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1.
Arch Med Res ; 51(7): 608-612, 2020 10.
Article in English | MEDLINE | ID: covidwho-1023468

ABSTRACT

Corona Virus Disease 2019 (COVID-19) pandemic is rapidly spreading all over the world. Excessive immune responses trigger life-threatening cytokine release syndrome (CRS) which can result in overproduction of pro-inflammatory cytokines including tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1ß with different pro-inflammatory roles. Anecdotal evidence suggests that the modulation of systemic immune responses may have a potential role in the treatment of patients with COVID-19. Given the importance of the issue and the lack of therapeutic treatment or vaccine; anti-cytokine therapy such as IL-6, TNFα and IL-1 antagonists have been suggested for the alleviation of hyper-inflammation status in these patients. In this mini-review, we addressed the inflammatory pathways of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its relationship with the host cytokine storm. Furthermore, the proposed therapeutic options to reverse hyper-inflammation in infected patients were mentioned.


Subject(s)
Cytokine Release Syndrome , /complications , /physiopathology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/physiopathology , Cytokine Release Syndrome/therapy , Cytokine Release Syndrome/virology , Humans , Immunotherapy , /immunology
2.
Front Immunol ; 11: 596631, 2020.
Article in English | MEDLINE | ID: covidwho-1004678

ABSTRACT

COVID-19 is a distinctive infection characterized by elevated inter-human transmission and presenting from absence of symptoms to severe cytokine storm that can lead to dismal prognosis. Like for HIV, lymphopenia and drastic reduction of CD4+ T cell counts in COVID-19 patients have been linked with poor clinical outcome. As CD4+ T cells play a critical role in orchestrating responses against viral infections, important lessons can be drawn by comparing T cell response in COVID-19 and in HIV infection and by studying HIV-infected patients who became infected by SARS-CoV-2. We critically reviewed host characteristics and hyper-inflammatory response in these two viral infections to have a better insight on the large difference in clinical outcome in persons being infected by SARS-CoV-2. The better understanding of mechanism of T cell dysfunction will contribute to the development of targeted therapy against severe COVID-19 and will help to rationally design vaccine involving T cell response for the long-term control of viral infection.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , Lymphopenia/pathology , /immunology , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Cytokines/blood , Dysbiosis/pathology , Gastrointestinal Microbiome/physiology , HIV Infections/pathology , Humans , Tight Junctions/pathology
3.
Eur Rev Med Pharmacol Sci ; 24(24): 13062-13064, 2020 12.
Article in English | MEDLINE | ID: covidwho-1000852

ABSTRACT

Cytokine storm in COVID-19 is linked to disease severity and mortality. 40% of patients with severe COVID-19 require mechanical ventilation. Analgesia and sedation are used for treatment of pain, facilitation of mechanical ventilation, or management of acute agitation. Herein, we present the immunomodulating actions of morphine that may either improve or worsen the clinical course of COVID-19 once cytokine storm develops. A literature search was performed to find articles on potential immunomodulatory effects of morphine. Taken together, the results of in vitro and in vivo models in non-COVID-19 conditions suggest that morphine could have a beneficial effect by mitigating the cytokine storm in the early stages of severe COVID-19. In contrast, it could be potentially harmful in late stages of severe COVID-19, especially in the presence of septic shock.


Subject(s)
Analgesics, Opioid/adverse effects , Cytokine Release Syndrome/immunology , Immunomodulation , Morphine/adverse effects , Analgesics, Opioid/therapeutic use , Cytokines/immunology , Humans , Morphine/therapeutic use , Respiration, Artificial , Shock, Septic/immunology
6.
Eur Rev Med Pharmacol Sci ; 24(23): 12527-12535, 2020 12.
Article in English | MEDLINE | ID: covidwho-995013

ABSTRACT

Since December 2019, an outbreak of a new coronavirus, COVID-19, infection has been taking place. At present, COVID-19 has spread to most countries worldwide. The latest evidence suggests that cytokine storm syndrome (CSS) is an important cause of the transition from mild to critical pneumonia and critically ill patients' death. The sudden exacerbation of COVID-19 may be related to a cytokine storm. Therefore, early identification and active treatment of CSS may play very important roles in improving the patients' prognosis, and these tasks are given attention in the current treatment of new Coronavirus pneumonia. However, there is still no specific medicine for this purpose. This article reviews cytokine storms and conducts an exploratory review of pharmacotherapy for cytokine storms to provide a reference for clinical treatment.


Subject(s)
/immunology , Cytokine Release Syndrome/immunology , Myocarditis/immunology , /metabolism , Antibodies, Monoclonal, Humanized/therapeutic use , Antioxidants/therapeutic use , Apoptosis , Atrial Natriuretic Factor/therapeutic use , Azetidines/therapeutic use , Benzyl Compounds/therapeutic use , Cytokine Release Syndrome/drug therapy , Enzyme Inhibitors/therapeutic use , Glucocorticoids/therapeutic use , Glycoproteins/therapeutic use , Humans , Hypoxia/metabolism , Hypoxia/therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Myocardial Ischemia/metabolism , Myocarditis/metabolism , Myocarditis/therapy , Myocytes, Cardiac/metabolism , Oxidative Stress , Oxygen Inhalation Therapy , Respiration, Artificial , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Trypsin Inhibitors/therapeutic use , Tumor Necrosis Factor Inhibitors/therapeutic use , alpha-Methyltyrosine/therapeutic use
7.
Eur Rev Med Pharmacol Sci ; 24(23): 12500-12509, 2020 12.
Article in English | MEDLINE | ID: covidwho-995007

ABSTRACT

OBJECTIVE: Since the emergence of coronavirus disease (COVID-19), the death toll has been increasing daily. Many risk factors are associated with a high mortality rate in COVID-19. Establishment of a common pathway among these risk factors could improve our understanding of COVID-19 severity and mortality. This review aims at establishing this common pathway and its possible effect on COVID-19 mortality. MATERIALS AND METHODS: The current review was executed in five consecutive stages starting from determining the risk factors of COVID-19 mortality and trying to find a common pathway among them depending on the available literature. This was followed by proposing a mechanism explaining how this common pathway could increase the mortality. Finally, its potential role in managing COVID-19 was proposed. RESULTS: This review identified this common pathway to be a low baseline of reduced glutathione (i.e., GSH) level. In particular, this review provided an in-depth discussion regarding the pathophysiology by which COVID-19 leads to GSH depletion, tissue damage, and acute respiratory distress syndrome. In addition, the current review demonstrated how GSH depletion could result in failure of the immune system and rendering the end organs vulnerable to damage from the oxidative stress. CONCLUSIONS: This preclinical study shows that GSH depletion may have a central role in COVID-19 mortality and pathophysiology. Therefore, elevating the GSH level in tissues may decrease the severity and mortality rates of COVID-19.


Subject(s)
/mortality , Cytokine Release Syndrome/immunology , Glutathione/metabolism , Acute Lung Injury/metabolism , Age Factors , Antioxidants/metabolism , Apoptosis , /metabolism , Cytokine Release Syndrome/metabolism , Diabetes Mellitus/epidemiology , Diabetes Mellitus/metabolism , Glutathione/immunology , Humans , Hypertension/epidemiology , Hypertension/metabolism , Macrophages/immunology , Myocardial Ischemia/epidemiology , Myocardial Ischemia/metabolism , Obesity/epidemiology , Obesity/metabolism , Reactive Oxygen Species/metabolism , Risk Factors , Smoking/epidemiology , Smoking/metabolism
8.
PLoS Pathog ; 16(12): e1009128, 2020 12.
Article in English | MEDLINE | ID: covidwho-992722

ABSTRACT

Cytokine storm is suggested as one of the major pathological characteristics of SARS-CoV-2 infection, although the mechanism for initiation of a hyper-inflammatory response, and multi-organ damage from viral infection is poorly understood. In this virus-cell interaction study, we observed that SARS-CoV-2 infection or viral spike protein expression alone inhibited angiotensin converting enzyme-2 (ACE2) receptor protein expression. The spike protein promoted an angiotensin II type 1 receptor (AT1) mediated signaling cascade, induced the transcriptional regulatory molecules NF-κB and AP-1/c-Fos via MAPK activation, and increased IL-6 release. SARS-CoV-2 infected patient sera contained elevated levels of IL-6 and soluble IL-6R. Up-regulated AT1 receptor signaling also influenced the release of extracellular soluble IL-6R by the induction of the ADAM-17 protease. Use of the AT1 receptor antagonist, Candesartan cilexetil, resulted in down-regulation of IL-6/soluble IL-6R release in spike expressing cells. Phosphorylation of STAT3 at the Tyr705 residue plays an important role as a transcriptional inducer for SOCS3 and MCP-1 expression. Further study indicated that inhibition of STAT3 Tyr705 phosphorylation in SARS-CoV-2 infected and viral spike protein expressing epithelial cells did not induce SOCS3 and MCP-1 expression. Introduction of culture supernatant from SARS-CoV-2 spike expressing cells on a model human liver endothelial Cell line (TMNK-1), where transmembrane IL-6R is poorly expressed, resulted in the induction of STAT3 Tyr705 phosphorylation as well as MCP-1 expression. In conclusion, our results indicated that the presence of SARS-CoV-2 spike protein in epithelial cells promotes IL-6 trans-signaling by activation of the AT1 axis to initiate coordination of a hyper-inflammatory response.


Subject(s)
/immunology , Interleukin-6/immunology , Receptors, Angiotensin/metabolism , Spike Glycoprotein, Coronavirus/immunology , /metabolism , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Interleukin-6/metabolism , Respiratory Mucosa/immunology , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology , Signal Transduction/physiology , Transcriptional Activation
9.
Front Immunol ; 11: 598404, 2020.
Article in English | MEDLINE | ID: covidwho-983710

ABSTRACT

Background: Bacterial sepsis has been used as a prototype to understand the pathogenesis of severe coronavirus disease 2019 (COVID-19). In addition, some management programs for critically ill COVID-19 patients are also based on experience with bacterial sepsis. However, some differences may exist between these two types of sepsis. Methods: This retrospective study investigated whether there are differences in the immune system status of these two types of sepsis. A total of 64 bacterial sepsis patients and 43 patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sepsis were included in this study. Demographic data were obtained from medical records. Laboratory results within 24 h after the diagnosis of sepsis were provided by the clinical laboratory. Results: The results of blood routine (neutrophil, lymphocyte, and monocyte counts), infection biomarkers (C-reactive protein, ferritin, and procalcitonin levels), lymphocyte subset counts (total T lymphocyte, CD4+ T cell, CD8+ T cell, B cell, and NK cell counts), and lymphocyte subset functions (the proportions of PMA/ionomycin-stimulated IFN-γ positive cells in CD4+, CD8+ T cells, and NK cells) were similar in bacterial sepsis patients and SARS-CoV-2 sepsis patients. Cytokine storm was milder, and immunoglobulin and complement protein levels were higher in SARS-CoV-2 sepsis patients. Conclusions: There are both similarities and differences in the immune system status of bacterial sepsis and SARS-CoV-2 sepsis. Our findings do not support blocking the cytokine storm or supplementing immunoglobulins in SARS-CoV-2 sepsis, at least in the early stages of the disease. Treatments for overactivation of the complement system and lymphocyte depletion may be worth exploring further.


Subject(s)
Bacterial Infections , Cytokine Release Syndrome , Lymphocyte Subsets , Sepsis , Adult , Aged , Bacterial Infections/blood , Bacterial Infections/immunology , /immunology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Female , Humans , Lymphocyte Count , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Male , Middle Aged , Retrospective Studies , /metabolism , Sepsis/blood , Sepsis/immunology
10.
Front Immunol ; 11: 570993, 2020.
Article in English | MEDLINE | ID: covidwho-983708

ABSTRACT

Corona virus disease 2019 (COVID-19) has caused a global outbreak and severely posed threat to people's health and social stability. Mounting evidence suggests that immunopathological changes, including diminished lymphocytes and elevated cytokines, are important drivers of disease progression and death in coronavirus infections. Cytokine storm not only limits further spread of virus in the body but also induces secondary tissue damage through the secretion of large amounts of active mediators and inflammatory factors. It has been determined that cytokine storm is a major cause of deaths in COVID-19; therefore, in order to reverse the deterioration of severe and critically ill patients from this disease, the cytokine storm has become a key therapeutic target. Although specific mechanisms of the occurrences of cytokine storms in COVID-19 have not been fully illuminated, hyper-activated innate immune responses, and dysregulation of ACE2 (angiotensin converting enzyme 2) expression and its downstream pathways might provide possibilities. Tailored immunoregulatory therapies have been applied to counteract cytokine storms, such as inhibition of cytokines, corticosteroids, blood purification therapy, and mesenchymal stem cell therapy. This review will summarize advances in the research of cytokine storms induced by COVID-19, as well as potential intervention strategies to control cytokine storms.


Subject(s)
Cytokine Release Syndrome , Disease Outbreaks , Immunotherapy , /immunology , /immunology , /epidemiology , /therapy , Cytokine Release Syndrome/epidemiology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/therapy , Humans , Immunity, Innate/immunology
11.
Molecules ; 25(22)2020 Nov 16.
Article in English | MEDLINE | ID: covidwho-979112

ABSTRACT

Low levels of micronutrients have been associated with adverse clinical outcomes during viral infections. Therefore, to maximize the nutritional defense against infections, a daily allowance of vitamins and trace elements for malnourished patients at risk of or diagnosed with coronavirus disease 2019 (COVID-19) may be beneficial. Recent studies on COVID-19 patients have shown that vitamin D and selenium deficiencies are evident in patients with acute respiratory tract infections. Vitamin D improves the physical barrier against viruses and stimulates the production of antimicrobial peptides. It may prevent cytokine storms by decreasing the production of inflammatory cytokines. Selenium enhances the function of cytotoxic effector cells. Furthermore, selenium is important for maintaining T cell maturation and functions, as well as for T cell-dependent antibody production. Vitamin C is considered an antiviral agent as it increases immunity. Administration of vitamin C increased the survival rate of COVID-19 patients by attenuating excessive activation of the immune response. Vitamin C increases antiviral cytokines and free radical formation, decreasing viral yield. It also attenuates excessive inflammatory responses and hyperactivation of immune cells. In this mini-review, the roles of vitamin C, vitamin D, and selenium in the immune system are discussed in relation to COVID-19.


Subject(s)
Ascorbic Acid/therapeutic use , Coronavirus Infections/prevention & control , Cytokine Release Syndrome/prevention & control , Dietary Supplements , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Selenium/therapeutic use , Vitamin D/therapeutic use , Antibodies, Viral/biosynthesis , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Coronavirus Infections/diet therapy , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokine Release Syndrome/diet therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/antagonists & inhibitors , Cytokines/biosynthesis , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Immune System/drug effects , Immunologic Factors/therapeutic use , Micronutrients/therapeutic use , Pneumonia, Viral/diet therapy , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/virology
12.
Front Immunol ; 11: 570251, 2020.
Article in English | MEDLINE | ID: covidwho-976246

ABSTRACT

Several countries around the world have faced an important obesity challenge for the past four decades as the result of an obesogenic environment. This disease has a multifactorial origin and it is associated with multiple comorbidities including type 2 diabetes, hypertension, osteoarthritis, metabolic syndrome, cancer, and dyslipidemia. With regard to dyslipidemia, hypertriglyceridemia is a well-known activator of the NLRP3 inflammasome, triggering adipokines and cytokines secretion which in addition induce a systemic inflammatory state that provides an adequate scenario for infections, particularly those mediated by viruses such as HIV, H1N1 influenza, and SARS-CoV-2. The SARS-CoV-2 infection causes the coronavirus disease 2019 (COVID-19) and it is responsible for the pandemic that we are currently living. COVID-19 causes an aggressive immune response known as cytokine release syndrome or cytokine storm that causes multiorgan failure and in most cases leads to death. In the present work, we aimed to review the molecular mechanisms by which obesity-associated systemic inflammation could cause a more severe clinical presentation of COVID-19. The SARS-CoV-2 infection could potentiate or accelerate the pre-existing systemic inflammatory state of individuals with obesity, via the NLRP3 inflammasome activation and the release of pro-inflammatory cytokines from cells trough Gasdermin-pores commonly found in cell death by pyroptosis.


Subject(s)
/immunology , Cytokine Release Syndrome/immunology , Diabetes Mellitus, Type 2/immunology , Inflammasomes/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , /physiology , Animals , /virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/immunology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/virology , Humans , Inflammasomes/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , /genetics
13.
J Immunother Cancer ; 8(2)2020 12.
Article in English | MEDLINE | ID: covidwho-971586

ABSTRACT

The COVID-19 outbreak caused by SARS-CoV-2 challenges the medical system by interfering with routine therapies for many patients with chronic diseases. In patients with cancer receiving immune checkpoint inhibitors (ICIs), difficulties also arise from the incomplete understanding of the intricate interplay between their routine treatment and pathogenesis of the novel virus. By referring to previous ICI-based investigations, we speculate that ICIs themselves are not linked to high-infection risks of respiratory diseases or inflammation-related adverse effects in patients with cancer. Moreover, ICI treatment may even enhance coronavirus clearance in some patients with malignant tumor by boosting antiviral T-cell responsiveness. However, the 'explosive' inflammation during COVID-19 in some ICI-treated patients with cancer was illustrated as exuberant immunopathological damage or even death. In case of the COVID-19 immunopathogenesis fueled by ICIs, we propose a regular monitor of pathogenic T-cell subsets and their exhaustion marker expression (eg, Th17 and interleukin (IL)-6-producing Th1 subsets with surface programmed death 1 expression) to guide the usage of ICI. Here we aimed to address these considerations, based on available literature and experience from our practice, that may assist with the decision-making of ICI administration during the pandemic.


Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Cytokine Release Syndrome/prevention & control , Neoplasms/drug therapy , /immunology , Antineoplastic Agents, Immunological/therapeutic use , /diagnosis , Clinical Decision-Making , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Drug Monitoring , Humans , Lung/diagnostic imaging , Neoplasms/blood , Neoplasms/immunology , Pandemics , Patient Selection , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , Th1 Cells/drug effects , Th1 Cells/immunology , Th1 Cells/metabolism , Th17 Cells/drug effects , Th17 Cells/immunology , Th17 Cells/metabolism , Tomography, X-Ray Computed
16.
Virus Res ; 292: 198235, 2021 01 15.
Article in English | MEDLINE | ID: covidwho-967583

ABSTRACT

The first incidence of COVID-19 was reported in the Wuhan city of Hubei province in China in late December 2019. Because of failure in timely closing of borders of the affected region, COVID-19 spread across like a wildfire through air travel initiating a pandemic. It is a serious lower respiratory track viral infection caused by highly contagious, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Coronavirus including COVID-19 causing SARS-CoV-2 causes zoonotic diseases and thought to be originated from bats. Since its first incidence, the virus has spread all across the world, causing serious human casualties, economic losses, and disrupting global supply chains. As with SARS-CoV, COVID-19 causing SARS-CoV-2 follows a similar path of airborne infection, but is less lethal and more infectious than SARS and MERS. This review focusses on the pathogenesis of SARS-CoV-2, especially on the dysfunctional immune responses following a cytokine storm in severely affected persons. The mode of entry of SARS-CoV-2 is via the angiotensin converting enzyme 2 (ACE-2) receptors present on the epithelial lining of lungs, gastrointestinal tract, and mucus membranes. Older persons with weaker immune system and associated co-morbidities are more vulnerable to have dysfunctional immune responses, as most of them concomitantly have severe hypovitaminosis D. Consequently, causing severe damage to key organs of the body including lungs and the cardiovascular system. Since, vast majority of persons enters to the intensive care units and died, had severe vitamin D deficiency, thus, this area must be investigated seriously. In addition, this article assesses the role of vitamin D in reducing the risk of COVID-19. Vitamin D is a key regulator of the renin-angiotensin system that is exploited by SARS-CoV-2 for entry into the host cells. Further, vitamin D modulates multiple mechanisms of the immune system to contain the virus that includes dampening the entry and replication of SARS-CoV-2, reduces concentration of pro-inflammatory cytokines and increases levels of anti-inflammatory cytokines, enhances the production of natural antimicrobial peptide and activates defensive cells such as macrophages that could destroy SARS-CoV-2. Thus, this article provides the urgency of needed evidences through large population based randomized controlled trials and ecological studies to evaluate the potential role of vitamin D in COVID-19.


Subject(s)
/immunology , Vitamin D/immunology , Adaptive Immunity , Animals , Clinical Trials as Topic , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Disease Management , Humans , Immunity, Innate , Immunologic Factors , Inflammation/immunology , Inflammation/prevention & control , Vitamin D/therapeutic use , Zoonoses/immunology
17.
Mediators Inflamm ; 2020: 8829674, 2020.
Article in English | MEDLINE | ID: covidwho-961174

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a virus-induced respiratory disease that may progress to acute respiratory distress syndrome (ARDS) and is triggered by immunopathological mechanisms that cause excessive inflammation and leukocyte dysfunction. Neutrophils play a critical function in the clearance of bacteria with specific mechanisms to combat viruses. The aim of this review is to highlight the current advances in the pathways of neutrophilic inflammation against viral infection over the past ten years, focusing on the production of neutrophil extracellular traps (NETs) and its impact on severe lung diseases, such as COVID-19. We focused on studies regarding hyperinflammation, cytokine storms, neutrophil function, and viral infections. We discuss how the neutrophil's role could influence COVID-19 symptoms in the interaction between hyperinflammation (overproduction of NETs and cytokines) and the clearance function of neutrophils to eliminate the viral infection. We also propose a more in-depth investigation into the neutrophil response mechanism targeting NETosis in the different phases of COVID-19.


Subject(s)
/immunology , Inflammation/immunology , Neutrophils/immunology , /complications , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Extracellular Traps/immunology , Extracellular Traps/virology , Host Microbial Interactions/immunology , Humans , Immunity, Innate , Inflammation/etiology , Inflammation/virology , Inflammation Mediators/immunology , Lung/immunology , Lung/virology , Models, Immunological , Neutrophils/virology , Pandemics , /immunology , /immunology , /pathogenicity
18.
Nat Commun ; 11(1): 6122, 2020 11 30.
Article in English | MEDLINE | ID: covidwho-952011

ABSTRACT

Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease would benefit from validated small animal models. Here, we show that transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2 transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2 transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 6. K18 hACE2 transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease.


Subject(s)
Disease Models, Animal , /genetics , Animals , Brain/immunology , Brain/pathology , Brain/virology , /pathology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Disease Susceptibility , Genetic Predisposition to Disease , Keratin-18/genetics , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Transgenic , Mortality , Promoter Regions, Genetic/genetics , Respiratory Mucosa/immunology , Respiratory Mucosa/pathology , Respiratory Mucosa/virology , Virus Diseases/immunology , Virus Diseases/pathology
19.
BMJ Open ; 10(11): e039951, 2020 11 14.
Article in English | MEDLINE | ID: covidwho-944946

ABSTRACT

INTRODUCTION: About 25% of patients with COVID-19 develop acute respiratory distress syndrome (ARDS) associated with a high release of pro-inflammatory cytokines such as interleukin-6 (IL-6). The aim of the SARICOR study is to demonstrate that early administration of sarilumab (an IL-6 receptor inhibitor) in hospitalised patients with COVID-19, pulmonary infiltrates and a high IL-6 or D-dimer serum level could reduce the progression of ARDS requiring high-flow nasal oxygen or mechanical ventilation (non-invasive or invasive). METHODS AND ANALYSIS: Phase II, open-label, randomised, multicentre, controlled clinical trial to study the efficacy and safety of the administration of two doses of sarilumab (200 and 400 mg) plus best available therapy (BAT) in hospitalised adults with COVID-19 presenting cytokine release syndrome. This strategy will be compared with a BAT control group. The efficacy and safety will be monitored up to 28 days postadministration. A total of 120 patients will be recruited (40 patients in each arm). ETHICS AND DISSEMINATION: The clinical trial has been approved by the Research Ethics Committee of the coordinating centre and authorised by the Spanish Agency of Medicines and Medical Products. If the hypothesis is verified, the dissemination of the results could change clinical practice by increasing early administration of sarilumab in adult patients with COVID-19 presenting cytokine release syndrome, thus reducing intensive care unit admissions. TRIAL REGISTRATION NUMBER: NCT04357860.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome, Adult/drug therapy , Adolescent , Adult , Aged , Betacoronavirus , Clinical Trials, Phase II as Topic , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Interleukin-6/immunology , Male , Middle Aged , Multicenter Studies as Topic , Pandemics , Pneumonia, Viral/immunology , Randomized Controlled Trials as Topic , Respiration, Artificial , Respiratory Distress Syndrome, Adult/immunology , Young Adult
20.
Biochim Biophys Acta Mol Basis Dis ; 1867(2): 166014, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-938765

ABSTRACT

The coronavirus disease 2019 (COVID-19) has been threatening the globe since the end of November 2019. The disease revealed cracks in the health care system as health care providers across the world were left without guidelines on definitive usage of pharmaceutical agents or vaccines. The World Health Organization (WHO) declared COVID-19 as a pandemic on the 11th of March 2020. Individuals with underlying systemic disorders have reported complications, such as cytokine storms, when infected with the virus. As the number of positive cases and the death toll across the globe continue to rise, various researchers have turned to cell based therapy using stem cells to combat COVID-19. The field of stem cells and regenerative medicine has provided a paradigm shift in treating a disease with minimally invasive techniques that provides maximal clinical and functional outcome for patients. With the available evidence of immunomodulatory and immune-privilege actions, mesenchymal stem cells (MSCs) can repair, regenerate and remodulate the native homeostasis of pulmonary parenchyma with improved pulmonary compliance. This article revolves around the usage of novel MSCs therapy for combating COVID-19.


Subject(s)
/epidemiology , Cytokine Release Syndrome/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/immunology , Pandemics , /immunology , /immunology , Cytokine Release Syndrome/epidemiology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Female , Humans , Male , Mesenchymal Stem Cells/pathology
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