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3.
Front Immunol ; 13: 820350, 2022.
Article in English | MEDLINE | ID: covidwho-1731777

ABSTRACT

Growth differentiation factor 15 (GDF-15) is a transforming growth factor (TGF)-ß superfamily cytokine that plays a central role in metabolism regulation. Produced in response to mitochondrial stress, tissue damage or hypoxia, this cytokine has emerged as one of the strongest predictors of disease severity during inflammatory conditions, cancers and infections. Reports suggest that GDF-15 plays a tissue protective role via sympathetic and metabolic adaptation in the context of mitochondrial damage, although the exact mechanisms involved remain uncertain. In this review, we discuss the emergence of GDF-15 as a distinctive marker of viral infection severity, especially in the context of COVID-19. We will critically review the role of GDF-15 as an inflammation-induced mediator of disease tolerance, through metabolic and immune reprogramming. Finally, we discuss potential mechanisms of GDF-15 elevation during COVID-19 cytokine storm and its limitations. Altogether, this cytokine seems to be involved in disease tolerance to viral infections including SARS-CoV-2, paving the way for novel therapeutic interventions.


Subject(s)
Adaptation, Psychological/physiology , Biomarkers/metabolism , COVID-19/metabolism , Growth Differentiation Factor 15/metabolism , Animals , COVID-19/virology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Cytokines/metabolism , Humans
4.
Int J Mol Sci ; 23(3)2022 Feb 08.
Article in English | MEDLINE | ID: covidwho-1674674

ABSTRACT

Preventing the cytokine storm observed in COVID-19 is a crucial goal for reducing the occurrence of severe acute respiratory failure and improving outcomes. Here, we identify Aldo-Keto Reductase 1B10 (AKR1B10) as a key enzyme involved in the expression of pro-inflammatory cytokines. The analysis of transcriptomic data from lung samples of patients who died from COVID-19 demonstrates an increased expression of the gene encoding AKR1B10. Measurements of the AKR1B10 protein in sera from hospitalised COVID-19 patients suggests a significant link between AKR1B10 levels and the severity of the disease. In macrophages and lung cells, the over-expression of AKR1B10 induces the expression of the pro-inflammatory cytokines Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß) and Tumor Necrosis Factor a (TNFα), supporting the biological plausibility of an AKR1B10 involvement in the COVID-19-related cytokine storm. When macrophages were stressed by lipopolysaccharides (LPS) exposure and treated by Zopolrestat, an AKR1B10 inhibitor, the LPS-induced production of IL-6, IL-1ß, and TNFα is significantly reduced, reinforcing the hypothesis that the pro-inflammatory expression of cytokines is AKR1B10-dependant. Finally, we also show that AKR1B10 can be secreted and transferred via extracellular vesicles between different cell types, suggesting that this protein may also contribute to the multi-organ systemic impact of COVID-19. These experiments highlight a relationship between AKR1B10 production and severe forms of COVID-19. Our data indicate that AKR1B10 participates in the activation of cytokines production and suggest that modulation of AKR1B10 activity might be an actionable pharmacological target in COVID-19 management.


Subject(s)
Aldo-Keto Reductases/physiology , COVID-19/genetics , Cytokine Release Syndrome/genetics , Respiratory Distress Syndrome/genetics , Aldo-Keto Reductases/antagonists & inhibitors , Aldo-Keto Reductases/genetics , Animals , COVID-19/complications , COVID-19/metabolism , COVID-19/pathology , Case-Control Studies , Cells, Cultured , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Cytokines/metabolism , Enzyme Inhibitors/pharmacology , Humans , Macrophages/drug effects , Macrophages/metabolism , Mice , Patient Acuity , RAW 264.7 Cells , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/physiology , Transcriptome
5.
Cells ; 11(2)2022 01 17.
Article in English | MEDLINE | ID: covidwho-1625673

ABSTRACT

Acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection continues to be a worldwide public health crisis. Among the several severe manifestations of this disease, thrombotic processes drive the catastrophic organ failure and mortality in these patients. In addition to a well-established cytokine storm associated with the disease, perturbations in platelets, endothelial cells, and the coagulation system are key in triggering systemic coagulopathy, involving both the macro- and microvasculatures of different organs. Of the several mechanisms that might contribute to dysregulation of these cells following SARS-CoV-2 infection, the current review focuses on the role of activated Janus kinase (JAK) signaling in augmenting thrombotic processes and organ dysfunction. The review concludes with presenting the current understanding and emerging controversies concerning the potential therapeutic applications of JAK inhibitors for ameliorating the inflammation-thrombosis phenotype in COVID-19 patients.


Subject(s)
COVID-19/metabolism , Endothelial Cells/metabolism , Janus Kinases/metabolism , SARS-CoV-2/metabolism , Signal Transduction , Thrombosis/metabolism , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Endothelial Cells/virology , Humans , Thrombosis/virology
6.
Front Immunol ; 12: 749291, 2021.
Article in English | MEDLINE | ID: covidwho-1566649

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. ß2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. ß-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, ß-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of ß-blockers in the management of Covid-19.


Subject(s)
Adrenergic beta-Antagonists/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Sympathetic Nervous System/drug effects , Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/metabolism , COVID-19/physiopathology , Catecholamines/metabolism , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/physiopathology , Cytokines/metabolism , Humans , /etiology , /physiopathology , SARS-CoV-2/pathogenicity , Sympathetic Nervous System/metabolism , Sympathetic Nervous System/physiopathology
7.
Inflammopharmacology ; 29(5): 1347-1355, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1557643

ABSTRACT

The natural pathway of antioxidant production is mediated through Kelch-like erythroid cell-derived protein with Cap and collar homology [ECH]-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2) system. Keap1 maintains a low level of Nrf2 by holding it in its protein complex. Also, Keap1 facilitates the degradation of Nrf2 by ubiquitination. In other words, Keap1 is a down-regulator of Nrf2. To boost the production of biological antioxidants, Keap1 has to be inhibited and Nrf2 has to be released. Liberated Nrf2 is in an unbound state, so it travels to the nucleus to stimulate the antioxidant response element (ARE) present on the antioxidant genes. AREs activate biosynthesis of biological antioxidants through genes responsible for the production of antioxidants. In some cases of coronavirus disease 2019 (COVID-19), there is an enormous release of cytokines. The antioxidant defense mechanism in the body helps in counteracting symptoms induced by the cytokine storm in COVID-19. So, boosting the production of antioxidants is highly desirable in such a condition. In this review article, we have compiled the role of Keap1-Nrf2 system in antioxidant production. We further propose its potential therapeutic use in managing cytokine storm in COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/therapy , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/therapy , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Antioxidants/therapeutic use , Disease Management , Humans , Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors , NF-E2-Related Factor 2/agonists , Oxidative Stress/drug effects , Oxidative Stress/physiology
8.
Biochim Biophys Acta Mol Basis Dis ; 1868(2): 166294, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-1525694

ABSTRACT

Ivermectin (IVM) is an FDA approved macrocyclic lactone compound traditionally used to treat parasitic infestations and has shown to have antiviral potential from previous in-vitro studies. Currently, IVM is commercially available as a veterinary drug but have also been applied in humans to treat onchocerciasis (river blindness - a parasitic worm infection) and strongyloidiasis (a roundworm/nematode infection). In light of the recent pandemic, the repurposing of IVM to combat SARS-CoV-2 has acquired significant attention. Recently, IVM has been proven effective in numerous in-silico and molecular biology experiments against the infection in mammalian cells and human cohort studies. One promising study had reported a marked reduction of 93% of released virion and 99.98% unreleased virion levels upon administration of IVM to Vero-hSLAM cells. IVM's mode of action centres around the inhibition of the cytoplasmic-nuclear shuttling of viral proteins by disrupting the Importin heterodimer complex (IMPα/ß1) and downregulating STAT3, thereby effectively reducing the cytokine storm. Furthermore, the ability of IVM to block the active sites of viral 3CLpro and S protein, disrupts important machinery such as viral replication and attachment. This review compiles all the molecular evidence to date, in review of the antiviral characteristics exhibited by IVM. Thereafter, we discuss IVM's mechanism and highlight the clinical advantages that could potentially contribute towards disabling the viral replication of SARS-CoV-2. In summary, the collective review of recent efforts suggests that IVM has a prophylactic effect and would be a strong candidate for clinical trials to treat SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Ivermectin/therapeutic use , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , Antiparasitic Agents/pharmacology , Antiparasitic Agents/therapeutic use , Antiviral Agents/pharmacology , COVID-19/metabolism , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/metabolism , Humans , Ivermectin/pharmacology , Karyopherins/metabolism , SARS-CoV-2/physiology
9.
Mol Biol Rep ; 49(2): 1475-1490, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1507001

ABSTRACT

In viral respiratory infections, disrupted pathophysiological outcomes have been attributed to hyper-activated and unresolved inflammation responses of the immune system. Integration between available drugs and natural therapeutics have reported benefits in relieving inflammation-related physiological outcomes and microalgae may be a feasible source from which to draw from against future coronavirus-infections. Microalgae represent a large and diverse source of chemically functional compounds such as carotenoids and lipids that possess various bioactivities, including anti-inflammatory properties. Therefore in this paper, some implicated pathways causing inflammation in viral respiratory infections are discussed and juxtaposed along with available research done on several microalgal metabolites. Additionally, the therapeutic properties of some known anti-inflammatory, antioxidant and immunomodulating compounds sourced from microalgae are reported for added clarity.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , COVID-19/complications , Cytokine Release Syndrome/drug therapy , Microalgae/metabolism , Animals , Bioprospecting/methods , COVID-19/metabolism , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Humans , Inflammation/drug therapy , Inflammation/metabolism
10.
Naunyn Schmiedebergs Arch Pharmacol ; 394(12): 2471-2474, 2021 12.
Article in English | MEDLINE | ID: covidwho-1473989

ABSTRACT

The pathophysiological process of the disease, Covid-19, is mediated by innate immunity, with the presence of macrophages responsible for secreting type 1 and 6 interleukins (IL), tumor necrosis factor (TNF) leading to dilation of endothelial cells with a consequent increase in capillary permeability. The treatment of this disease has been much discussed, but the variability in the clinical picture, the difficulties for diagnosis and treatment, especially of those patients who have the most severe clinical condition of the disease. Immunization is an effective tool for controlling the spread and overload of health services, but its effectiveness involves high investments in the acquisition of inputs, development of vaccines, and logistics of storage and distribution. These factors can be obstacles for countries with lower economic, technological, and infrastructure indexes. Reflecting on these difficulties, we raised the possibility of adjuvant therapies with imminent research feasibility, as is the case with the use of carvacrol, a monoterpenic phenol whose has biological properties that serve as a barrier to processes mediated by free radicals, such as irritation and inflammation, due to its antioxidant action. Many authors highlighted the activity of carvacrol as a potent suppressor of COX-2 expression minimizing the acute inflammatory process, decreasing the release of some pro-inflammatory mediators such as IL-1ß, TNF-α, PGE2. Anyway, the benefits of carvacrol are numerous and the therapeutic possibilities too. With this description, the question arises: would carvacrol be a supporting treatment option, effective in minimizing the deleterious effects of Covid-19? There is still a lot to discover and research.


Subject(s)
Antioxidants/therapeutic use , COVID-19/drug therapy , COVID-19/metabolism , Cymenes/therapeutic use , Animals , Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antioxidants/pharmacology , COVID-19/immunology , Cymenes/pharmacology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/metabolism , Humans , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/immunology , Inflammation Mediators/metabolism
11.
Int J Mol Sci ; 22(20)2021 Oct 13.
Article in English | MEDLINE | ID: covidwho-1470887

ABSTRACT

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has infected >235 million people and killed over 4.8 million individuals worldwide. Although vaccines have been developed for prophylactic management, there are no clinically proven antivirals to treat the viral infection. Continuous efforts are being made all over the world to develop effective drugs but these are being delayed by periodic outbreak of mutated SARS-CoV-2 and a lack of knowledge of molecular mechanisms underlying viral pathogenesis and post-infection complications. In this regard, the involvement of Annexin A2 (AnxA2), a lipid-raft related phospholipid-binding protein, in SARS-CoV-2 attachment, internalization, and replication has been discussed. In addition to the evidence from published literature, we have performed in silico docking of viral spike glycoprotein and RNA-dependent RNA polymerase with human AnxA2 to find the molecular interactions. Overall, this review provides the molecular insights into a potential role of AnxA2 in the SARS-CoV-2 pathogenesis and post-infection complications, especially thrombosis, cytokine storm, and insulin resistance.


Subject(s)
Annexin A2/metabolism , COVID-19/pathology , Annexin A2/chemistry , COVID-19/virology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/pathology , Humans , Molecular Docking Simulation , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/metabolism , Thrombosis/pathology , Virus Internalization
12.
Signal Transduct Target Ther ; 6(1): 347, 2021 09 25.
Article in English | MEDLINE | ID: covidwho-1437669

ABSTRACT

SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants-alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 µg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a "spike protein-CD147-CyPA signaling axis": Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Basigin/antagonists & inhibitors , Basigin/metabolism , COVID-19/drug therapy , COVID-19/metabolism , Cytokine Release Syndrome/drug therapy , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Basigin/genetics , COVID-19/genetics , Chlorocebus aethiops , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/metabolism , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Mice , Mice, Transgenic , SARS-CoV-2/genetics , Vero Cells
13.
Cell Death Differ ; 29(2): 420-438, 2022 02.
Article in English | MEDLINE | ID: covidwho-1406388

ABSTRACT

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-CoV-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homolog in myeloid cells triggered a STAT3-linked, progressive, and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury, and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.


Subject(s)
COVID-19/physiopathology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/metabolism , Inflammation/metabolism , STAT3 Transcription Factor/metabolism , Aged , Aged, 80 and over , Animals , COVID-19/metabolism , Caspase 8/metabolism , Cytokines/immunology , Cytokines/metabolism , Female , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , SARS-CoV-2/immunology , STAT3 Transcription Factor/genetics , Signal Transduction
14.
Trends Endocrinol Metab ; 32(11): 875-889, 2021 11.
Article in English | MEDLINE | ID: covidwho-1401891

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of respiratory and cardiovascular diseases, known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 encodes the structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N). The receptor-binding domain on the surface subunit S1 is responsible for attachment of the virus to angiotensin (Ang)-converting enzyme 2 (ACE2), which is highly expressed in host cells. The cytokine storm observed in patients with COVID-19 contributes to the endothelial vascular dysfunction, which can lead to acute respiratory distress syndrome, multiorgan failure, alteration in iron homeostasis, and death. Growth and differentiation factor 15 (GDF15), which belongs to the transforming growth factor-ß (TGF-ß) superfamily of proteins, has a pivotal role in the development and progression of diseases because of its role as a metabolic regulator. In COVID-19, GDF15 activity increases in response to tissue damage. GDF15 appears to be a strong predictor of poor outcomes in patients critically ill with COVID-19 and acts as an 'inflammation-induced central mediator of tissue tolerance' via its metabolic properties. In this review, we examine the potential properties of GDF15 as an emerging modulator of immunity in COVID-19 in association with iron metabolism. The virus life cycle in host cell provides potential targets for drug therapy.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Endothelium, Vascular/immunology , Growth Differentiation Factor 15/immunology , Iron/metabolism , Apoptosis/immunology , COVID-19/drug therapy , COVID-19/metabolism , Cytokine Release Syndrome/metabolism , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Glial Cell Line-Derived Neurotrophic Factor Receptors/immunology , Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism , Growth Differentiation Factor 15/metabolism , Humans , Immunologic Factors/therapeutic use , Oxidative Stress/immunology , Prognosis , Pyroptosis/immunology , SARS-CoV-2
15.
Hum Immunol ; 83(1): 86-98, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1401492

ABSTRACT

The global outbreak of coronavirus-2019 (COVID-19) still claims more lives daily around the world due to the lack of a definitive treatment and the rapid tendency of virus to mutate, which even jeopardizes vaccination efficacy. At the forefront battle against SARS-CoV-2, an effective innate response to the infection has a pivotal role in the initial control and treatment of disease. However, SARS-CoV-2 subtly interrupts the equations of immune responses, disrupting the cytolytic antiviral effects of NK cells, while seriously activating infected macrophages and other immune cells to induce an unleashed "cytokine storm", a dangerous and uncontrollable inflammatory response causing life-threatening symptoms in patients. Notably, the NK cell exhaustion with ineffective cytolytic function against the sources of exaggerated cytokine release, acts as an Achilles' heel which exacerbates the severity of COVID-19. Given this, approaches that improve NK cell cytotoxicity may benefit treatment protocols. As a suggestion, adoptive transfer of NK or CAR-NK cells with proper cytotolytic potentials and the lowest capacity of cytokine-release (for example CD56dim NK cells brightly express activating receptors), to severe COVID-19 patients may provide an effective cure especially in cases suffering from cytokine storms. More intriguingly, the ongoing evidence for persistent clonal expansion of NK memory cells characterized by an activating phenotype in response to viral infections, can benefit the future studies on vaccine development and adoptive NK cell therapy in COVID-19. Whether vaccinated volunteers or recovered patients can also be considered as suitable candidates for cell donation could be the subject of future research.


Subject(s)
Adoptive Transfer , COVID-19/therapy , Cytokine Release Syndrome/therapy , Cytokines/immunology , Killer Cells, Natural/transplantation , SARS-CoV-2/immunology , Adoptive Transfer/adverse effects , Animals , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Cytokines/metabolism , Cytotoxicity, Immunologic , Host-Pathogen Interactions , Humans , Immunologic Memory , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Killer Cells, Natural/virology , SARS-CoV-2/pathogenicity , Treatment Outcome
16.
Clin Pharmacol Ther ; 111(3): 579-584, 2022 03.
Article in English | MEDLINE | ID: covidwho-1396859

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) may experience a cytokine storm with elevated interleukin-6 (IL-6) levels in response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). IL-6 suppresses hepatic enzymes, including CYP3A; however, the effect on drug exposure and drug-drug interaction magnitudes of the cytokine storm and resulting elevated IL-6 levels have not been characterized in patients with COVID-19. We used physiologically-based pharmacokinetic (PBPK) modeling to simulate the effect of inflammation on the pharmacokinetics of CYP3A metabolized drugs. A PBPK model was developed for lopinavir boosted with ritonavir (LPV/r), using clinically observed data from people living with HIV (PLWH). The inhibition of CYPs by IL-6 was implemented by a semimechanistic suppression model and verified against clinical data from patients with COVID-19, treated with LPV/r. Subsequently, the verified model was used to simulate the effect of various clinically observed IL-6 levels on the exposure of LPV/r and midazolam, a CYP3A model drug. Clinically observed LPV/r concentrations in PLWH and patients with COVID-19 were predicted within the 95% confidence interval of the simulation results, demonstrating its predictive capability. Simulations indicated a twofold higher LPV exposure in patients with COVID-19 compared with PLWH, whereas ritonavir exposure was predicted to be comparable. Varying IL-6 levels under COVID-19 had only a marginal effect on LPV/r pharmacokinetics according to our model. Simulations showed that a cytokine storm increased the exposure of the CYP3A paradigm substrate midazolam by 40%. Our simulations suggest that CYP3A metabolism is altered in patients with COVID-19 having increased cytokine release. Caution is required when prescribing narrow therapeutic index drugs particularly in the presence of strong CYP3A inhibitors.


Subject(s)
COVID-19/complications , Cytochrome P-450 CYP3A/metabolism , Cytokine Release Syndrome/virology , Lopinavir/pharmacokinetics , Midazolam/pharmacokinetics , Ritonavir/pharmacokinetics , Adult , COVID-19/drug therapy , COVID-19/metabolism , Cytochrome P-450 CYP3A/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/metabolism , Cytokines/metabolism , Humans , Metabolic Clearance Rate/drug effects , Middle Aged , Models, Biological
17.
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
19.
Int Immunopharmacol ; 99: 108049, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1347666

ABSTRACT

Setting up treatment strategies is the highest concern today to reduce the fatality of COVID-19. Due to a very new kind of virus attack, no specific treatment has been discovered to date. The most crucial way to dominate the disease severity is now the repurposing of drugs. In this review, we focused on the current treatment approaches targeting the crucial causative factors for the disease burden through cytokine storm or cytokine release syndrome. Several vaccines have been developed and have been applied already for prevention purposes, and several are on the way to be developed, although the effects and side effects are under observation. Presently, regulation of the immune response through intervention treatment methods has been adjusted on the basis of the COVID-19 severity stage and generally includes vaccines, immunotherapies including convalescent plasma and immunoglobulin treatment, monoclonal antibodies, cytokine therapy, complement inhibition, regenerative medicine, and repurposed anti-inflammatory and immune-regulatory drugs. Combination therapy is not acceptable in all respects because there is no concrete evidence in clinical trials or in vivo data. Target-specific drug therapies, such as inhibition of cytokine-producing signaling pathways, could be an excellent solution and thus reduce the severity of inflammation and disease severity. Therefore, gathering information about the mechanism of disease progression, possible goals, and drug efficacy of immune-based approaches to combat COVID-19 in the context of orderly review analysis is consequential.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , COVID-19/immunology , Cytokine Release Syndrome/metabolism , Cytokines/metabolism , Disease Progression , Drug Repositioning , Humans , SARS-CoV-2 , Severity of Illness Index
20.
Int J Mol Sci ; 22(15)2021 Jul 31.
Article in English | MEDLINE | ID: covidwho-1335102

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. Patients may present as asymptomatic or demonstrate mild to severe and life-threatening symptoms. Although COVID-19 has a respiratory focus, there are major cardiovascular complications (CVCs) associated with infection. The reported CVCs include myocarditis, heart failure, arrhythmias, thromboembolism and blood pressure abnormalities. These occur, in part, because of dysregulation of the Renin-Angiotensin-Aldosterone System (RAAS) and Kinin-Kallikrein System (KKS). A major route by which SARS-CoV-2 gains cellular entry is via the docking of the viral spike (S) protein to the membrane-bound angiotensin converting enzyme 2 (ACE2). The roles of ACE2 within the cardiovascular and immune systems are vital to ensure homeostasis. The key routes for the development of CVCs and the recently described long COVID have been hypothesised as the direct consequences of the viral S protein/ACE2 axis, downregulation of ACE2 and the resulting damage inflicted by the immune response. Here, we review the impact of COVID-19 on the cardiovascular system, the mechanisms by which dysregulation of the RAAS and KKS can occur following virus infection and the future implications for pharmacological therapies.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/etiology , Kallikrein-Kinin System , Renin-Angiotensin System , Angiotensin-Converting Enzyme 2/metabolism , Bradykinin/metabolism , COVID-19/drug therapy , Cardiovascular Diseases/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/metabolism , Humans
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