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3.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Article in English | MEDLINE | ID: covidwho-1758461

ABSTRACT

Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are ineffective when administered late after the onset of symptoms. Pneumonia is caused by an exaggerated inflammatory cytokine response to infection, but tissue necrosis and damage caused by virus also contribute to lung pathology. We hypothesized that viral pneumonia can be treated effectively if both virus and inflammation are simultaneously targeted. Combined treatment with the antiviral drug cidofovir and etanercept, which targets tumor necrosis factor (TNF), down-regulated nuclear factor kappa B-signaling and effectively reduced morbidity and mortality during respiratory ectromelia virus (ECTV) infection in mice even when treatment was initiated after onset of clinical signs. Treatment with cidofovir alone reduced viral load, but animals died from severe lung pathology. Treatment with etanercept had no effect on viral load but diminished levels of inflammatory cytokines and chemokines including TNF, IL-6, IL-1ß, IL-12p40, TGF-ß, and CCL5 and dampened activation of the STAT3 cytokine-signaling pathway, which transduces signals from multiple cytokines implicated in lung pathology. Consequently, combined treatment with a STAT3 inhibitor and cidofovir was effective in improving clinical disease and lung pathology in ECTV-infected mice. Thus, the simultaneous targeting of virus and a specific inflammatory cytokine or cytokine-signaling pathway is effective in the treatment of pneumonia. This approach might be applicable to pneumonia caused by emerging and re-emerging viruses, like seasonal and pandemic influenza A virus strains and severe acute respiratory syndrome coronavirus 2.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Antiviral Agents/therapeutic use , Cidofovir/therapeutic use , Etanercept/administration & dosage , Pneumonia, Viral/drug therapy , Animals , Antiviral Agents/pharmacology , Cell Line , Chlorocebus aethiops , Cidofovir/pharmacology , Cytokines/metabolism , Drug Evaluation, Preclinical , Drug Therapy, Combination , Ectromelia virus/drug effects , Female , Lung/drug effects , Lung/metabolism , Mice, Inbred C57BL , NF-kappa B/metabolism , Pneumonia, Viral/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Viral Load/drug effects
5.
Brain Behav Immun ; 87: 115-119, 2020 07.
Article in English | MEDLINE | ID: covidwho-1719345

ABSTRACT

OBJECTIVE: Acute stroke remains a medical emergency even during the COVID-19 pandemic. Most patients with COVID-19 infection present with constitutional and respiratory symptoms; while others present with atypical gastrointestinal, cardiovascular, or neurological manifestations. Here we present a series of four patients with COVID-19 that presented with acute stroke. METHODS: We searched the hospital databases for patients that presented with acute stroke and concomitant features of suspected COVID-19 infection. All patients who had radiographic evidence of stroke and PCR-confirmed COVID-19 infection were included in the study. Patients admitted to the hospital with PCR- confirmed COVID-19 disease whose hospital course was complicated with acute stroke while inpatient were excluded from the study. Retrospective patient data were obtained from electronic medical records. Informed consent was obtained. RESULTS: We identified four patients who presented with radiographic confirmation of acute stroke and PCR-confirmed SARS-CoV-2 infection. We elucidate the clinical characteristics, imaging findings, and the clinical course. CONCLUSIONS: Timely assessment and hyperacute treatment is the key to minimize mortality and morbidity of patients with acute stroke. Stroke teams should be wary of the fact that COVID-19 patients can present with cerebrovascular accidents and should dawn appropriate personal protective equipment in every suspected patient. Further studies are urgently needed to improve current understandings of neurological pathology in the setting of COVID-19 infection.


Subject(s)
Coronavirus Infections/complications , Pneumonia, Viral/complications , Stroke/metabolism , Aged , Aged, 80 and over , Betacoronavirus , COVID-19 , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/metabolism , Female , Hospitalization , Humans , Male , Pandemics , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/metabolism , Retrospective Studies , SARS-CoV-2 , Stroke/complications
6.
Protein J ; 39(3): 198-216, 2020 06.
Article in English | MEDLINE | ID: covidwho-1718840

ABSTRACT

The devastating effects of the recent global pandemic (termed COVID-19 for "coronavirus disease 2019") caused by the severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) are paramount with new cases and deaths growing at an exponential rate. In order to provide a better understanding of SARS CoV-2, this article will review the proteins found in the SARS CoV-2 that caused this global pandemic.


Subject(s)
Betacoronavirus/chemistry , Betacoronavirus/physiology , Coronavirus Infections/virology , Pneumonia, Viral/virology , Viral Proteins/chemistry , Viral Proteins/metabolism , Amino Acid Sequence , Betacoronavirus/genetics , COVID-19 , Coronavirus Envelope Proteins , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Nucleocapsid Proteins , Drug Discovery/methods , Genome, Viral , Host-Pathogen Interactions/drug effects , Humans , Nucleocapsid Proteins/chemistry , Nucleocapsid Proteins/genetics , Nucleocapsid Proteins/metabolism , Pandemics , Phosphoproteins , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Polyproteins , Protein Interaction Maps/drug effects , SARS-CoV-2 , Sequence Alignment , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Viral Envelope Proteins/chemistry , Viral Envelope Proteins/genetics , Viral Envelope Proteins/metabolism , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/genetics , Viral Matrix Proteins/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Viral Proteins/genetics , Viral Regulatory and Accessory Proteins/chemistry , Viral Regulatory and Accessory Proteins/genetics , Viral Regulatory and Accessory Proteins/metabolism , Viroporin Proteins
7.
Am J Epidemiol ; 190(10): 2094-2106, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1447568

ABSTRACT

Longitudinal trajectories of vital signs and biomarkers during hospital admission of patients with COVID-19 remain poorly characterized despite their potential to provide critical insights about disease progression. We studied 1884 patients with severe acute respiratory syndrome coronavirus 2 infection from April 3, 2020, to June 25, 2020, within 1 Maryland hospital system and used a retrospective longitudinal framework with linear mixed-effects models to investigate relevant biomarker trajectories leading up to 3 critical outcomes: mechanical ventilation, discharge, and death. Trajectories of 4 vital signs (respiratory rate, ratio of oxygen saturation (Spo2) to fraction of inspired oxygen (Fio2), pulse, and temperature) and 4 laboratory values (C-reactive protein (CRP), absolute lymphocyte count (ALC), estimated glomerular filtration rate, and D-dimer) clearly distinguished the trajectories of patients with COVID-19. Before any ventilation, log(CRP), log(ALC), respiratory rate, and Spo2-to-Fio2 ratio trajectories diverge approximately 8-10 days before discharge or death. After ventilation, log(CRP), log(ALC), respiratory rate, Spo2-to-Fio2 ratio, and estimated glomerular filtration rate trajectories again diverge 10-20 days before death or discharge. Trajectories improved until discharge and remained unchanged or worsened until death. Our approach characterizes the distribution of biomarker trajectories leading up to competing outcomes of discharge versus death. Moving forward, this model can contribute to quantifying the joint probability of biomarkers and outcomes when provided clinical data up to a given moment.


Subject(s)
Biomarkers/metabolism , COVID-19/metabolism , Outcome Assessment, Health Care , Pneumonia, Viral/metabolism , COVID-19/diagnosis , COVID-19/epidemiology , Case-Control Studies , Disease Progression , Female , Humans , Longitudinal Studies , Male , Maryland/epidemiology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Predictive Value of Tests , Retrospective Studies , SARS-CoV-2 , Vital Signs
8.
Cells ; 10(5)2021 04 21.
Article in English | MEDLINE | ID: covidwho-1436054

ABSTRACT

Extracellular vesicles (EVs) refer to a heterogenous population of membrane-bound vesicles that are released by cells under physiological and pathological conditions. The detection of EVs in the majority of the bodily fluids, coupled with their diverse cargo comprising of DNA, RNA, lipids, and proteins, have led to the accumulated interests in leveraging these nanoparticles for diagnostic and therapeutic purposes. In particular, emerging studies have identified enhanced levels of a wide range of specific subclasses of non-coding RNAs (ncRNAs) in EVs, thereby suggesting the existence of highly selective and regulated molecular processes governing the sorting of these RNAs into EVs. Recent studies have also illustrated the functional relevance of these enriched ncRNAs in a variety of human diseases. This review summarizes the current state of knowledge on EV-ncRNAs, as well as their functions and significance in lung infection and injury. As a majority of the studies on EV-ncRNAs in lung diseases have focused on EV-microRNAs, we will particularly highlight the relevance of these molecules in the pathophysiology of these conditions, as well as their potential as novel biomarkers therein. We also outline the current challenges in the EV field amidst the tremendous efforts to propel the clinical utility of EVs for human diseases. The lack of published literature on the functional roles of other EV-ncRNA subtypes may in turn provide new avenues for future research to exploit their feasibility as novel diagnostic and therapeutic targets in human diseases.


Subject(s)
Extracellular Vesicles/physiology , Lung Injury/metabolism , Pneumonia, Bacterial/metabolism , Pneumonia, Viral/metabolism , RNA, Untranslated/physiology , Animals , Biomarkers/metabolism , Humans , Lung/metabolism , Lung/pathology
9.
Cell Rep ; 37(1): 109798, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1415262

ABSTRACT

Despite the worldwide effect of the coronavirus disease 2019 (COVID-19) pandemic, the underlying mechanisms of fatal viral pneumonia remain elusive. Here, we show that critical COVID-19 is associated with enhanced eosinophil-mediated inflammation when compared to non-critical cases. In addition, we confirm increased T helper (Th)2-biased adaptive immune responses, accompanying overt complement activation, in the critical group. Moreover, enhanced antibody responses and complement activation are associated with disease pathogenesis as evidenced by formation of immune complexes and membrane attack complexes in airways and vasculature of lung biopsies from six fatal cases, as well as by enhanced hallmark gene set signatures of Fcγ receptor (FcγR) signaling and complement activation in myeloid cells of respiratory specimens from critical COVID-19 patients. These results suggest that SARS-CoV-2 infection may drive specific innate immune responses, including eosinophil-mediated inflammation, and subsequent pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial drivers of critical disease in COVID-19 patients.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Complement System Proteins/immunology , Eosinophils/immunology , Inflammation/immunology , Pneumonia, Viral/immunology , SARS-CoV-2/immunology , Adaptive Immunity , Adult , Aged , Aged, 80 and over , Antigen-Antibody Complex/metabolism , COVID-19/metabolism , COVID-19/virology , Complement Activation , Complement Membrane Attack Complex/metabolism , Eosinophils/virology , Female , Humans , Inflammation/metabolism , Inflammation/virology , Lung Injury/immunology , Lung Injury/pathology , Lung Injury/virology , Male , Middle Aged , Pneumonia, Viral/metabolism , Receptors, IgG/immunology , Receptors, IgG/metabolism , Severity of Illness Index , Signal Transduction , Th2 Cells/immunology , Viral Load , Young Adult
10.
Viruses ; 12(10)2020 10 16.
Article in English | MEDLINE | ID: covidwho-1389518

ABSTRACT

To address the expression pattern of the SARS-CoV-2 receptor ACE2 and the viral priming protease TMPRSS2 in the respiratory tract, this study investigated RNA sequencing transcriptome profiling of samples of airway and oral mucosa. As shown, ACE2 has medium levels of expression in both small airway epithelium and masticatory mucosa, and high levels of expression in nasal epithelium. The expression of ACE2 is low in mucosal-associated invariant T (MAIT) cells and cannot be detected in alveolar macrophages. TMPRSS2 is highly expressed in small airway epithelium and nasal epithelium and has lower expression in masticatory mucosa. Our results provide the molecular basis that the nasal mucosa is the most susceptible locus in the respiratory tract for SARS-CoV-2 infection and consequently for subsequent droplet transmission and should be the focus for protection against SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/genetics , Peptidyl-Dipeptidase A/biosynthesis , Pneumonia, Viral/genetics , Serine Endopeptidases/biosynthesis , Virus Internalization , Angiotensin-Converting Enzyme 2 , COVID-19 , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Epithelium/metabolism , Epithelium/virology , Gene Expression , Gene Expression Profiling , Humans , Nasal Mucosa/metabolism , Nasal Mucosa/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Respiratory System/metabolism , Respiratory System/virology , SARS-CoV-2 , Serine Endopeptidases/genetics
11.
Molecules ; 25(12)2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-1389454

ABSTRACT

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Data Mining/methods , HIV Infections/epidemiology , HIV Infections/metabolism , Host-Pathogen Interactions/immunology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Anti-Inflammatory Agents/therapeutic use , Antigens, Differentiation/genetics , Antigens, Differentiation/immunology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Complement System Proteins/genetics , Complement System Proteins/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Databases, Genetic , Gene Expression Regulation , HIV Infections/drug therapy , HIV Infections/immunology , HIV-1/drug effects , HIV-1/immunology , HIV-1/pathogenicity , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Inflammation , Interferons/genetics , Interferons/immunology , Interleukins/genetics , Interleukins/immunology , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Repressor Proteins/genetics , Repressor Proteins/immunology , SARS-CoV-2 , Signal Transduction , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/immunology
15.
Sci Rep ; 10(1): 16824, 2020 10 08.
Article in English | MEDLINE | ID: covidwho-1387453

ABSTRACT

The biological mechanisms involved in SARS-CoV-2 infection are only partially understood. Thus we explored the plasma metabolome of patients infected with SARS-CoV-2 to search for diagnostic and/or prognostic biomarkers and to improve the knowledge of metabolic disturbance in this infection. We analyzed the plasma metabolome of 55 patients infected with SARS-CoV-2 and 45 controls by LC-HRMS at the time of viral diagnosis (D0). We first evaluated the ability to predict the diagnosis from the metabotype at D0 in an independent population. Next, we assessed the feasibility of predicting the disease evolution at the 7th and 15th day. Plasma metabolome allowed us to generate a discriminant multivariate model to predict the diagnosis of SARS-CoV-2 in an independent population (accuracy > 74%, sensitivity, specificity > 75%). We identified the role of the cytosine and tryptophan-nicotinamide pathways in this discrimination. However, metabolomic exploration modestly explained the disease evolution. Here, we present the first metabolomic study in SARS-CoV-2 patients which showed a high reliable prediction of early diagnosis. We have highlighted the role of the tryptophan-nicotinamide pathway clearly linked to inflammatory signals and microbiota, and the involvement of cytosine, previously described as a coordinator of cell metabolism in SARS-CoV-2. These findings could open new therapeutic perspectives as indirect targets.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Cytosine/blood , Metabolome , Metabolomics/methods , Niacinamide/blood , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Tryptophan/blood , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Early Diagnosis , Female , France/epidemiology , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Prognosis , Reproducibility of Results , SARS-CoV-2 , Sensitivity and Specificity , Severity of Illness Index
18.
Fertil Steril ; 114(2): 223-232, 2020 08.
Article in English | MEDLINE | ID: covidwho-1385570

ABSTRACT

OBJECTIVE: To determine the susceptibility of the endometrium to infection by-and thereby potential damage from-SARS-CoV-2. DESIGN: Analysis of SARS-Cov-2 infection-related gene expression from endometrial transcriptomic data sets. SETTING: Infertility research department affiliated with a public hospital. PATIENT(S): Gene expression data from five studies in 112 patients with normal endometrium collected throughout the menstrual cycle. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Gene expression and correlation between viral infectivity genes and age throughout the menstrual cycle. RESULT(S): Gene expression was high for TMPRSS4, CTSL, CTSB, FURIN, MX1, and BSG; medium for TMPRSS2; and low for ACE2. ACE2, TMPRSS4, CTSB, CTSL, and MX1 expression increased toward the window of implantation. TMPRSS4 expression was positively correlated with ACE2, CTSB, CTSL, MX1, and FURIN during several cycle phases; TMPRSS2 was not statistically significantly altered across the cycle. ACE2, TMPRSS4, CTSB, CTSL, BSG, and MX1 expression increased with age, especially in early phases of the cycle. CONCLUSION(S): Endometrial tissue is likely safe from SARS-CoV-2 cell entry based on ACE2 and TMPRSS2 expression, but susceptibility increases with age. Further, TMPRSS4, along with BSG-mediated viral entry into cells, could imply a susceptible environment for SARS-CoV-2 entry via different mechanisms. Additional studies are warranted to determine the true risk of endometrial infection by SARS-CoV-2 and implications for fertility treatments.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Endometrium/metabolism , Endometrium/virology , Gene Expression Regulation, Viral , Pneumonia, Viral/metabolism , Adult , Age Factors , Angiotensin-Converting Enzyme 2 , Betacoronavirus/genetics , COVID-19 , Coronavirus Infections/genetics , Female , Humans , Menstrual Cycle , Middle Aged , Pandemics , Peptidyl-Dipeptidase A/biosynthesis , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Risk Assessment/methods , SARS-CoV-2 , Virus Internalization , Young Adult
20.
Med Sci Monit ; 27: e930776, 2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1344551

ABSTRACT

During the coronavirus disease 2019 (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, patients presented with COVID-19 pneumonia of varying severity. The phenomenon of severe hypoxemia without signs of respiratory distress is also known as silent or hidden hypoxemia. Although silent hypoxemia is not unique to pneumonia due to SARS-CoV-2 infection, this phenomenon is now recognized to be associated with severe COVID-19 pneumonia. Proper management of critically ill patients is the key to reducing mortality. Herein, we summarize the possible and rare factors contributing to silent hypoxemia in patients with COVID-19. Microvascular thrombosis causes dead space ventilation in the lungs, and the flow of pulmonary capillaries is reduced, which leads to an imbalance in the V/Q ratio. The dissociation curve of oxyhemoglobin shifts to the left and limits the release of oxygen to the tissue. SARS-CoV-2 interferes with the synthesis of hemoglobin and reduces the ability to carry oxygen. The accumulation of endogenous carbon monoxide and carboxyhemoglobin will reduce the total oxygen carrying capacity and interfere with pulse oxygen saturation readings. There are also some non-specific factors that cause the difference between pulse oximetry and oxygen partial pressure. We propose some potentially more effective clinical alternatives and recommendations for optimizing the clinical management processes of patients with COVID-19. This review aims to describe the prevalence of silent hypoxemia in COVID-19 pneumonia, to provide an update on what is known of the pathophysiology, and to highlight the importance of diagnosing silent hypoxemia in patients with COVID-19 pneumonia.


Subject(s)
COVID-19/metabolism , Hypoxia/virology , Pneumonia, Viral/virology , Asymptomatic Diseases/epidemiology , COVID-19/epidemiology , COVID-19/virology , Humans , Hypoxia/epidemiology , Hypoxia/metabolism , Lung/cytology , Lung/metabolism , Lung/virology , Microvessels/metabolism , Oximetry , Oxygen/metabolism , Pneumonia, Viral/metabolism , Prevalence , SARS-CoV-2/isolation & purification , Thrombosis/metabolism , Thrombosis/virology
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