vpr was used, pseudotyped viruses were able to infect a broad spectrum of cell types regardless of whether viruses were produced in the presence or absence of FBS. Infection sensitivities of various cell types did not correlate with mRNA abundance of hACE2, TMPRSS2, or TMPRSS4. Pseudotyped SARS-CoV-2 viruses and replication-competent SARS-CoV-2 virus were equally sensitive to neutralization by an anti-spike RBD antibody in cells with high abundance of hACE2. However, the anti-spike RBD antibody did not block pseudotyped viral entry into cell lines with low abundance of hACE2. We further found that CD147 was involved in viral entry in A549 cells with low abundance of hACE2. Thus, our assay is useful for drug and antibody screening as well as for investigating cellular receptors, including hACE2, CD147, and tyrosine-protein kinase receptor UFO (AXL), for the SARS-CoV-2 entry event in various cell lines.

scholarly journals Neurological and Neuropsychological Changes Associated with SARS-CoV-2 Infection: New Observations, New Mechanisms

2021 ◽  
pp. 107385842098410
Author(s):  
Muhammad Ali Haidar ◽  
Hussam Jourdi ◽  
Zeinab Haj Hassan ◽  
Ohanes Ashekyan ◽  
Manal Fardoun ◽  
...  
Keyword(s):  
Viral Entry ◽  
Health Workers ◽  
The Elderly ◽  
Circumventricular Organs ◽  
Depression And Anxiety ◽  
Virus Surface ◽  
Angiotensin Converting Enzyme 2 ◽  
Neuropsychological Changes ◽  
High Risk Populations ◽  
The Central Nervous System

SARS-CoV-2 infects cells through angiotensin-converting enzyme 2 (ACE2), a ubiquitous receptor that interacts with the virus’ surface S glycoprotein. Recent reports show that the virus affects the central nervous system (CNS) with symptoms and complications that include dizziness, altered consciousness, encephalitis, and even stroke. These can immerge as indirect immune effects due to increased cytokine production or via direct viral entry into brain tissue. The latter is possible through neuronal access via the olfactory bulb, hematogenous access through immune cells or directly across the blood-brain barrier (BBB), and through the brain’s circumventricular organs characterized by their extensive and highly permeable capillaries. Last, the COVID-19 pandemic increases stress, depression, and anxiety within infected individuals, those in isolation, and high-risk populations like children, the elderly, and health workers. This review surveys the recent updates of CNS manifestations post SARS-CoV-2 infection along with possible mechanisms that lead to them.

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