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1.
Front Immunol ; 12: 791753, 2021.
Article in English | MEDLINE | ID: covidwho-1639168

ABSTRACT

Background: Infection of SARS-CoV-2 may cause acute respiratory syndrome. It has been reported that SARS-CoV-2 nucleocapsid protein (N-protein) presents early in body fluids during infection. The direct involvement of N-protein in lung injury is poorly understood. Methods: Recombinant N-protein was pretreated with polymyxin B, a lipopolysaccharide (LPS)-neutralizing agent. C57BL/6, C3H/HeJ (resistant to LPS), and C3H/HeN (control for C3H/HeJ) mice were exposed to N-protein via intratracheal administration to examine acute lung injury. In vitro, bone marrow-derived macrophages (BMDMs) were cultured with N-protein to study phosphorylation of nuclear factor kappa B (NF-ĸB) p65, macrophage polarization, and expression of proinflammatory cytokines. Results: N-protein produced acute lung injury in C57BL/6 mice, with elevated protein permeability, total cell count, neutrophil infiltration, and proinflammatory cytokines in the bronchioalveolar lavage. N-protein also induced lung injury in both C3H/HeJ and C3H/HeN mice, indicating that the effect could not be attributed to the LPS contamination. N-protein triggered phosphorylation of NF-ĸB p65 in vitro, which was abolished by both N-protein denaturation and treatment with an antibody for N-protein, demonstrating that the effect is N-protein specific. In addition, N-protein promoted M1 macrophage polarization and the expression of proinflammatory cytokines, which was also blocked by N-protein denaturation and antibody for N-protein. Furthermore, N-protein induced NF-ĸB p65 phosphorylation in the lung, while pyrrolidine dithiocarbamate, an NF-ĸB inhibitor, alleviated the effect of N-protein on acute lung injury. Conclusions: SARS-CoV-2 N-protein itself is toxic and induces acute lung injury in mice. Both N-protein and NF-ĸB pathway may be therapeutic targets for treating multi-organ injuries in Coronavirus disease 2019 (COVID-19).


Subject(s)
Acute Lung Injury/virology , COVID-19 , Coronavirus Nucleocapsid Proteins/toxicity , NF-kappa B/metabolism , Acute Lung Injury/metabolism , Animals , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Phosphoproteins/toxicity , SARS-CoV-2
2.
Int Immunopharmacol ; 104: 108516, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1611782

ABSTRACT

Coronavirus disease 2019 (Covid-19) is a worldwide infectious disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2). In severe SARS-CoV-2 infection, there is severe inflammatory reactions due to neutrophil recruitments and infiltration in the different organs with the formation of neutrophil extracellular traps (NETs), which involved various complications of SARS-CoV-2 infection. Therefore, the objective of the present review was to explore the potential role of NETs in the pathogenesis of SARS-CoV-2 infection and to identify the targeting drugs against NETs in Covid-19 patients. Different enzyme types are involved in the formation of NETs, such as neutrophil elastase (NE), which degrades nuclear protein and release histones, peptidyl arginine deiminase type 4 (PADA4), which releases chromosomal DNA and gasdermin D, which creates pores in the NTs cell membrane that facilitating expulsion of NT contents. Despite of the beneficial effects of NETs in controlling of invading pathogens, sustained formations of NETs during respiratory viral infections are associated with collateral tissue injury. Excessive development of NETs in SARS-CoV-2 infection is linked with the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) due to creation of the NETs-IL-1ß loop. Also, aberrant NTs activation alone or through NETs formation may augment SARS-CoV-2-induced cytokine storm (CS) and macrophage activation syndrome (MAS) in patients with severe Covid-19. Furthermore, NETs formation in SARS-CoV-2 infection is associated with immuno-thrombosis and the development of ALI/ARDS. Therefore, anti-NETs therapy of natural or synthetic sources may mitigate SARS-CoV-2 infection-induced exaggerated immune response, hyperinflammation, immuno-thrombosis, and other complications.


Subject(s)
Acute Lung Injury/immunology , Anti-Inflammatory Agents/pharmacology , COVID-19/immunology , Cytokine Release Syndrome/immunology , Extracellular Traps/immunology , Acute Lung Injury/prevention & control , Acute Lung Injury/virology , Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Cytokine Release Syndrome/prevention & control , Cytokine Release Syndrome/virology , Extracellular Traps/drug effects , Extracellular Traps/metabolism , Humans , Immunity, Innate/drug effects , Leukocyte Elastase/antagonists & inhibitors , Leukocyte Elastase/metabolism , Neutrophil Infiltration/drug effects , Phosphate-Binding Proteins/antagonists & inhibitors , Phosphate-Binding Proteins/metabolism , Pore Forming Cytotoxic Proteins/antagonists & inhibitors , Pore Forming Cytotoxic Proteins/metabolism , Protein-Arginine Deiminase Type 4/antagonists & inhibitors , Protein-Arginine Deiminase Type 4/metabolism , SARS-CoV-2/immunology
3.
Heart Surg Forum ; 24(6): E940-E946, 2021 11 12.
Article in English | MEDLINE | ID: covidwho-1538255

ABSTRACT

BACKGROUND: The aim of this study was to investigate the clinical outcomes of cardiac surgery in patients who were incidentally diagnosed with Covid-19 in the postoperative period. PATIENTS AND METHODS: We performed 826 open cardiac surgeries in five tertiary centers. Most of the surgeries were elective coronary artery bypass grafting (CABG) (93.8%). A preoperative RT-PCR test and transcutaneous oxygen saturation were routinely investigated prior to surgery. We also investigated whether the patients already received Covid-19 treatment or had any contact with a Covid-19 patient in the last two weeks. We analyzed high sensitive C-reactive protein (hs-CRP), d-dimer, and fibrinogen, which plays a main role in the activation of procoagulant state after surgeries. RESULTS: Acute lung injury related to Covid-19 activation was observed in 48 out of 826 patients (5.8%). The median age of 48 patients was 63.9±12.4 years. Euro-Score and body mass index (BMI) were 6.1±1.1 and 29.2±4.1kg/m², respectively. RT-PCR test results were positive in 29 patients (60.4%). We performed thoracic computed tomography (CT) in all patients with or without positive RT-PCR test results. Thoracic CT images showed that there was a different degree of ARDS (mild, moderate, and serious). The median time of extracorporeal circulation (ECC) was 93.2±14.6 min. in on-pump surgery (IQR, 68-155 min.). Common symptoms included dyspnea (N = 22; 45.8%) and fever (N = 12; 25%). Eleven patients needed readmission to ICU. Compared with non-admitted to ICU patients, ICU patients were higher comorbidities and severe laboratory abnormalities (eg, high blood d-dimer and fibrinogen). We also detected significantly low oxygen saturation, hypercapnia, and severe acidosis in readmitted patients. Radiologic investigations showed that there were severe ARDS with bilateral pneumonic infiltration resistant to medical treatment in 6 out of 11 patients who died (54.5%). CONCLUSION: Diffuse pneumonic infiltration related to Covid-19 may develop in asymptomatic cardiac surgery patients with negative RT-PCR test results. Immunologic disorders resulting from ECC, physiologic distress, and anesthesia may activate Covid-19 during the incubation period. We need randomized clinical trials to explain Covid-19 activation in the latent period of the virus, and clinical outcomes in cardiac surgery.


Subject(s)
Acute Lung Injury/diagnosis , Acute Lung Injury/virology , COVID-19/diagnosis , COVID-19/virology , Cardiac Surgical Procedures , Postoperative Period , Acute Lung Injury/diagnostic imaging , Aged , COVID-19/diagnostic imaging , COVID-19 Nucleic Acid Testing , Critical Care , Female , Humans , Incidental Findings , Male , Middle Aged , Patient Readmission , Retrospective Studies , SARS-CoV-2 , Stress, Physiological , Tomography, X-Ray Computed , Virus Activation
4.
PLoS One ; 16(11): e0259732, 2021.
Article in English | MEDLINE | ID: covidwho-1518359

ABSTRACT

Mesenchymal stem cell derived extracellular vesicles (MSC-EVs) are bioactive particles that evoke beneficial responses in recipient cells. We identified a role for MSC-EV in immune modulation and cellular salvage in a model of SARS-CoV-2 induced acute lung injury (ALI) using pulmonary epithelial cells and exposure to cytokines or the SARS-CoV-2 receptor binding domain (RBD). Whereas RBD or cytokine exposure caused a pro-inflammatory cellular environment and injurious signaling, impairing alveolar-capillary barrier function, and inducing cell death, MSC-EVs reduced inflammation and reestablished target cell health. Importantly, MSC-EV treatment increased active ACE2 surface protein compared to RBD injury, identifying a previously unknown role for MSC-EV treatment in COVID-19 signaling and pathogenesis. The beneficial effect of MSC-EV treatment was confirmed in an LPS-induced rat model of ALI wherein MSC-EVs reduced pro-inflammatory cytokine secretion and respiratory dysfunction associated with disease. MSC-EV administration was dose-responsive, demonstrating a large effective dose range for clinical translation. These data provide direct evidence of an MSC-EV-mediated improvement in ALI and contribute new insights into the therapeutic potential of MSC-EVs in COVID-19 or similar pathologies of respiratory distress.


Subject(s)
Acute Lung Injury/complications , Acute Lung Injury/virology , COVID-19/pathology , Extracellular Vesicles/metabolism , Mesenchymal Stem Cells/metabolism , Pneumonia/complications , Pneumonia/virology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Disease Models, Animal , Extracellular Vesicles/ultrastructure , Humans , Immunomodulation , Male , Models, Biological , Pneumonia/pathology , Rats, Sprague-Dawley , SARS-CoV-2/physiology , Signal Transduction , THP-1 Cells
5.
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
6.
mBio ; 12(4): e0157221, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1349194

ABSTRACT

Tissue- and cell-specific expression patterns are highly variable within and across individuals, leading to altered host responses after acute virus infection. Unraveling key tissue-specific response patterns provides novel opportunities for defining fundamental mechanisms of virus-host interaction in disease and the identification of critical tissue-specific networks for disease intervention in the lung. Currently, there are no approved therapeutics for Middle East respiratory syndrome coronavirus (MERS-CoV) patients, and little is understood about how lung cell types contribute to disease outcomes. MERS-CoV replicates equivalently in primary human lung microvascular endothelial cells (MVE) and fibroblasts (FB) and to equivalent peak titers but with slower replication kinetics in human airway epithelial cell cultures (HAE). However, only infected MVE demonstrate observable virus-induced cytopathic effect. To explore mechanisms leading to reduced MVE viability, donor-matched human lung MVE, HAE, and FB were infected, and their transcriptomes, proteomes, and lipidomes were monitored over time. Validated functional enrichment analysis demonstrated that MERS-CoV-infected MVE were dying via an unfolded protein response (UPR)-mediated apoptosis. Pharmacologic manipulation of the UPR in MERS-CoV-infected primary lung cells reduced viral titers and in male mice improved respiratory function with accompanying reductions in weight loss, pathological signatures of acute lung injury, and times to recovery. Systems biology analysis and validation studies of global kinetic transcript, protein, and lipid data sets confirmed that inhibition of host stress pathways that are differentially regulated following MERS-CoV infection of different tissue types can alleviate symptom progression to end-stage lung disease commonly seen following emerging coronavirus outbreaks. IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe atypical pneumonia in infected individuals, but the underlying mechanisms of pathogenesis remain unknown. While much has been learned from the few reported autopsy cases, an in-depth understanding of the cells targeted by MERS-CoV in the human lung and their relative contribution to disease outcomes is needed. The host response in MERS-CoV-infected primary human lung microvascular endothelial (MVE) cells and fibroblasts (FB) was evaluated over time by analyzing total RNA, proteins, and lipids to determine the cellular pathways modulated postinfection. Findings revealed that MERS-CoV-infected MVE cells die via apoptotic mechanisms downstream of the unfolded protein response (UPR). Interruption of enzymatic processes within the UPR in MERS-CoV-infected male mice reduced disease symptoms, virus-induced lung injury, and time to recovery. These data suggest that the UPR plays an important role in MERS-CoV infection and may represent a host target for therapeutic intervention.


Subject(s)
Acute Lung Injury/pathology , Apoptosis/physiology , Coronavirus Infections/pathology , Unfolded Protein Response/physiology , Acute Lung Injury/virology , Animals , Cell Line , Endothelial Cells/metabolism , Endothelial Cells/virology , Female , Fibroblasts/metabolism , Fibroblasts/virology , Humans , Male , Mice , Middle East Respiratory Syndrome Coronavirus/immunology
7.
Front Immunol ; 12: 705080, 2021.
Article in English | MEDLINE | ID: covidwho-1389187

ABSTRACT

Respiratory viral infections have been a long-standing global burden ranging from seasonal recurrences to the unexpected pandemics. The yearly hospitalizations from seasonal viruses such as influenza can fluctuate greatly depending on the circulating strain(s) and the congruency with the predicted strains used for the yearly vaccine formulation, which often are not predicted accurately. While antiviral agents are available against influenza, efficacy is limited due to a temporal disconnect between the time of infection and symptom development and viral resistance. Uncontrolled, influenza infections can lead to a severe inflammatory response initiated by pathogen-associated molecular patterns (PAMPs) or host-derived danger-associated molecular patterns (DAMPs) that ultimately signal through pattern recognition receptors (PRRs). Overall, these pathogen-host interactions result in a local cytokine storm leading to acute lung injury (ALI) or the more severe acute respiratory distress syndrome (ARDS) with concomitant systemic involvement and more severe, life threatening consequences. In addition to traditional antiviral treatments, blocking the host's innate immune response may provide a more viable approach to combat these infectious pathogens. The SARS-CoV-2 pandemic illustrates a critical need for novel treatments to counteract the ALI and ARDS that has caused the deaths of millions worldwide. This review will examine how antagonizing TLR4 signaling has been effective experimentally in ameliorating ALI and lethal infection in challenge models triggered not only by influenza, but also by other ALI-inducing viruses.


Subject(s)
Acute Lung Injury/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Signal Transduction/immunology , Toll-Like Receptor 4/immunology , Acute Lung Injury/prevention & control , Acute Lung Injury/virology , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/prevention & control , Humans , Lung/drug effects , Lung/immunology , Lung/virology , Pandemics , SARS-CoV-2/physiology , Signal Transduction/drug effects , Toll-Like Receptor 4/metabolism
8.
Hepatology ; 74(4): 1750-1765, 2021 10.
Article in English | MEDLINE | ID: covidwho-1274697

ABSTRACT

BACKGROUND AND AIMS: We compared risk of acute liver injury and mortality in patients with COVID-19 and current, past, and no HBV infection. APPROACH AND RESULTS: This was a territory-wide retrospective cohort study in Hong Kong. Patients with COVID-19 between January 23, 2020, and January 1, 2021, were identified. Patients with hepatitis C or no HBsAg results were excluded. The primary outcome was mortality. Acute liver injury was defined as alanine aminotransferase or aspartate aminotransferase ≥2 × upper limit of normal (ULN; i.e., 80 U/L), with total bilirubin ≥2 × ULN (i.e., 2.2 mg/dL) and/or international normalized ratio ≥1.7. Of 5,639 patients included, 353 (6.3%) and 359 (6.4%) had current and past HBV infection, respectively. Compared to patients without known HBV exposure, current HBV-infected patients were older and more likely to have cirrhosis. Past HBV-infected patients were the oldest, and more had diabetes and cardiovascular disease. At a median follow-up of 14 (9-20) days, 138 (2.4%) patients died; acute liver injury occurred in 58 (1.2%), 8 (2.3%), and 11 (3.1%) patients with no, current, and past HBV infection, respectively. Acute liver injury (adjusted HR [aHR], 2.45; 95% CI, 1.52-3.96; P < 0.001), but not current (aHR, 1.29; 95% CI, 0.61-2.70; P = 0.507) or past (aHR, 0.90; 95% CI, 0.56-1.46; P = 0.681) HBV infection, was associated with mortality. Use of corticosteroid, antifungal, ribavirin, or lopinavir-ritonavir (adjusted OR [aOR], 2.55-5.63), but not current (aOR, 1.93; 95% CI, 0.88-4.24; P = 0.102) or past (aOR, 1.25; 95% CI, 0.62-2.55; P = 0.533) HBV infection, was associated with acute liver injury. CONCLUSION: Current or past HBV infections were not associated with more liver injury and mortality in COVID-19.


Subject(s)
Acute Lung Injury/epidemiology , COVID-19/mortality , Hepatitis B, Chronic/epidemiology , Acute Lung Injury/blood , Acute Lung Injury/diagnosis , Acute Lung Injury/virology , Adult , Age Factors , Aged , Alanine Transaminase , Aspartate Aminotransferases , COVID-19/complications , COVID-19/diagnosis , COVID-19/virology , Female , Hepatitis B Surface Antigens/isolation & purification , Hepatitis B virus/immunology , Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/virology , Hong Kong/epidemiology , Humans , Male , Medical History Taking/statistics & numerical data , Middle Aged , Retrospective Studies , Risk Assessment/statistics & numerical data , Risk Factors
9.
Emerg Microbes Infect ; 10(1): 1156-1168, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1249264

ABSTRACT

ABSTRACTThe risk of secondary infection with SARS-CoV-2 and influenza A virus is becoming a practical problem that must be addressed as the flu season merges with the COVID-19 pandemic. As SARS-CoV-2 and influenza A virus have been found in patients, understanding the in vivo characteristics of the secondary infection between these two viruses is a high priority. Here, hACE2 transgenic mice were challenged with the H1N1 virus at a nonlethal dose during the convalescent stage on 7 and 14 days post SARS-CoV-2 infection, and importantly, subsequent H1N1 infection showed enhanced viral shedding and virus tissue distribution. Histopathological observation revealed an extensive pathological change in the lungs related to H1N1 infection in mice recovered from SARS-CoV-2 infection, with severe inflammation infiltration and bronchiole disruption. Moreover, upon H1N1 exposure on 7 and 14 dpi of SARS-CoV-2 infection, the lymphocyte population activated at a lower level with T cell suppressed in both PBMC and lung. These findings will be valuable for evaluating antiviral therapeutics and vaccines as well as guiding public health work.


Subject(s)
Acute Lung Injury/pathology , Angiotensin-Converting Enzyme 2/genetics , COVID-19/pathology , Orthomyxoviridae Infections/pathology , Acute Lung Injury/virology , Animals , COVID-19/therapy , Coinfection/pathology , Coinfection/virology , Cytokines/blood , Disease Models, Animal , Female , Humans , Influenza A Virus, H1N1 Subtype/isolation & purification , Lung/pathology , Lymphocyte Count , Lymphocytes/immunology , Mice , Mice, Transgenic , Orthomyxoviridae Infections/therapy , SARS-CoV-2/isolation & purification , Viral Load , Virus Replication/physiology , Virus Shedding/physiology
10.
Int J Mol Sci ; 22(10)2021 May 15.
Article in English | MEDLINE | ID: covidwho-1236794

ABSTRACT

Acute lung injury (ALI) afflicts approximately 200,000 patients annually and has a 40% mortality rate. The COVID-19 pandemic has massively increased the rate of ALI incidence. The pathogenesis of ALI involves tissue damage from invading microbes and, in severe cases, the overexpression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). This study aimed to develop a therapy to normalize the excess production of inflammatory cytokines and promote tissue repair in the lipopolysaccharide (LPS)-induced ALI. Based on our previous studies, we tested the insulin-like growth factor I (IGF-I) and BTP-2 therapies. IGF-I was selected, because we and others have shown that elevated inflammatory cytokines suppress the expression of growth hormone receptors in the liver, leading to a decrease in the circulating IGF-I. IGF-I is a growth factor that increases vascular protection, enhances tissue repair, and decreases pro-inflammatory cytokines. It is also required to produce anti-inflammatory 1,25-dihydroxyvitamin D. BTP-2, an inhibitor of cytosolic calcium, was used to suppress the LPS-induced increase in cytosolic calcium, which otherwise leads to an increase in proinflammatory cytokines. We showed that LPS increased the expression of the primary inflammatory mediators such as toll like receptor-4 (TLR-4), IL-1ß, interleukin-17 (IL-17), TNF-α, and interferon-γ (IFN-γ), which were normalized by the IGF-I + BTP-2 dual therapy in the lungs, along with improved vascular gene expression markers. The histologic lung injury score was markedly elevated by LPS and reduced to normal by the combination therapy. In conclusion, the LPS-induced increases in inflammatory cytokines, vascular injuries, and lung injuries were all improved by IGF-I + BTP-2 combination therapy.


Subject(s)
Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Anilides/pharmacology , Cytokines/metabolism , Gene Expression Regulation/drug effects , Insulin-Like Growth Factor I/pharmacology , Thiadiazoles/pharmacology , Acute Lung Injury/pathology , Acute Lung Injury/virology , Anilides/therapeutic use , Animals , COVID-19/complications , Calcium/metabolism , Calcium Channels/metabolism , Cytokines/genetics , Disease Models, Animal , Female , Gene Expression Regulation/genetics , Immunohistochemistry , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor I/therapeutic use , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-17/genetics , Interleukin-17/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharides/toxicity , Mice , Mice, Inbred C57BL , Signal Transduction/drug effects , Signal Transduction/genetics , Thiadiazoles/therapeutic use , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
11.
J Gen Virol ; 102(5)2021 05.
Article in English | MEDLINE | ID: covidwho-1219293

ABSTRACT

SARS-CoV-2 is the causative agent of COVID-19 and human infections have resulted in a global health emergency. Small animal models that reproduce key elements of SARS-CoV-2 human infections are needed to rigorously screen candidate drugs to mitigate severe disease and prevent the spread of SARS-CoV-2. We and others have reported that transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2) viral receptor under the control of the Keratin 18 (K18) promoter develop severe and lethal respiratory disease subsequent to SARS-CoV-2 intranasal challenge. Here we report that some infected mice that survive challenge have residual pulmonary damages and persistent brain infection on day 28 post-infection despite the presence of anti-SARS-COV-2 neutralizing antibodies. Because of the hypersensitivity of K18-hACE2 mice to SARS-CoV-2 and the propensity of virus to infect the brain, we sought to determine if anti-infective biologics could protect against disease in this model system. We demonstrate that anti-SARS-CoV-2 human convalescent plasma protects K18-hACE2 against severe disease. All control mice succumbed to disease by day 7; however, all treated mice survived infection without observable signs of disease. In marked contrast to control mice, viral antigen and lesions were reduced or absent from lungs and absent in brains of antibody-treated mice. Our findings support the use of K18-hACE2 mice for protective efficacy studies of anti-SARS-CoV-2 medical countermeasures (MCMs). They also support the use of this system to study SARS-CoV-2 persistence and host recovery.


Subject(s)
COVID-19/therapy , Acute Lung Injury/prevention & control , Acute Lung Injury/virology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Brain/pathology , Brain/virology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Disease Models, Animal , Female , Humans , Immunization, Passive , Lung/pathology , Lung/virology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Coronavirus/genetics , Receptors, Coronavirus/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Severity of Illness Index , Viral Load , Virus Replication
12.
Infect Genet Evol ; 88: 104682, 2021 03.
Article in English | MEDLINE | ID: covidwho-1065473

ABSTRACT

BACKGROUND: The reported association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene and the risk for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) remains controversial despite the publication of four meta-analyses on this topic. Here, we updated the meta-analysis with more studies and additional assessments that include adults and children within the context of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Sixteen articles (22 studies) were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using three genetic models (allele, recessive and dominant), in which ARDS patients were compared with non-ARDS patients (A1) and healthy controls (A2). Mortality outcomes were also assessed (A3). The influence of covariates was examined by meta-regression. Bonferroni correction was performed for multiple pooled associations. Subgroup analyses based on ethnicity (Asians, Caucasians) and life stage (adults, children) were conducted. Heterogeneity was addressed with outlier treatment. RESULTS: This meta-analysis generated 68 comparisons, 21 of which were significant. Of the 21, four A1 and three A3 highly significant (Pa = 0.00001-0.0008) outcomes withstood Bonferroni correction. For A1, allele and recessive associations were found in overall (OR 0.49, 95% CI 0.39-0.61), Caucasians (OR 0.46, 95% CI 0.35-0.61) and children (ORs 0.49-0.66, 95% CI 0.33-0.84) analyses. For A3, associations were found in overall (dominant: OR 0.45, 95% CI 0.29-0.68) and Asian subgroup (allele/ dominant: ORs 0.31-0.39, 95% CIs 0.18-0.63) analyses. These outcomes were either robust, or statistically powered or both and uninfluenced by covariates. CONCLUSIONS: Significant associations of the ACE I/D polymorphism with the risk of ALI/ARDS were indicated in Caucasians and children as well as in Asians in mortality analysis. These findings were underpinned by high significance, high statistical power and robustness. ACE genotypes may be useful for ALI/ARDS therapy for patients with COVID-19.


Subject(s)
Acute Lung Injury/genetics , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Genetic Predisposition to Disease , INDEL Mutation , Respiratory Distress Syndrome/genetics , Acute Lung Injury/ethnology , Acute Lung Injury/pathology , Acute Lung Injury/virology , Adult , Age Factors , Alleles , COVID-19/ethnology , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Child , Gene Frequency , Humans , Respiratory Distress Syndrome/ethnology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/pathogenicity , Survival Analysis
13.
Clin Lab ; 67(1)2021 Jan 01.
Article in English | MEDLINE | ID: covidwho-1045294

ABSTRACT

BACKGROUND: Since December 2019, a series of pneumonia cases caused by COVID-19 emerged in Wuhan, Hubei Province, China. People are generally susceptible to COVID-19 because people lack immunity to this new virus. With the spread of this epidemic disease from Wuhan, a national outbreak soon appeared, and now many countries have this disease. Unfortunately, no effective drug for COVID-19 treatment has been found so far. METHODS: We designed a retrospective study based on patients admitted to The Affiliated Infectious Hospital of Soochow University from January 22, 2020, to February 25, 2020, with diagnosed COVID-19. We analyzed correlations between RT-PCR negative time and laboratory indicators, then divided all cases into 2 groups according to oxygenation index, data of RT-PCR negative time and related laboratory indicators of the two groups were com-pared. RESULTS: We collected 84 confirmed patients whose RT-PCR had turned negative, including 23 patients with the lowest oxygenation index ≤ 300 mmHg and 61 patients had > 300 mmHg. There was a positive correlation between the RT-PCR negative time and age, WBC count, LDH, SCr. There were statistically significant differences in fever numbers, WBC count, lymphocyte count, CRP, ALT, AST, albumin, LDH, SCr, D-dimer, and fibrinogen between the two groups based on the oxygenation index. CONCLUSIONS: Age, WBC count, LDH, and SCr may be related to the duration of COVID-19 disease. Fever, WBC count, lymphocyte count, CRP, ALT, AST, albumin, LDH, SCr, D-dimer, and fibrinogen are related to the severity of acute lung injury.


Subject(s)
Acute Lung Injury/diagnosis , Blood Chemical Analysis , COVID-19 Testing , COVID-19/complications , Acute Lung Injury/blood , Acute Lung Injury/virology , Adolescent , Adult , Aged , Aged, 80 and over , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Biomarkers/blood , C-Reactive Protein/analysis , COVID-19/diagnosis , COVID-19/virology , COVID-19 Nucleic Acid Testing , Child , Child, Preschool , China , Creatinine/blood , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Infant , Infant, Newborn , L-Lactate Dehydrogenase/blood , Leukocyte Count , Male , Middle Aged , Oxygen/blood , Predictive Value of Tests , Prognosis , Real-Time Polymerase Chain Reaction , Retrospective Studies , Serum Albumin, Human/analysis , Severity of Illness Index , Time Factors , Young Adult
14.
Arch Med Res ; 51(7): 631-635, 2020 10.
Article in English | MEDLINE | ID: covidwho-1023470

ABSTRACT

The novel coronavirus 2019-nCoV (SARS-CoV-2) infection that emerged in China in December 2019 has rapidly spread to become a global pandemic. This article summarizes the potential benefits of erythropoietin (EPO) in alleviating SARS-CoV-2 pathogenesis which is now called COVID-19. As with other coronavirus infection, the lethality of COVID-19 is associated with respiratory dysfunction due to overexpression of proinflammatory cytokines induced by the host immune responses. The resulting cytokine storm leads to the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Erythropoietin, well known for its role in the regulation of erythropoiesis, may have protective effects against ALI/ARDS induced by viral and other pathogens. EPO exerts antiapoptotic and cytoprotective properties under various pathological conditions. With a high safety profile, EPO promotes the production of endothelial progenitor cells and reduce inflammatory processes through inhibition of the nuclear factor-κB (NF-κB) and JAK-STAT3 signaling pathways. Thus, it may be considered as a safe drug candidate for COVID-19 patients if given at the early stage of the disease. The potential effects of erythropoietin on different aspects of ALI/ARDS associated with SARS-CoV-2 infection are reviewed.


Subject(s)
Acute Lung Injury , Anti-Inflammatory Agents/therapeutic use , COVID-19 , Erythropoietin/therapeutic use , Respiratory Distress Syndrome , Acute Lung Injury/drug therapy , Acute Lung Injury/virology , COVID-19/complications , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Humans , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/virology , SARS-CoV-2
15.
Biomed Pharmacother ; 136: 111193, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1009322

ABSTRACT

The recent emergence of coronavirus disease-2019 (COVID-19) as a pandemic affecting millions of individuals has raised great concern throughout the world, and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the causative agent for COVID-19. The multifunctional protein angiotensin converting enzyme 2 (ACE2) is accepted as its primary target for entry into host cells. In its enzymatic function, ACE2, like its homologue ACE, regulates the renin-angiotensin system (RAS) critical for cardiovascular and renal homeostasis in mammals. Unlike ACE, however, ACE2 drives an alternative RAS pathway by degrading Ang-II and thus operates to balance RAS homeostasis in the context of hypertension, heart failure, and cardiovascular as well as renal complications of diabetes. Outside the RAS, ACE2 hydrolyzes key peptides, such as amyloid-ß, apelin, and [des-Arg9]-bradykinin. In addition to its enzymatic functions, ACE2 is found to regulate intestinal amino acid homeostasis and the gut microbiome. Although the non-enzymatic function of ACE2 as the entry receptor for SARS-CoV-2 has been well established, the contribution of enzymatic functions of ACE2 to the pathogenesis of COVID-19-related lung injury has been a matter of debate. A complete understanding of this central enzyme may begin to explain the various symptoms and pathologies seen in SARS-CoV-2 infected individuals, and may aid in the development of novel treatments for COVID-19.


Subject(s)
Acute Lung Injury/virology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , SARS-CoV-2/physiology , Virus Internalization , COVID-19/pathology , Humans
16.
Redox Biol ; 38: 101794, 2021 01.
Article in English | MEDLINE | ID: covidwho-922123

ABSTRACT

Acute lung injury (ALI), a devastating illness induced by systemic inflammation e.g., sepsis or local lung inflammation e.g., COVID-19 mediated severe pneumonia, has an unacceptably high mortality and has no effective therapy. ALI is associated with increased pulmonary microvascular hyperpermeability and alveolar flooding. The small Rho GTPases, RhoA and Rac1 are central regulators of vascular permeability through cytoskeleton rearrangements. RhoA and Rac1 have opposing functional outcome: RhoA induces an endothelial contractile phenotype and barrier disruption, while Rac1 stabilizes endothelial junctions and increases barrier integrity. In ALI, RhoA activity is increased while Rac1 activity is reduced. We have shown that the activation of RhoA in lipopolysaccharide (LPS)-mediated ALI, is dependent, at least in part, on a single nitration event at tyrosine (Y)34. Thus, the purpose of this study was to determine if the inhibition of Rac1 is also dependent on its nitration. Our data show that Rac1 inhibition by LPS is associated with its nitration that mass spectrometry identified as Y32, within the switch I region adjacent to the nucleotide-binding site. Using a molecular modeling approach, we designed a nitration shielding peptide for Rac1, designated NipR2 (nitration inhibitor peptide for the Rho GTPases 2), which attenuated the LPS-induced nitration of Rac1 at Y32, preserves Rac1 activity and attenuates the LPS-mediated disruption of the endothelial barrier in human lung microvascular endothelial cells (HLMVEC). Using a murine model of ALI induced by intratracheal installation of LPS we found that NipR2 successfully prevented Rac1 nitration and Rac1 inhibition, and more importantly attenuated pulmonary inflammation, reduced lung injury and prevented the loss of lung function. Together, our data identify a new post-translational mechanism of Rac1 inhibition through its nitration at Y32. As NipR2 also reduces sepsis induced ALI in the mouse lung, we conclude that Rac1 nitration is a therapeutic target in ALI.


Subject(s)
Acute Lung Injury , Blood-Air Barrier , COVID-19 , Endothelial Cells , Lipopolysaccharides/toxicity , Neuropeptides/metabolism , SARS-CoV-2/metabolism , rac1 GTP-Binding Protein/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/enzymology , Acute Lung Injury/pathology , Acute Lung Injury/virology , Animals , Blood-Air Barrier/enzymology , Blood-Air Barrier/pathology , Blood-Air Barrier/virology , COVID-19/chemically induced , COVID-19/enzymology , COVID-19/pathology , Cell Line , Endothelial Cells/metabolism , Endothelial Cells/pathology , Endothelial Cells/virology , Humans , Male , Mice , Neuropeptides/genetics , rac1 GTP-Binding Protein/genetics
17.
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
18.
Front Immunol ; 11: 584514, 2020.
Article in English | MEDLINE | ID: covidwho-874482

ABSTRACT

Physical trauma can be considered an unrecognized "pandemic" because it can occur anywhere and affect anyone and represents a global burden. Following severe tissue trauma, patients frequently develop acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) despite modern surgical and intensive care concepts. The underlying complex pathophysiology of life-threatening ALI/ARDS has been intensively studied in experimental and clinical settings. However, currently, the coronavirus family has become the focus of ALI/ARDS research because it represents an emerging global public health threat. The clinical presentation of the infection is highly heterogeneous, varying from a lack of symptoms to multiple organ dysfunction and mortality. In a particular subset of patients, the primary infection progresses rapidly to ALI and ARDS. The pathophysiological mechanisms triggering and driving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced ALI/ARDS are still poorly understood. Although it is also generally unknown whether insights from trauma-induced ARDS may be readily translated to SARS-CoV-2-associated ARDS, it was still recommended to treat coronavirus-positive patients with ALI/ARDS with standard protocols for ALI/ARDS. However, this strategy was questioned by clinical scientists, because it was documented that some severely hypoxic SARS-CoV-2-infected patients exhibited a normal respiratory system compliance, a phenomenon rarely observed in ARDS patients with another underlying etiology. Therefore, coronavirus-induced ARDS was defined as a specific ARDS phenotype, which accordingly requires an adjusted therapeutic approach. These suggestions reflect previous attempts of classifying ARDS into different phenotypes that might overall facilitate ARDS diagnosis and treatment. Based on the clinical data from ARDS patients, two major phenotypes have been proposed: hyper- and hypo-inflammatory. Here, we provide a comparative review of the pathophysiological pathway of trauma-/hemorrhagic shock-induced ARDS and coronavirus-induced ARDS, with an emphasis on the crucial key points in the pathogenesis of both these ARDS forms. Therefore, the manifold available data on trauma-/hemorrhagic shock-induced ARDS may help to better understand coronavirus-induced ARDS.


Subject(s)
Acute Lung Injury/pathology , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , Severe Acute Respiratory Syndrome/pathology , Thrombosis/pathology , Acute Lung Injury/virology , Betacoronavirus , COVID-19 , Coronavirus Infections/drug therapy , Cytokines/blood , Humans , Immunity, Innate/immunology , Inflammation/pathology , Inflammation/virology , Lung/pathology , Pandemics , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/virology , Thrombosis/virology
19.
Stem Cell Res Ther ; 11(1): 437, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-864994

ABSTRACT

The COVID-19 pandemic has negatively impacted the global public health and the international economy; therefore, there is an urgent need for an effective therapy to treat COVID-19 patients. Mesenchymal stem cells (MSCs) have been proposed as an emerging therapeutic option for the SARS-CoV-2 infection. Recently, numerous clinical trials have been registered to examine the safety and efficacy of different types of MSCs and their exosomes for treating COVID-19 patients, with less published data on the mechanism of action. Although there is no approved effective therapy for COVID-19 as of yet, MSC therapies showed an improvement in the treatment of some COVID-19 patients. MSC's therapeutic effect is displayed in their ability to reduce the cytokine storm, enhance alveolar fluid clearance, and promote epithelial and endothelial recovery; however, the safest and most effective route of MSC delivery remains unclear. The use of poorly characterized MSC products remains one of the most significant drawbacks of MSC-based therapy, which could theoretically promote the risk for thromboembolism. Optimizing the clinical-grade production of MSCs and establishing a consensus on registered clinical trials based on cell-product characterization and mode of delivery would aid in laying the foundation for a safe and effective therapy in COVID-19. In this review, we shed light on the mechanistic view of MSC therapeutic role based on preclinical and clinical studies on acute lung injury and ARDS; therefore, offering a unique correlation and applicability in COVID-19 patients. We further highlight the challenges and opportunities in the use of MSC-based therapy.


Subject(s)
Acute Lung Injury/therapy , Coronavirus Infections/therapy , Cytokine Release Syndrome/therapy , Exosomes/transplantation , Mesenchymal Stem Cell Transplantation/methods , Pneumonia, Viral/therapy , Acute Lung Injury/virology , Betacoronavirus , COVID-19 , Cell- and Tissue-Based Therapy/methods , Humans , Mesenchymal Stem Cells/metabolism , Pandemics , SARS-CoV-2
20.
Biomed Pharmacother ; 131: 110643, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-726408

ABSTRACT

Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has been widely spread in the world with a high mortality. Cytokine storm syndrome (CSS) and acute lung injury caused by SARS-CoV-2 infection severely threaten the patients. With the purpose to find effective and low-toxic drugs to mitigate CSS, entecavir and imipenem were identified to reduce TNF-α using a LPS-induced macrophage model from the anti-infective drug library. Entecavir and imipenem efficiently suppressed the release of inflammatory cytokines by partly intervention of NF-κB activity. The acute lung injury was also alleviated and the survival time was prolonged in mice. In addition, entecavir and imipenem inhibited the release of TNF-α and IL-10 in human peripheral blood mononuclear cells (hPBMCs). Collectively, we proposed that entecavir and imipenem might be candidates for the treatment of CSS.


Subject(s)
Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Guanine/analogs & derivatives , Imipenem/pharmacology , Pneumonia, Viral/drug therapy , Acute Lung Injury/drug therapy , Acute Lung Injury/virology , Animals , COVID-19 , Coronavirus Infections/complications , Cytokine Release Syndrome/virology , Cytokines/immunology , Drug Repositioning , Guanine/pharmacology , Humans , Interleukin-10/immunology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Lipopolysaccharides , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , Pandemics , Pneumonia, Viral/complications , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolism
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