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1.
Oxid Med Cell Longev ; 2022: 5397733, 2022.
Article in English | MEDLINE | ID: covidwho-1635531

ABSTRACT

The infection of coronavirus disease (COVID-19) seriously threatens human life. It is urgent to generate effective and safe specific antibodies (Abs) against the pathogenic elements of COVID-19. Mice were immunized with SARS-CoV-2 spike protein antigens: S ectodomain-1 (CoV, in short) mixed in Alum adjuvant for 2 times and boosted with CoV weekly for 6 times. A portion of mice were treated with Maotai liquor (MTL, in short) or/and heat stress (HS) together with CoV boosting. We observed that the anti-CoV Ab was successfully induced in mice that received the CoV/Alum immunization for 2 times. However, upon boosting with CoV, the CoV Ab production diminished progressively; spleen CoV Ab-producing plasma cell counts reduced, in which substantial CoV-specific Ab-producing plasma cells (sPC) were apoptotic. Apparent oxidative stress signs were observed in sPCs; the results were reproduced by exposing sPCs to CoV in the culture. The presence of MTL or/and HS prevented the CoV-induced oxidative stress in sPCs and promoted and stabilized the CoV Ab production in mice in re-exposure to CoV. In summary, CoV/Alum immunization can successfully induce CoV Ab production in mice that declines upon reexposure to CoV. Concurrent administration of MTL/HS stabilizes and promotes the CoV Ab production in mice.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Apoptosis , COVID-19/immunology , Plasma Cells/immunology , SARS-CoV-2/physiology , Superoxide Dismutase-1/physiology , Adjuvants, Immunologic , Alcoholic Beverages , Alum Compounds , Angiotensin-Converting Enzyme 2/physiology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/enzymology , COVID-19 Vaccines/immunology , Heat-Shock Response , Immunization, Secondary , Immunogenicity, Vaccine , Janus Kinase 2/physiology , Male , Mice , Mice, Inbred C57BL , Oxidative Stress , Plasma Cells/drug effects , Plasma Cells/pathology , Reactive Oxygen Species/metabolism , STAT1 Transcription Factor/physiology , Signal Transduction , Specific Pathogen-Free Organisms , Spike Glycoprotein, Coronavirus/immunology , Vaccination
2.
PLoS Biol ; 19(12): e3001510, 2021 12.
Article in English | MEDLINE | ID: covidwho-1592147

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infects a broader range of mammalian species than previously predicted, binding a diversity of angiotensin converting enzyme 2 (ACE2) orthologs despite extensive sequence divergence. Within this sequence degeneracy, we identify a rare sequence combination capable of conferring SARS-CoV-2 resistance. We demonstrate that this sequence was likely unattainable during human evolution due to deleterious effects on ACE2 carboxypeptidase activity, which has vasodilatory and cardioprotective functions in vivo. Across the 25 ACE2 sites implicated in viral binding, we identify 6 amino acid substitutions unique to mouse-one of the only known mammalian species resistant to SARS-CoV-2. Substituting human variants at these positions is sufficient to confer binding of the SARS-CoV-2 S protein to mouse ACE2, facilitating cellular infection. Conversely, substituting mouse variants into either human or dog ACE2 abolishes viral binding, diminishing cellular infection. However, these same substitutions decrease human ACE2 activity by 50% and are predicted as pathogenic, consistent with the extreme rarity of human polymorphisms at these sites. This trade-off can be avoided, however, depending on genetic background; if substituted simultaneously, these same mutations have no deleterious effect on dog ACE2 nor that of the rodent ancestor estimated to exist 70 million years ago. This genetic contingency (epistasis) may have therefore opened the road to resistance for some species, while making humans susceptible to viruses that use these ACE2 surfaces for binding, as does SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Disease Resistance/genetics , Epistasis, Genetic , SARS-CoV-2/physiology , Amino Acids , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Binding Sites , COVID-19/enzymology , COVID-19/genetics , Dogs , Evolution, Molecular , Gene Frequency , Humans , Hydrolysis , Mice , Mutation , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment
3.
Rev Med Virol ; 31(5): 1-12, 2021 09.
Article in English | MEDLINE | ID: covidwho-1575376

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2) receptor. Other important proteins involved in this process include disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) also known as tumour necrosis factor-α-converting enzyme and transmembrane serine protease 2. ACE2 converts angiotensin II (Ang II) to angiotensin (1-7), to balance the renin angiotensin system. Membrane-bound ACE2 ectodomain shedding is mediated by ADAM17 upon viral spike binding, Ang II overproduction and in several diseases. The shed soluble ACE2 (sACE2) retains its catalytic activity, but its precise role in viral entry is still unclear. Therapeutic sACE2 is claimed to exert dual effects; reduction of excess Ang II and blocking viral entry by masking the spike protein. Nevertheless, the paradox is why SARS-CoV-2 comorbid patients struggle to attain such benefit in viral infection despite having a high amount of sACE2. In this review, we discuss the possible detrimental role of sACE2 and speculate on a series of events where protease primed or non-primed virus-sACE2 complex might enter the host cell. As extracellular virus can bind many sACE2 molecules, sACE2 level could be reduced drastically upon endocytosis by the host cell. A consequential rapid rise in Ang II level could potentially aggravate disease severity through Ang II-angiotensin II receptor type 1 (AT1R) axis in comorbid patients. Hence, monitoring sACE2 and Ang II level in coronavirus disease 2019 comorbid patients are crucial to ensure safe and efficient intervention using therapeutic sACE2 and vaccines.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/enzymology , ADAM17 Protein/genetics , ADAM17 Protein/metabolism , Angiotensin I/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , COVID-19/virology , Comorbidity , Humans , Peptide Fragments/metabolism , SARS-CoV-2/physiology
4.
Gastroenterology ; 160(3): 925-928.e4, 2021 02.
Article in English | MEDLINE | ID: covidwho-1575253
5.
Biomed Pharmacother ; 146: 112517, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1561313

ABSTRACT

Rapid changes in the viral genome allow viruses to evade threats posed by the host immune response or antiviral drugs, and can lead to viral persistence in the host cells. RNA-dependent RNA polymerase (RdRp) is an essential enzyme in RNA viruses, which is involved in RNA synthesis through the formation of phosphodiester bonds. Therefore, in RNA viral infections such as SARS-CoV-2, RdRp could be a crucial therapeutic target. The present review discusses the promising application of RdRp inhibitors, previously approved or currently being tested in human clinical trials, in the treatment of RNA virus infections. Nucleoside inhibitors (NIs) bind to the active site of RdRp, while nonnucleoside inhibitors (NNIs) bind to allosteric sites. Given the absence of highly effective drugs for the treatment of COVID-19, the discovery of an efficient treatment for this pandemic is an urgent concern for researchers around the world. We review the evidence for molnupiravir (MK-4482, EIDD-2801), an antiviral drug originally designed for Alphavirus infections, as a potential preventive and therapeutic agent for the management of COVID-19. At the beginning of this pandemic, molnupiravir was in preclinical development for seasonal influenza. When COVID-19 spread dramatically, the timeline for development was accelerated to focus on the treatment of this pandemic. Real time consultation with regulators took place to expedite this program. We summarize the therapeutic potential of RdRp inhibitors, and highlight molnupiravir as a new small molecule drug for COVID-19 treatment.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/enzymology , Cytidine/analogs & derivatives , Hydroxylamines/therapeutic use , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Animals , Antiviral Agents/pharmacology , Clinical Trials as Topic/methods , Cytidine/pharmacology , Cytidine/therapeutic use , Humans , Hydroxylamines/pharmacology , RNA-Dependent RNA Polymerase/metabolism
6.
J Med Virol ; 93(12): 6798-6802, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1530182

ABSTRACT

Viral infections have been on the rise for the past decades. The impact of the viruses worsened amidst the pandemic burdening the already overwhelmed health care system in African countries. This article sheds light on how the coronavirus together with the already existing viral infections, some of which re-emerged, impacted the continent. The strategies in place such as immunization, education, will have to be strengthened in all African countries to reduce the burden. Furthermore, governments can further collaborate with other countries in creating guidelines to reduce co-infection of the diseases.


Subject(s)
COVID-19/enzymology , COVID-19/virology , Coinfection/epidemiology , Coinfection/virology , Virus Diseases/epidemiology , Africa/epidemiology , COVID-19/immunology , Coinfection/immunology , Humans , Pandemics/prevention & control , SARS-CoV-2/immunology , Vaccination/methods , Virus Diseases/immunology , Virus Diseases/virology
7.
Immunology ; 164(4): 722-736, 2021 12.
Article in English | MEDLINE | ID: covidwho-1494730

ABSTRACT

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/metabolism , B-Lymphocytes/enzymology , Immune System/enzymology , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/enzymology , Autoimmune Diseases/immunology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/immunology , Humans , Immune System/drug effects , Immune System/immunology , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/enzymology , Lymphoproliferative Disorders/immunology , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Receptors, Antigen, B-Cell/metabolism , Receptors, Chemokine/metabolism , Signal Transduction , Toll-Like Receptors/metabolism
8.
Dis Markers ; 2021: 3440714, 2021.
Article in English | MEDLINE | ID: covidwho-1484098

ABSTRACT

Background: It has been observed that COVID-19 may cause myocardial damage, but there are few detailed reports on myocardial enzyme abnormalities. Methods: In this retrospective study, we analyzed data from 157 consecutive laboratory-confirmed and hospitalized COVID-19 patients from Wuhan. We collected information on demographic and clinical characteristics, laboratory findings, and clinical outcomes. Logistic regression analysis was used to explore the risk factors associated with the severity of COVID-19. The association between myocardial enzyme abnormalities and the mortality was also investigated. Results: The mortality in abnormal myocardial enzyme group was obviously higher than the normal group (P < 0.001). The majority of patients (n = 72, 97.3%) with normal cardiac enzyme group were of the common novel coronavirus pneumonia (NCP) type, whereas half of the patients with cardiac enzyme abnormalities (n = 40, 48.2%) developed critical and severe NCP type. The multivariable logistic regression analysis indicated that COVID-19 patients with increasing age (P = 0.035), higher levels of CRP (P = 0.038), and TNI (P = 0.036) were associated with increased death than other patients. Conclusions: Myocardial enzyme abnormality and myocardial injury were associated with the severity and fatal outcomes of COVID-19. Clinicians should pay attention to the markers of myocardial injury in COVID-19 patients, especially those with older age, comorbidities, and inflammation.


Subject(s)
COVID-19/enzymology , COVID-19/mortality , Enzymes/blood , Myocardium/enzymology , Adult , Alanine Transaminase/blood , COVID-19/blood , Creatine Kinase, MB Form/blood , Female , Humans , L-Lactate Dehydrogenase/blood , Logistic Models , Male , Middle Aged , Retrospective Studies , Troponin I/blood
9.
Int J Mol Sci ; 22(21)2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1480801

ABSTRACT

Despite the protracted battle against coronavirus acute respiratory infection (COVID-19) and the rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), no specific and effective drugs have to date been reported. Angiotensin-converting enzyme 2 (ACE2) is a zinc metalloproteinase and a critical modulator of the renin-angiotensin system (RAS). In addition, ACE2 has anti-inflammatory and antifibrosis functions. ACE has become widely known in the past decade as it has been identified as the primary receptor for SARS-CoV and SARS-CoV-2, being closely associated with their infection. SARS-CoV-2 primarily targets the lung, which induces a cytokine storm by infecting alveolar cells, resulting in tissue damage and eventually severe acute respiratory syndrome. In the lung, innate immunity acts as a critical line of defense against pathogens, including SARS-CoV-2. This review aims to summarize the regulation of ACE2, and lung host cells resist SARS-CoV-2 invasion by activating innate immunity response. Finally, we discuss ACE2 as a therapeutic target, providing reference and enlightenment for the clinical treatment of COVID-19.


Subject(s)
Acute Lung Injury/enzymology , Acute Lung Injury/immunology , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Immunity, Innate , SARS-CoV-2/immunology , Acute Lung Injury/virology , COVID-19/complications , COVID-19/enzymology , COVID-19/virology , Humans
11.
EBioMedicine ; 72: 103629, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1469839

ABSTRACT

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) poses an unprecedented challenge to humanity. SARS-CoV-2 infections range from asymptomatic to severe courses of COVID-19 with acute respiratory distress syndrome (ARDS), multiorgan involvement and death. Risk factors for disease severity include older age, male sex, increased BMI and pre-existing comorbidities. Ethnicity is also relevant to COVID-19 susceptibility and severity. Host genetic predisposition to COVID-19 is now increasingly recognized and whole genome and candidate gene association studies regarding COVID-19 susceptibility have been performed. Several common and rare variants in genes related to inflammation or immune responses have been identified. We summarize research on COVID-19 host genetics and compile genetic variants associated with susceptibility to COVID-19 and disease severity. We discuss candidate genes that should be investigated further to understand such associations and provide insights relevant to pathogenesis, risk classification, therapy response, precision medicine, and drug repurposing.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease , Immunity , COVID-19/enzymology , COVID-19/immunology , COVID-19/metabolism , Humans , Severity of Illness Index
12.
Front Immunol ; 12: 718136, 2021.
Article in English | MEDLINE | ID: covidwho-1468341

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is a receptor for the spike protein of SARS-COV-2 that allows viral binding and entry and is expressed on the surface of several pulmonary and non-pulmonary cell types, with induction of a "cytokine storm" upon binding. Other cell types present the receptor and can be infected, including cardiac, renal, intestinal, and endothelial cells. High ACE2 levels protect from inflammation. Despite the relevance of ACE2 levels in COVID-19 pathogenesis, experimental studies to comprehensively address the question of ACE2 regulations are still limited. A relevant observation from the clinic is that, besides the pro-inflammatory cytokines, such as IL-6 and IL-1ß, the anti-inflammatory cytokine IL-10 is also elevated in worse prognosis patients. This could represent somehow a "danger signal", an alarmin from the host organism, given the immuno-regulatory properties of the cytokine. Here, we investigated whether IL-10 could increase ACE2 expression in the lung-derived Calu-3 cell line. We provided preliminary evidence of ACE2 mRNA increase in cells of lung origin in vitro, following IL-10 treatment. Endothelial cell infection by SARS-COV-2 is associated with vasculitis, thromboembolism, and disseminated intravascular coagulation. We confirmed ACE2 expression enhancement by IL-10 treatment also on endothelial cells. The sartans (olmesartan and losartan) showed non-statistically significant ACE2 modulation in Calu-3 and endothelial cells, as compared to untreated control cells. We observed that the antidiabetic biguanide metformin, a putative anti-inflammatory agent, also upregulates ACE2 expression in Calu-3 and endothelial cells. We hypothesized that IL-10 could be a danger signal, and its elevation could possibly represent a feedback mechanism fighting inflammation. Although further confirmatory studies are required, inducing IL-10 upregulation could be clinically relevant in COVID-19-associated acute respiratory distress syndrome (ARDS) and vasculitis, by reinforcing ACE2 levels.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Anti-Inflammatory Agents/pharmacology , COVID-19/enzymology , Human Umbilical Vein Endothelial Cells/drug effects , Interleukin-10/pharmacology , Lung/drug effects , RNA, Messenger/metabolism , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , COVID-19/immunology , Cell Line , Host-Pathogen Interactions , Human Umbilical Vein Endothelial Cells/enzymology , Human Umbilical Vein Endothelial Cells/immunology , Humans , Lung/enzymology , Lung/immunology , Metformin/pharmacology , RNA, Messenger/genetics , SARS-CoV-2/immunology , Up-Regulation
13.
Respir Res ; 22(1): 200, 2021 Jul 07.
Article in English | MEDLINE | ID: covidwho-1450712

ABSTRACT

BACKGROUND: The first step in SARS-CoV-2 infection is binding of the virus to angiotensin converting enzyme 2 (ACE2) on the airway epithelium. Asthma affects over 300 million people world-wide, many of whom may encounter SARS-CoV-2. Epidemiologic data suggests that asthmatics who get infected may be at increased risk of more severe disease. Our objective was to assess whether maintenance inhaled corticosteroids (ICS), a major treatment for asthma, is associated with airway ACE2 expression in asthmatics. METHODS: Large airway epithelium (LAE) of asthmatics treated with maintenance ICS (ICS+), asthmatics not treated with ICS (ICS-), and healthy controls (controls) was analyzed for expression of ACE2 and other coronavirus infection-related genes using microarrays. RESULTS: As a group, there was no difference in LAE ACE2 expression in all asthmatics vs controls. In contrast, subgroup analysis demonstrated that LAE ACE2 expression was higher in asthmatics ICS+ compared to ICS‾ and ACE2 expression was higher in male ICS+ compared to female ICS+ and ICS‾ of either sex. ACE2 expression did not correlate with serum IgE, absolute eosinophil level, or change in FEV1 in response to bronchodilators in either ICS- or ICS+. CONCLUSION: Airway ACE2 expression is increased in asthmatics on long-term treatment with ICS, an observation that should be taken into consideration when assessing the use of inhaled corticosteroids during the pandemic.


Subject(s)
Adrenal Cortex Hormones/administration & dosage , Angiotensin-Converting Enzyme 2/metabolism , Asthma/drug therapy , Receptors, Virus/metabolism , Respiratory Mucosa/drug effects , Administration, Inhalation , Adrenal Cortex Hormones/adverse effects , Adult , Angiotensin-Converting Enzyme 2/genetics , Asthma/diagnosis , Asthma/enzymology , Asthma/genetics , COVID-19/enzymology , COVID-19/virology , Case-Control Studies , Female , Host-Pathogen Interactions , Humans , Male , Middle Aged , Receptors, Virus/genetics , Respiratory Mucosa/enzymology , SARS-CoV-2/pathogenicity , Time Factors , Up-Regulation , Virus Internalization , Young Adult
14.
Microvasc Res ; 138: 104232, 2021 11.
Article in English | MEDLINE | ID: covidwho-1446976

ABSTRACT

The mechanisms by which the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) induces neurological complications remain to be elucidated. We aimed to identify possible effects of hypoxia on the expression of SARS-CoV-2 cell entry mediators, angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease serine 2 (TMPRSS2) protein, in human brain endothelial cells, in vitro. hCMEC/D3 cells were exposed to different oxygen tensions: 20% (Control group), 8% or 2% O2 (Hypoxia groups). Cells were harvested 6-, 24- and 48 h following hypoxic challenge for assessment of mRNA and protein, using qPCR and Western Blot. The response of the brain endothelial cells to hypoxia was replicated using modular incubator chambers. We observed an acute increase (6 h, p < 0.05), followed by a longer-term decrease (48 h, p < 0.05) in ACE2 mRNA and protein expression, accompanied by reduced expression of TMPRSS2 protein levels (48 h, p < 0.05) under the more severe hypoxic condition (2% O2). No changes in levels of von Willebrand Factor (vWF - an endothelial cell damage marker) or interleukin 6 (IL-6 - a pro-inflammatory cytokine) mRNA were observed. We conclude that hypoxia regulates brain endothelial cell ACE2 and TMPRSS2 expression in vitro, which may indicate human brain endothelial susceptibility to SARS-CoV-2 infection and subsequent brain sequelae.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Brain/blood supply , COVID-19/virology , Endothelial Cells/virology , SARS-CoV-2/pathogenicity , Serine Endopeptidases/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2/genetics , COVID-19/enzymology , Cell Hypoxia , Cell Line , Endothelial Cells/enzymology , Gene Expression Regulation , Host-Pathogen Interactions , Humans , Serine Endopeptidases/genetics
15.
Science ; 374(6567): eabj3624, 2021 10 29.
Article in English | MEDLINE | ID: covidwho-1440797
16.
Am J Pathol ; 191(9): 1511-1519, 2021 09.
Article in English | MEDLINE | ID: covidwho-1432756

ABSTRACT

Chemosensory changes are well-reported symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The virus targets cells for entry by binding of its spike protein to cell-surface angiotensin-converting enzyme 2 (ACE2). It is not known whether ACE2 is expressed on taste receptor cells (TRCs), or whether TRCs are infected directly. in situ hybridization probe and an antibody specific to ACE2 indicated presence of ACE2 on a subpopulation of TRCs (namely, type II cells in taste buds in taste papillae). Fungiform papillae of a SARS-CoV-2+ patient exhibiting symptoms of coronavirus disease 2019 (COVID-19), including taste changes, were biopsied. Presence of replicating SARS-CoV-2 in type II cells was verified by in situ hybridization. Therefore, taste type II cells provide a potential portal for viral entry that predicts vulnerabilities to SARS-CoV-2 in the oral cavity. The continuity and cell turnover of a patient's fungiform papillae taste stem cell layer were disrupted during infection and had not completely recovered 6 weeks after symptom onset. Another patient experiencing post-COVID-19 taste disturbances also had disrupted stem cells. These results demonstrate the possibility that novel and sudden taste changes, frequently reported in COVID-19, may be the result of direct infection of taste papillae by SARS-CoV-2. This may result in impaired taste receptor stem cell activity and suggest that further work is needed to understand the acute and postacute dynamics of viral kinetics in the human taste bud.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19 , Gene Expression Regulation, Enzymologic , SARS-CoV-2/metabolism , Stem Cells , Taste Buds , COVID-19/enzymology , COVID-19/pathology , COVID-19/virology , Female , Humans , Male , Stem Cells/enzymology , Stem Cells/pathology , Stem Cells/virology , Taste Buds/enzymology , Taste Buds/pathology , Taste Buds/virology
17.
Immunology ; 164(4): 722-736, 2021 12.
Article in English | MEDLINE | ID: covidwho-1429802

ABSTRACT

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/metabolism , B-Lymphocytes/enzymology , Immune System/enzymology , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/enzymology , Autoimmune Diseases/immunology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/immunology , Humans , Immune System/drug effects , Immune System/immunology , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/enzymology , Lymphoproliferative Disorders/immunology , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Receptors, Antigen, B-Cell/metabolism , Receptors, Chemokine/metabolism , Signal Transduction , Toll-Like Receptors/metabolism
18.
Physiol Rep ; 9(17): e15014, 2021 09.
Article in English | MEDLINE | ID: covidwho-1410554

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is threatening people's lives and impacting their health. It is still unclear whether people engaged in physical activity are at an increased risk of SARS-CoV-2 infection and severe forms of COVID-19. In order to provide data to help answer this question, we, therefore, investigated the effects of endurance training on the levels of host proteins involved in SARS-CoV-2 infection in mice. Eight-week-old C57BL/6J mice were subjected to treadmill running (17-25 m/min, 60-90 min, 5 sessions/week, 8 weeks). After the intervention, the levels of angiotensin-converting enzyme 2 (ACE2; host receptor for SARS-CoV-2), transmembrane protease serine 2 (TMPRSS2; host protease priming fusion of SARS-CoV-2 to host cell membranes), FURIN (host protease that promotes binding of SARS-CoV-2 to host receptors), and Neuropilin-1 (host coreceptor for SARS-CoV-2) were measured in 10 organs that SARS-CoV-2 can infect (larynx, trachea, lung, heart, jejunum, ileum, colon, liver, kidney, and testis). Six organs (heart, lung, jejunum, liver, trachea, and ileum) showed changes in the levels of at least one of the proteins. Endurance training increased ACE2 levels in heart (+66.4%), lung (+37.1%), jejunum (+24.7%) and liver (+27.4%), and FURIN in liver (+17.9%) tissue. In contrast, endurance training decreased Neuropilin-1 levels in liver (-39.7%), trachea (-41.2%), and ileum (-39.7%), and TMPRSS2 in lung (-11.3%). Taken together, endurance training altered the levels of host proteins involved in SARS-CoV-2 cell entry in an organ-dependent manner.


Subject(s)
COVID-19/virology , Physical Conditioning, Animal , Physical Endurance , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , Virus Internalization , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/enzymology , Furin/metabolism , Host-Pathogen Interactions , Male , Mice, Inbred C57BL , Neuropilin-1/metabolism , Running , Serine Endopeptidases/metabolism
19.
Int J Mol Sci ; 22(18)2021 Sep 11.
Article in English | MEDLINE | ID: covidwho-1409703

ABSTRACT

Recently, inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) have been proposed as potential therapeutic agents for COVID-19. Studying effects of amino acid mutations in the conformation of drug targets is necessary for anticipating drug resistance. In this study, with the structure of the SARS-CoV-2 Mpro complexed with a non-covalent inhibitor, we performed molecular dynamics (MD) simulations to determine the conformation of the complex when single amino acid residue in the active site is mutated. As a model of amino acid mutation, we constructed mutant proteins with one residue in the active site mutated to alanine. This method is called virtual alanine scan. The results of the MD simulations showed that the conformation and configuration of the ligand was changed for mutants H163A and E166A, although the structure of the whole protein and of the catalytic dyad did not change significantly, suggesting that mutations in His163 and Glu166 may be linked to drug resistance.


Subject(s)
COVID-19 , Coronavirus 3C Proteases , Molecular Dynamics Simulation , Mutation, Missense , SARS-CoV-2 , Alanine , Amino Acid Substitution , COVID-19/enzymology , COVID-19/genetics , Catalytic Domain/genetics , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Humans , SARS-CoV-2/enzymology , SARS-CoV-2/genetics
20.
Int J Mol Sci ; 22(11)2021 May 29.
Article in English | MEDLINE | ID: covidwho-1389398

ABSTRACT

Trypsin-like proteases (TLPs) belong to a family of serine enzymes with primary substrate specificities for the basic residues, lysine and arginine, in the P1 position. Whilst initially perceived as soluble enzymes that are extracellularly secreted, a number of novel TLPs that are anchored in the cell membrane have since been discovered. Muco-obstructive lung diseases (MucOLDs) are characterised by the accumulation of hyper-concentrated mucus in the small airways, leading to persistent inflammation, infection and dysregulated protease activity. Although neutrophilic serine proteases, particularly neutrophil elastase, have been implicated in the propagation of inflammation and local tissue destruction, it is likely that the serine TLPs also contribute to various disease-relevant processes given the roles that a number of these enzymes play in the activation of both the epithelial sodium channel (ENaC) and protease-activated receptor 2 (PAR2). More recently, significant attention has focused on the activation of viruses such as SARS-CoV-2 by host TLPs. The purpose of this review was to highlight key TLPs linked to the activation of ENaC and PAR2 and their association with airway dehydration and inflammatory signalling pathways, respectively. The role of TLPs in viral infectivity will also be discussed in the context of the inhibition of TLP activities and the potential of these proteases as therapeutic targets.


Subject(s)
COVID-19/enzymology , Lung Diseases, Obstructive/enzymology , SARS-CoV-2/metabolism , Trypsin/metabolism , Animals , COVID-19/pathology , Epithelial Sodium Channels/metabolism , Humans , Lung Diseases, Obstructive/pathology , Receptor, PAR-2/metabolism
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