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1.
J Pathol ; 256(3): 256-261, 2022 03.
Article in English | MEDLINE | ID: covidwho-1549277

ABSTRACT

COVID-19 is a pandemic with high morbidity and mortality. In an autopsy cohort of COVID-19 patients, we found extensive accumulation of the tryptophan degradation products 3-hydroxy-anthranilic acid and quinolinic acid in the lungs, heart, and brain. This was not related to the expression of the tryptophan-catabolizing indoleamine 2,3-dioxygenase (IDO)-1, but rather to that of its isoform IDO-2, which otherwise is expressed rarely. Bioavailability of tryptophan is an absolute requirement for proper cell functioning and synthesis of hormones, whereas its degradation products can cause cell death. Markers of apoptosis and severe cellular stress were associated with IDO-2 expression in large areas of lung and heart tissue, whereas affected areas in brain were more restricted. Analyses of tissue, cerebrospinal fluid, and sequential plasma samples indicate early initiation of the kynurenine/aryl-hydrocarbon receptor/IDO-2 axis as a positive feedback loop, potentially leading to severe COVID-19 pathology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Subject(s)
Brain/enzymology , COVID-19/enzymology , Indoleamine-Pyrrole 2,3,-Dioxygenase/analysis , Lung/enzymology , Myocardium/enzymology , 3-Hydroxyanthranilic Acid/analysis , Adult , Aged , Apoptosis , Autopsy , Brain/pathology , COVID-19/mortality , COVID-19/pathology , COVID-19/virology , Humans , Kynurenine/analysis , Lung/pathology , Middle Aged , Myocardium/pathology , Prospective Studies , Quinolinic Acid/analysis , Severity of Illness Index , Tryptophan/analysis
2.
J Mol Cell Cardiol ; 164: 13-16, 2022 03.
Article in English | MEDLINE | ID: covidwho-1527886

ABSTRACT

Aged males disproportionately succumb to increased COVID-19 severity, hospitalization, and mortality compared to females. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2) facilitate SARS-CoV-2 viral entry and may have sexually dimorphic regulation. As viral load dictates disease severity, we investigated the expression, protein levels, and activity of ACE2 and TMPRSS2. Our data reveal that aged males have elevated ACE2 in both mice and humans across organs. We report the first comparative study comprehensively investigating the impact of sex and age in murine and human levels of ACE2 and TMPRSS2, to begin to elucidate the sex bias in COVID-19 severity.


Subject(s)
Aging/metabolism , Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/epidemiology , Gene Expression Regulation, Enzymologic , Receptors, Virus/biosynthesis , SARS-CoV-2/physiology , Sex Characteristics , Aging/genetics , Angiotensin-Converting Enzyme 2/genetics , Animals , Disease Susceptibility , Female , Heart/virology , Humans , Intestine, Small/enzymology , Intestine, Small/virology , Kidney/enzymology , Kidney/virology , Lung/enzymology , Lung/virology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Myocardium/enzymology , Organ Specificity , Receptors, Virus/genetics , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/genetics , Young Adult
3.
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
7.
Viruses ; 13(8)2021 08 05.
Article in English | MEDLINE | ID: covidwho-1341730

ABSTRACT

The emergence and ensuing dominance of COVID-19 on the world stage has emphasized the urgency of efficient animal models for the development of therapeutics for and assessment of immune responses to SARS-CoV-2 infection. Shortcomings of current animal models for SARS-CoV-2 include limited lower respiratory disease, divergence from clinical COVID-19 disease, and requirements for host genetic modifications to permit infection. In this study, n = 12 specific-pathogen-free domestic cats were infected intratracheally with SARS-CoV-2 to evaluate clinical disease, histopathologic lesions, and viral infection kinetics at 4 and 8 days post-inoculation; n = 6 sham-inoculated cats served as controls. Intratracheal inoculation of SARS-CoV-2 produced a significant degree of clinical disease (lethargy, fever, dyspnea, and dry cough) consistent with that observed in the early exudative phase of COVID-19. Pulmonary lesions such as diffuse alveolar damage, hyaline membrane formation, fibrin deposition, and proteinaceous exudates were also observed with SARS-CoV-2 infection, replicating lesions identified in people hospitalized with ARDS from COVID-19. A significant correlation was observed between the degree of clinical disease identified in infected cats and pulmonary lesions. Viral loads and ACE2 expression were also quantified in nasal turbinates, distal trachea, lungs, and other organs. Results of this study validate a feline model for SARS-CoV-2 infection that results in clinical disease and histopathologic lesions consistent with acute COVID-19 in humans, thus encouraging its use for future translational studies.


Subject(s)
COVID-19 , Cats , Disease Models, Animal , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/pathology , COVID-19/physiopathology , COVID-19/virology , Female , Genome, Viral , Humans , Lung/enzymology , Lung/pathology , Lung/virology , Lymph Nodes/virology , Male , RNA, Viral/analysis , SARS-CoV-2/genetics , Specific Pathogen-Free Organisms , Trachea/enzymology , Trachea/virology , Turbinates/enzymology , Turbinates/virology
8.
Genes (Basel) ; 12(7)2021 07 09.
Article in English | MEDLINE | ID: covidwho-1302193

ABSTRACT

Chronic inflammatory lung diseases are characterized by uncontrolled immune response in the airways as their main pathophysiological manifestation. The lack of specific diagnostic and therapeutic biomarkers for many pulmonary diseases represents a major challenge for pulmonologists. The majority of the currently approved therapeutic approaches are focused on achieving disease remission, although there is no guarantee of complete recovery. It is known that angiotensin-converting enzyme 2 (ACE2), an important counter-regulatory component of the renin-angiotensin-aldosterone system (RAAS), is expressed in the airways. It has been shown that ACE2 plays a role in systemic regulation of the cardiovascular and renal systems, lungs and liver by acting on blood pressure, electrolyte balance control mechanisms and inflammation. Its protective role in the lungs has also been presented, but the exact pathophysiological mechanism of action is still elusive. The aim of this study is to review and discuss recent findings about ACE2, including its potential role in the pathophysiology of chronic inflammatory lung diseases:, i.e., chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. Additionally, in the light of the coronavirus 2019 disease (COVID-19), we will discuss the role of ACE2 in the pathophysiology of this disease, mainly represented by different grades of pulmonary problems. We believe that these insights will open up new perspectives for the future use of ACE2 as a potential biomarker for early diagnosis and monitoring of chronic inflammatory lung diseases.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Asthma/diagnosis , COVID-19 Testing , COVID-19/enzymology , Hypertension, Pulmonary/diagnosis , Lung/enzymology , Pulmonary Disease, Chronic Obstructive/diagnosis , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Asthma/enzymology , Asthma/genetics , COVID-19/genetics , Humans , Hypertension, Pulmonary/enzymology , Hypertension, Pulmonary/genetics , Inflammation/diagnosis , Inflammation/enzymology , Inflammation/genetics , Lung/pathology , Pulmonary Disease, Chronic Obstructive/enzymology , Pulmonary Disease, Chronic Obstructive/genetics , Renin-Angiotensin System
9.
Anesthesiology ; 134(5): 792-808, 2021 05 01.
Article in English | MEDLINE | ID: covidwho-1202432

ABSTRACT

Acute respiratory distress syndrome is characterized by hypoxemia, altered alveolar-capillary permeability, and neutrophil-dominated inflammatory pulmonary edema. Despite decades of research, an effective drug therapy for acute respiratory distress syndrome remains elusive. The ideal pharmacotherapy for acute respiratory distress syndrome should demonstrate antiprotease activity and target injurious inflammatory pathways while maintaining host defense against infection. Furthermore, a drug with a reputable safety profile, low possibility of off-target effects, and well-known pharmacokinetics would be desirable. The endogenous 52-kd serine protease α1-antitrypsin has the potential to be a novel treatment option for acute respiratory distress syndrome. The main function of α1-antitrypsin is as an antiprotease, targeting neutrophil elastase in particular. However, studies have also highlighted the role of α1-antitrypsin in the modulation of inflammation and bacterial clearance. In light of the current SARS-CoV-2 pandemic, the identification of a treatment for acute respiratory distress syndrome is even more pertinent, and α1-antitrypsin has been implicated in the inflammatory response to SARS-CoV-2 infection.


Subject(s)
Neutrophils/drug effects , Proteinase Inhibitory Proteins, Secretory/administration & dosage , Respiratory Distress Syndrome/drug therapy , alpha 1-Antitrypsin/administration & dosage , Animals , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/immunology , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/immunology , Lung/drug effects , Lung/enzymology , Lung/immunology , Neutrophils/enzymology , Neutrophils/immunology , Proteinase Inhibitory Proteins, Secretory/immunology , Respiratory Distress Syndrome/enzymology , Respiratory Distress Syndrome/immunology , alpha 1-Antitrypsin/immunology
10.
Cardiovasc Toxicol ; 21(6): 498-503, 2021 06.
Article in English | MEDLINE | ID: covidwho-1173998

ABSTRACT

In March 2019 began the global pandemic COVID-19 caused by the new Coronavirus SARS-CoV-2. The first cases of SARS-CoV-2 infection occurred in November-19 in Wuhan, China. The preventive measures taken did not prevent the rapid spread of the virus to all countries around the world. To date, there are about 2.54 million deaths, effective vaccines are in clinical trials. SARS-CoV-2 uses the ACE-2 protein as an intracellular gateway. ACE-2 is a key component of the Renin Angiotensin (RAS) system, a key regulator of cardiovascular function. Considering the key role of ACE-2 in COVID-19 infection, both as an entry receptor and as a protective role, especially for the respiratory tract, and considering the variations of ACE-2 and ACE during the stages of viral infection, it is clear the important role that the pharmacological regulation of RAS and ACE-2 can assume. This biological knowledge suggests different pharmacological approaches to treat COVID-19 by modulating RAS, ACE-2 and the ACE/ACE2 balance that we describe in this article.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Lung/drug effects , Receptors, Virus/metabolism , Renin-Angiotensin System/drug effects , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Antiviral Agents/adverse effects , COVID-19/enzymology , COVID-19/virology , Host-Pathogen Interactions , Humans , Lung/enzymology , Lung/virology , Recombinant Proteins/therapeutic use , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Virus Internalization
11.
Environ Toxicol Pharmacol ; 86: 103656, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1171468

ABSTRACT

Evidence in humans suggests a correlation between nicotine smoking and severe respiratory symptoms with COVID-19 infection. In lung tissue, angiotensin-converting enzyme 2 (ACE2) appears to mechanistically underlie viral entry. Here, we investigated whether e-cigarette vapor inhalation alters ACE2 and nicotinic acetylcholine receptor (nAChR) expression in male and female mice. In male lung, nicotine vapor inhalation induced a significant increase in ACE2 mRNA and protein, but surprisingly, these differences were not found in females. Further, both vehicle and nicotine vapor inhalation downregulated α5 nAChR subunits in both sexes, while differences were not found in α7 nAChR subunit expression. Finally, blood ACE2 levels did not differ with exposure, indicating that blood sampling is not a sufficient indicator of lung ACE2 changes. Together, these data indicate a direct link between e-cigarette vaping and increased ACE2 expression in male lung tissue, which thereby reveals an underlying mechanism of increased vulnerability to coronavirus infection in individuals vaping nicotine.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/epidemiology , Electronic Nicotine Delivery Systems , Lung/enzymology , Vaping/adverse effects , Angiotensin-Converting Enzyme 2/blood , Angiotensin-Converting Enzyme 2/genetics , Animals , DNA, Complementary/biosynthesis , Female , Lung/cytology , Male , Mice , Mice, Inbred C57BL , Nicotine/administration & dosage , Nicotine/pharmacology , Nicotinic Agonists/administration & dosage , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/biosynthesis , Sex Characteristics , alpha7 Nicotinic Acetylcholine Receptor/metabolism
13.
PLoS One ; 16(3): e0248730, 2021.
Article in English | MEDLINE | ID: covidwho-1136301

ABSTRACT

COVID-19 (coronavirus disease 2019) patients exhibiting gastrointestinal symptoms are reported to have worse prognosis. Ace2 (angiotensin-converting enzyme 2), the gene encoding the host protein to which SARS-CoV-2 spike proteins bind, is expressed in the gut and therefore may be a target for preventing or reducing severity of COVID-19. Here we test the hypothesis that Ace2 expression in the gastrointestinal and respiratory tracts is modulated by the microbiome. We used quantitative PCR to profile Ace2 expression in germ-free mice, conventional raised specific pathogen-free mice, and gnotobiotic mice colonized with different microbiota. Intestinal Ace2 expression levels were significantly higher in germ-free mice compared to conventional mice. A similar trend was observed in the respiratory tract. Intriguingly, microbiota depletion via antibiotics partially recapitulated the germ-free phenotype, suggesting potential for microbiome-mediated regulation of Ace2 expression. Variability in intestinal Ace2 expression was observed in gnotobiotic mice colonized with different microbiota, partially attributable to differences in microbiome-encoded proteases and peptidases. Together, these data suggest that the microbiome may be one modifiable factor determining COVID-19 infection risk and disease severity.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Colon/enzymology , Gastrointestinal Microbiome , Intestine, Small/enzymology , Lung/enzymology , Adenomatous Polyposis Coli Protein/deficiency , Adenomatous Polyposis Coli Protein/genetics , Angiotensin-Converting Enzyme 2/genetics , Animals , Female , Gene Expression , Interleukin-10/deficiency , Interleukin-10/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout
14.
Anesthesiology ; 134(5): 792-808, 2021 05 01.
Article in English | MEDLINE | ID: covidwho-1135903

ABSTRACT

Acute respiratory distress syndrome is characterized by hypoxemia, altered alveolar-capillary permeability, and neutrophil-dominated inflammatory pulmonary edema. Despite decades of research, an effective drug therapy for acute respiratory distress syndrome remains elusive. The ideal pharmacotherapy for acute respiratory distress syndrome should demonstrate antiprotease activity and target injurious inflammatory pathways while maintaining host defense against infection. Furthermore, a drug with a reputable safety profile, low possibility of off-target effects, and well-known pharmacokinetics would be desirable. The endogenous 52-kd serine protease α1-antitrypsin has the potential to be a novel treatment option for acute respiratory distress syndrome. The main function of α1-antitrypsin is as an antiprotease, targeting neutrophil elastase in particular. However, studies have also highlighted the role of α1-antitrypsin in the modulation of inflammation and bacterial clearance. In light of the current SARS-CoV-2 pandemic, the identification of a treatment for acute respiratory distress syndrome is even more pertinent, and α1-antitrypsin has been implicated in the inflammatory response to SARS-CoV-2 infection.


Subject(s)
Neutrophils/drug effects , Proteinase Inhibitory Proteins, Secretory/administration & dosage , Respiratory Distress Syndrome/drug therapy , alpha 1-Antitrypsin/administration & dosage , Animals , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/immunology , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/immunology , Lung/drug effects , Lung/enzymology , Lung/immunology , Neutrophils/enzymology , Neutrophils/immunology , Proteinase Inhibitory Proteins, Secretory/immunology , Respiratory Distress Syndrome/enzymology , Respiratory Distress Syndrome/immunology , alpha 1-Antitrypsin/immunology
15.
Biomolecules ; 11(3)2021 03 06.
Article in English | MEDLINE | ID: covidwho-1134010

ABSTRACT

Many individuals infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) develop no or only mild symptoms, but some can go on onto develop a spectrum of pathologies including pneumonia, acute respiratory distress syndrome, respiratory failure, systemic inflammation, and multiorgan failure. Many pathogens, viral and non-viral, can elicit these pathologies, which justifies reconsidering whether the target of therapeutic approaches to fight pathogen infections should be (a) the pathogen itself, (b) the pathologies elicited by the pathogen interaction with the human host, or (c) a combination of both. While little is known about the immunopathology of SARS-CoV-2, it is well-established that the above-mentioned pathologies are associated with hyper-inflammation, tissue damage, and the perturbation of target organ metabolism. Mounting evidence has shown that these processes are regulated by endoproteinases (particularly, matrix metalloproteinases (MMPs)). Here, we review what is known about the roles played by MMPs in the development of COVID-19 and postulate a mechanism by which MMPs could influence energy metabolism in target organs, such as the lung. Finally, we discuss the suitability of MMPs as therapeutic targets to increase the metabolic tolerance of the host to damage inflicted by the pathogen infection, with a focus on SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Lung/physiopathology , Matrix Metalloproteinases/metabolism , Protein Kinases/metabolism , Respiratory Distress Syndrome/metabolism , COVID-19/enzymology , COVID-19/physiopathology , COVID-19/virology , Comorbidity , Cytokines/metabolism , Humans , Inflammation/drug therapy , Inflammation/enzymology , Inflammation/metabolism , Inflammation/pathology , Lung/enzymology , Lung/metabolism , Lung/virology , Matrix Metalloproteinase Inhibitors/pharmacology , Respiratory Distress Syndrome/enzymology , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , Signal Transduction/genetics
16.
Biochem Biophys Res Commun ; 538: 92-96, 2021 01 29.
Article in English | MEDLINE | ID: covidwho-1125278

ABSTRACT

Obesity is a major risk factor for SARS-CoV-2 infection and COVID-19 severity. The underlying basis of this association is likely complex in nature. The host-cell receptor angiotensin converting enzyme 2 (ACE2) and the type II transmembrane serine protease (TMPRSS2) are important for viral cell entry. It is unclear whether obesity alters expression of Ace2 and Tmprss2 in the lower respiratory tract. Here, we show that: 1) Ace2 expression is elevated in the lung and trachea of diet-induced obese male mice and reduced in the esophagus of obese female mice relative to lean controls; 2) Tmprss2 expression is increased in the trachea of obese male mice but reduced in the lung and elevated in the trachea of obese female mice relative to lean controls; 3) in chow-fed lean mice, females have higher expression of Ace2 in the lung and esophagus as well as higher Tmprss2 expression in the lung but lower expression in the trachea compared to males; and 4) in diet-induced obese mice, males have higher expression of Ace2 in the trachea and higher expression of Tmprss2 in the lung compared to females, whereas females have higher expression of Tmprss2 in the trachea relative to males. Our data indicate diet- and sex-dependent modulation of Ace2 and Tmprss2 expression in the lower respiratory tract and esophagus. Given the high prevalence of obesity worldwide and a sex-biased mortality rate, we discuss the implications and relevance of our results for COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/enzymology , Esophagus/enzymology , Lung/enzymology , Obesity/enzymology , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Trachea/enzymology , Virus Internalization , Animals , COVID-19/virology , Diet , Esophagus/virology , Female , Lung/virology , Male , Mice , Obesity/virology , Sex Factors , Trachea/virology
18.
Curr Drug Discov Technol ; 18(6): e130921189567, 2021.
Article in English | MEDLINE | ID: covidwho-999946

ABSTRACT

A novel coronavirus termed nCoV-2019 that caused an epidemic of acute respiratory syndrome in humans was first detected in Wuhan, China, in December 2019. nCoV-2019 resulted in thousands of cases of lethal disease all around the world. Unfortunately, there is no specific treatment yet, so a better understanding of the pathobiology of the disease can be helpful. The renin-angiotensin system and its products have several important physiological actions. On the other hand, this system is involved in the pathogenesis of various diseases. In this context, this review article will briefly discuss insights for understanding the role of the angiotensin-converting enzyme 2 (ACE2) receptor as a potentially attractive target for the nCoV-2019-induced acute respiratory syndrome.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Lung/drug effects , Receptors, Virus/antagonists & inhibitors , Renin-Angiotensin System/drug effects , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/adverse effects , COVID-19/enzymology , COVID-19/virology , Host-Pathogen Interactions , Humans , Lung/enzymology , Lung/virology , Molecular Targeted Therapy , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity
19.
Eur J Clin Microbiol Infect Dis ; 40(2): 451-455, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-947035

ABSTRACT

The ACE2 receptor is, so far, the best-known host factor for SARS-CoV-2 entry, but another essential element, the TMPRSS2 protease, has recently been identified. Here, we have analysed TMPRSS2 expression data in the lung correlating them with age, sex, diabetes, smoking habits, exposure to pollutant and other stimuli, in order to highlight which factors might alter TMPRSS2 expression, and thus impact the susceptibility to infection and COVID-19 prognosis. Moreover, we reported TMPRSS2 polymorphisms affecting its expression and suggested the ethnic groups more prone to COVID-19. Finally, we also highlighted a gender-specific co-expression between TMPRSS2 and other genes related to SARS-CoV-2 entry, maybe explaining the higher observed susceptibility of infection in men. Our results could be useful in designing potential prevention and treatment strategies regarding the COVID-19.


Subject(s)
COVID-19/etiology , SARS-CoV-2 , Serine Endopeptidases/genetics , Aged , Female , Humans , Lung/enzymology , Male , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Serine Endopeptidases/physiology , Virus Internalization
20.
Am J Respir Cell Mol Biol ; 63(5): 571-590, 2020 11.
Article in English | MEDLINE | ID: covidwho-901528

ABSTRACT

PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)-associated ALI.


Subject(s)
Acute Lung Injury/drug therapy , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Lung/drug effects , Pneumonia, Viral/drug therapy , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Acute Lung Injury/enzymology , Acute Lung Injury/virology , Animals , Antiviral Agents/adverse effects , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Lung/enzymology , Lung/virology , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , SARS-CoV-2 , Signal Transduction/drug effects
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