scholarly journals Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes

2020 ◽  
Vol 10 (4) ◽  
pp. 146 ◽  
Author(s):  
Joshua Breidenbach ◽  
Prabhatchandra Dube ◽  
Subhanwita Ghosh ◽  
Belal Abdullah ◽  
Nikolai Modyanov ◽  
...  
Keyword(s):  
Viral Entry ◽  
Serine Proteases ◽  
Cathepsin L ◽  
Cell Types ◽  
Multiple Organ ◽  
Healthy Individuals ◽  
Host Cell Membrane ◽  
Organ Systems ◽  
Membrane Bound ◽  
Transmembrane Serine Protease

Viral entry mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an important aspect of virulence. Proposed mechanisms involve host cell membrane-bound angiotensin-converting enzyme 2 (ACE2), type II transmembrane serine proteases (TTSPs), such as transmembrane serine protease isoform 2 (TMPRSS2), lysosomal endopeptidase Cathepsin L (CTSL), subtilisin-like proprotein peptidase furin (FURIN), and even potentially membrane bound heparan sulfate proteoglycans. The distribution and expression of many of these genes across cell types representing multiple organ systems in healthy individuals has recently been demonstrated. However, comorbidities such as diabetes and cardiovascular disease are highly prevalent in patients with Coronavirus Disease 2019 (COVID-19) and are associated with worse outcomes. Whether these conditions contribute directly to SARS-CoV-2 virulence remains unclear. Here, we show that the expression levels of ACE2, TMPRSS2 and other viral entry-related genes, as well as potential downstream effector genes such as bradykinin receptors, are modulated in the target organs of select disease states. In tissues, such as the heart, which normally express ACE2 but minimal TMPRSS2, we found that TMPRSS2 as well as other TTSPs are elevated in individuals with comorbidities compared to healthy individuals. Additionally, we found the increased expression of viral entry-related genes in the settings of hypertension, cancer, or smoking across target organ systems. Our results demonstrate that common comorbidities may contribute directly to SARS-CoV-2 virulence and we suggest new therapeutic targets to improve outcomes in vulnerable patient populations.

scholarly journals Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes

2020 ◽  
Author(s):  
Joshua D. Breidenbach ◽  
Prabhatchandra Dube ◽  
Subhanwita Ghosh ◽  
Nikolai N. Modyanov ◽  
Deepak Malhotra ◽  
...  
Keyword(s):  
Viral Entry ◽  
Serine Proteases ◽  
Cell Types ◽  
Multiple Organ ◽  
Healthy Individuals ◽  
Host Cell Membrane ◽  
Disease States ◽  
Organ Systems ◽  
Vulnerable Patient ◽  
Transmembrane Serine Protease

AbstractViral entry mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an important aspect of virulence. Proposed mechanisms involve host cell membrane-bound angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine proteases (TTSPs), such as transmembrane serine protease isoform 2 (TMPRSS2). The distribution of expression of these genes across cell types representing multiple organ systems in healthy individuals has been recently demonstrated. However, comorbidities such as diabetes and cardiovascular disease are highly prevalent in patients with Coronavirus Disease 2019 (COVID-19) and associated with worse outcomes. Whether these conditions contribute directly to SARS-CoV-2 virulence remain unclear. Here we show that the expression levels of ACE2, TMPRSS2 and other viral entry-related genes are modulated in target organs of select disease states. In tissues such as heart, which normally express ACE2 but minimal TMPRSS2, we found that TMPRSS2 as well as other TTSPs are elevated in individuals with comorbidities vs healthy individuals. Additionally, we found increased expression of viral entry-related genes in the settings of hypertension, cancer or smoking across target organ systems. Our results demonstrate that common comorbidities may contribute directly to SARS-CoV-2 virulence and suggest new therapeutic targets to improve outcomes in vulnerable patient populations.

scholarly journals SARS-CoV-2 Viral Entry Proteins in Hyperandrogenemic Female Mice: Implications for Women with PCOS and COVID-19

2021 ◽  
Vol 22 (9) ◽  
pp. 4472
Author(s):  
Alexandra M. Huffman ◽  
Samar Rezq ◽  
Jelina Basnet ◽  
Licy L. Yanes Cardozo ◽  
Damian G. Romero
Keyword(s):  
Viral Entry ◽  
Fasting Glucose ◽  
Polycystic Ovary ◽  
Cathepsin L ◽  
Multiple Organ ◽  
Reproductive Age ◽  
Host Cells ◽  
Female Mice ◽  
Protein Levels ◽  
Organ Systems

SARS-CoV-2, the causative agent of COVID-19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including TMPRSS2. COVID-19 affects multiple organ systems, and male patients suffer increased severity and mortality. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic comorbidities, both being risk factors associated with severe COVID-19 pathology. We hypothesize that elevated androgens in PCOS regulate SARS-CoV-2 entry proteins in multiple tissues increasing the risk for this population. Female mice were treated with dihydrotestosterone (DHT) for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method. mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT-qPCR, Western-blot, or ELISA in tissues, serum, and urine. DHT treatment increased body weight, fat and lean mass, and fasting glucose. Ace2 mRNA was upregulated in the lung, cecum, heart, and kidney, while downregulated in the brain by DHT. ACE2 protein was upregulated by DHT in the small intestine, heart, and kidney. The SARS-CoV-2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney. ACE2 sheddase Adam17 mRNA was upregulated by DHT in the kidney, which corresponded with increased urinary ACE2 in DHT treated mice. Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID-19.

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.

Current perspective of COVID-19 on neurology: A mechanistic insight

2021 ◽  
Vol 24 ◽  
Author(s):  
Rajesh Kumar ◽  
Seetha Harilal ◽  
Sabitha M ◽  
Leena K Pappachan ◽  
P R Roshni ◽  
...  
Keyword(s):  
Cell Types ◽  
Systemic Circulation ◽  
Multiple Organ ◽  
Coagulation Cascade ◽  
Neurological Involvement ◽  
Causative Organism ◽  
Depth Study ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease ◽  
The Brain

: SARS-CoV-2, the novel coronavirus and the causative organism of Covid-19 pandemic wreaked havoc worldwide producing asymptomatic to symptomatic cases leading to significant morbidity and mortality even after infection. Most of the countries reported a mortality rate of 2-3 % majorly due to cardiorespiratory failures. Recent studies highlighted the neurological involvement playing a key role in cardiorespiratory failures and other symptoms such as headache, anosmia, and ageusia observed in Covid-19 patients. Studies suggests SARS-CoV-2 entry via olfactory epithelium (OE) and the expression of type 2 transmembrane serine protease (TMPRSS2) in addition to angiotensin converting enzyme 2 (ACE2) can facilitate SARS-CoV-2 neurotropism. The virus can either travel via peripheral blood vessel causing endothelial dysfunction, triggering coagulation cascade and multiple organ dysfunction or reach the systemic circulation and take a different route to the blood brain barrier (BBB), disrupting the BBB causing neuroinflammation or neuronal excitotoxicity resulting in the development of encephalitis, encephalopathy, seizures, and strokes. SARS-CoV-2 invasion on brain stem is believed to be responsible for the cardiorespiratory failures observed in Covid-19 patients. Apart from viral invasion via hematogenous route, SARS-CoV-2 neural invasion via PNS nerve terminal, resulting in viral replication and retrograde transportation to soma leading to invasion of the CNS including the brain producing neurological manifestations of the disease either in the initial stages or during the course of the disease and even in a long period post infection in many cases. The ACE2 receptors are expressed in the brain and glial cells and SARS-CoV-2 acts via neuronal as well as non-neuronal pathway. But the exact cell types involved and how they can trigger inflammatory pathways need further in-depth study for the development of targeted therapy.

scholarly journals Functional Analysis of Hepatitis C Virus Envelope Proteins, Using a Cell-Cell Fusion Assay

2006 ◽  
Vol 80 (4) ◽  
pp. 1817-1825 ◽  
Author(s):  
Mariko Kobayashi ◽  
Michael C. Bennett ◽  
Theodore Bercot ◽  
Ila R. Singh
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cell Fusion ◽  
Viral Entry ◽  
Antiviral Agents ◽  
Cell Types ◽  
Envelope Proteins ◽  
Virus Envelope ◽  
Host Cell Membrane ◽  
Cell Cell

ABSTRACT Hepatitis C virus (HCV) envelope proteins mediate the entry of virus into cells by binding to cellular receptors, resulting in fusion of the viral membrane with the host cell membrane and permitting the viral genome to enter the cytoplasm. We report the development of a robust and reproducible cell-cell fusion assay using envelope proteins from commonly occurring genotypes of HCV. The assay scored HCV envelope protein-mediated fusion by the production of fluorescent green syncytia and allowed us to elucidate many aspects of HCV fusion, including the pH of fusion, cell types that permit viral entry, and the conformation of envelope proteins essential for fusion. We found that fusion could be specifically inhibited by anti-HCV antibodies and by at least one peptide. We also generated a number of insertional mutations in the envelope proteins and tested nine of these using the fusion assay. We demonstrate that this fusion assay is a powerful tool for understanding the mechanism of HCV-mediated fusion, elucidating mutant function, and testing antiviral agents.

scholarly journals TMPRSS2 structure-phylogeny repositions Avoralstat for SARS-CoV-2 prophylaxis in mice

2021 ◽  
Author(s):  
Young Joo Sun ◽  
Gabriel Velez ◽  
Dylan Parsons ◽  
Kun Li ◽  
Miguel Ortiz ◽  
...  
Keyword(s):  
Viral Entry ◽  
Serine Proteases ◽  
Tertiary Structure ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Cell Infection ◽  
Effective Inhibition ◽  
Transmembrane Serine Protease

Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and vaccination. Transmembrane serine protease 2 (TMPRSS2) is a human protease required for SARS-CoV-2 viral entry and may represent such a target. We hypothesized drugs selected from proteins related by their tertiary structure, rather than their primary structure, were likely to interact with TMPRSS2. We created a structure-based phylogenetic computational tool 3DPhyloFold to systematically identify structurally similar serine proteases with known therapeutic inhibitors and demonstrated effective inhibition of SARS-CoV-2 infection in vitro and in vivo. Several candidate compounds, Avoralstat, PCI-27483, Antipain, and Soybean-Trypsin-Inhibitor, inhibited TMPRSS2 in biochemical and cell infection assays. Avoralstat, a clinically tested Kallikrein-related B1 inhibitor, inhibited SARS-CoV-2 entry and replication in human airway epithelial cells. In an in vivo proof of principle, Avoralstat significantly reduced lung tissue titers and mitigated weight-loss when administered prophylactically to SARS-CoV-2 susceptible mice indicating its potential to be repositioned for COVID-19 prophylaxis in humans.

scholarly journals Characterization of CFTR expression and chloride channel activity in human endothelia

1998 ◽  
Vol 275 (6) ◽  
pp. C1555-C1564 ◽  
Author(s):  
Albert Tousson ◽  
Brian A. Van Tine ◽  
Anjaparavanda P. Naren ◽  
George M. Shaw ◽  
Lisa M. Schwiebert
Keyword(s):  
Endothelial Cells ◽  
Cyclic Nucleotide ◽  
Umbilical Vein ◽  
Cell Types ◽  
Multiple Organ ◽  
Transmembrane Conductance Regulator ◽  
Channel Activity ◽  
Transmembrane Conductance ◽  
Whole Cell Patch Clamp ◽  
Organ Systems

The cystic fibrosis transmembrane conductance regulator (CFTR) functions as a low-conductance, cAMP-regulated chloride (Cl−) channel in a variety of cell types, such as exocrine epithelial cells. Our results demonstrate that human primary endothelial cells isolated from umbilical vein (HUVEC) and lung microvasculature (HLMVEC) also express CFTR as determined via RT-PCR and immunohistochemical and immunoprecipitation analyses. Moreover, Cl− efflux and whole cell patch-clamp analyses reveal that HUVEC ( n = 6 samples, P < 0.05) and HLMVEC ( n = 5 samples, P < 0.05) display cyclic nucleotide-stimulated Cl−transport that is inhibited by the CFTR selective Cl− channel blocker glibenclamide but not by the blocker DIDS, indicative of CFTR Cl− channel activity. Taken together, these findings demonstrate that human endothelial cells derived from multiple organ systems express CFTR and that CFTR functions as a cyclic nucleotide-regulated Cl− channel in human endothelia.

scholarly journals Molecular Mechanisms of Neuroimmune Crosstalk in the Pathogenesis of Stroke

2021 ◽  
Vol 22 (17) ◽  
pp. 9486
Author(s):  
Yun Hwa Choi ◽  
Collin Laaker ◽  
Martin Hsu ◽  
Peter Cismaru ◽  
Matyas Sandor ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Lymphatic Vessels ◽  
Immunological Response ◽  
Cell Types ◽  
Multiple Organ ◽  
Post Stroke ◽  
Organ Systems ◽  
The Brain

Stroke disrupts the homeostatic balance within the brain and is associated with a significant accumulation of necrotic cellular debris, fluid, and peripheral immune cells in the central nervous system (CNS). Additionally, cells, antigens, and other factors exit the brain into the periphery via damaged blood–brain barrier cells, glymphatic transport mechanisms, and lymphatic vessels, which dramatically influence the systemic immune response and lead to complex neuroimmune communication. As a result, the immunological response after stroke is a highly dynamic event that involves communication between multiple organ systems and cell types, with significant consequences on not only the initial stroke tissue injury but long-term recovery in the CNS. In this review, we discuss the complex immunological and physiological interactions that occur after stroke with a focus on how the peripheral immune system and CNS communicate to regulate post-stroke brain homeostasis. First, we discuss the post-stroke immune cascade across different contexts as well as homeostatic regulation within the brain. Then, we focus on the lymphatic vessels surrounding the brain and their ability to coordinate both immune response and fluid homeostasis within the brain after stroke. Finally, we discuss how therapeutic manipulation of peripheral systems may provide new mechanisms to treat stroke injury.

scholarly journals Lysophospholipid (S1P) receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Victoria Blaho ◽  
Jerold Chun ◽  
Deepa Jonnalagadda ◽  
Yasuyuki Kihara ◽  
Hirotaka Mizuno ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Radioligand Binding ◽  
Cell Types ◽  
Receptor Activation ◽  
Multiple Organ ◽  
S1p Receptors ◽  
Organ Systems ◽  
Sphingosine 1 Phosphate ◽  
Heterologous Expression Systems

Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [70]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family, current gene names have been designated as S1P1R through S1P5R [52]. S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [15, 39]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [74, 76]. A crystal structure of an S1P1-T4 fusion protein confirmed aspects of ligand binding, specificity, and receptor activation determined previously through biochemical and genetic studies [48, 14]. fingolimod (FTY720), the first drug to target any of the lysophospholipid receptors, binds to four of the five S1PRs, and was the first oral therapy for multiple sclerosis [26]. The mechanisms of action of fingolimod and other S1PR modulating drugs in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [107, 28, 43, 44].

scholarly journals Challenges for targeting SARS-CoV-2 proteases as a therapeutic strategy for COVID-19

2020 ◽  
Author(s):  
Kas Steuten ◽  
Heeyoung Kim ◽  
John C. Widen ◽  
Brett M. Babin ◽  
Ouma Onguka ◽  
...  
Keyword(s):  
Viral Entry ◽  
Therapeutic Strategy ◽  
Cathepsin L ◽  
Cysteine Proteases ◽  
Development Programs ◽  
Entry Pathway ◽  
Cysteine Cathepsins ◽  
Human Cathepsin ◽  
Transmembrane Serine Protease ◽  
Substantial Drop

ABSTRACTTwo proteases produced by the SARS-CoV-2 virus, Mpro and PLpro, are essential for viral replication and have become the focus of drug development programs for treatment of COVID-19. We screened a highly focused library of compounds containing covalent warheads designed to target cysteine proteases to identify new lead scaffolds for both Mpro and PLpro proteases. These efforts identified a small number of hits for the Mpro protease and no viable hits for the PLpro protease. Of the Mpro hits identified as inhibitors of the purified recombinant protease, only two compounds inhibited viral infectivity in cellular infection assays. However, we observed a substantial drop in antiviral potency upon expression of TMPRSS2, a transmembrane serine protease that acts in an alternative viral entry pathway to the lysosomal cathepsins. This loss of potency is explained by the fact that our lead Mpro inhibitors are also potent inhibitors of host cell cysteine cathepsins. To determine if this is a general property of Mpro inhibitors, we evaluated several recently reported compounds and found that they are also effective inhibitors of purified human cathepsin L and B and showed similar loss in activity in cells expressing TMPRSS2. Our results highlight the challenges of targeting Mpro and PLpro proteases and demonstrate the need to carefully assess selectivity of SARS-CoV-2 protease inhibitors to prevent clinical advancement of compounds that function through inhibition of a redundant viral entry pathway.

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