scholarly journals On the role of bacterial metalloproteases in COVID-19 associated cytokine storm

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
László Földvári-Nagy ◽  
Tamás Schnabel ◽  
Gabriella Dörnyei ◽  
Tamás Korcsmáros ◽  
Katalin Lenti
Keyword(s):  
Mortality Rate ◽  
Interleukin 6 ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Membrane Receptors ◽  
Critical Element ◽  
Cytokine Storm ◽  
Interleukin 6 Receptor ◽  
Membrane Bound ◽  
Prophylactic Use

AbstractThe cytokine release syndrome or cytokine storm, which is the hyper-induction of inflammatory responses has a central role in the mortality rate of COVID-19 and some other viral infections. Interleukin-6 (IL-6) is a key player in the development of cytokine storms. Shedding of interleukin-6 receptor (IL-6Rα) results in the accumulation of soluble interleukin-6 receptors (sIL-6R). Only relatively few cells express membrane-bound IL-6Rα. However, sIL-6R can act on potentially all cells and organs through the ubiquitously expressed gp130, the coreceptor of IL-6Rα. Through this, so-called trans-signaling, IL-6–sIL-6R is a powerful factor in the development of cytokine storms and multiorgan involvement. Some bacteria (e.g., Serratia marcescens, Staphylococcus aureus, Pseudomonas aeruginosa, Listeria monocytogenes), commonly considered to cause co-infections during viral pneumonia, can directly induce the shedding of membrane receptors, including IL-6Rα, or enhance endogenous shedding mechanisms causing the increase of sIL-6R level. Here we hypothesise that bacteria promoting shedding and increase the sIL-6R level can be an important contributing factor for the development of cytokine storms. Therefore, inhibition of IL-6Rα shedding by drastically reducing the number of relevant bacteria may be a critical element in reducing the chance of a cytokine storm. Validation of this hypothesis can support the consideration of the prophylactic use of antibiotics more widely and at an earlier stage of infection to decrease the mortality rate of COVID-19.

scholarly journals Cytokine Storm, Corticosteroids and İnterleukin-6 Receptor Antibodies in Context of Antiinflammatory Treatment in COVID-19

2020 ◽  
pp. 67-75
Author(s):  
Ozgur Karcioglu ◽  
Goksu Afacan ◽  
Bilgen Ozkaya ◽  
Ebru Yilmaz ◽  
Eylem Ersan ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Viral Infections ◽  
Signs And Symptoms ◽  
Clinical Findings ◽  
Rapid Progression ◽  
Cytokine Storm ◽  
Inflammatory Status ◽  
Interleukin 6 Receptor ◽  
Short Time ◽  
Receptor Antibodies

It is well established that cytokine storm is associated with more severe clinical course of COVID-19. Many clinical findings of COVID-19 and other severe viral infections (e.g. fever, muscle pain, respiratory distress, cough), are directly attributed to cytokine storm. For example, IL-6 and IL-10 can be used as predictors for expedient diagnosis of patients with higher risk of deterioration. Hyper-inflammatory status in patients with severe COVID-19 is to be mitigated to alleviate signs and symptoms in cytokine storm. In case of deterioration of oxygenation and rapid progression of imaging (CT) findings, glucocorticoids can be used for a short time (3-5 days) for patients in whom overactivation of the body's inflammatory response is suspected. On the other hand, interleukin-6 receptor antibodies tocilizumab, sarilumab, siltuximab can be used as immunomodulators, to suppress inflammation and to alleviate fever and other manifestations of immune response. Their beneficial efficacy is especially remarkable during the cytokine storm period. It should be kept in mind that the agents to be used in the management of any given patient should be tailored for each situation.

scholarly journals Inducible microRNA-590-5p inhibits host antiviral response by targeting the soluble interleukin-6 (IL6) receptor

2018 ◽  
Vol 293 (47) ◽  
pp. 18168-18179 ◽  
Author(s):  
Yaqin Zhou ◽  
Zhangchuan Xia ◽  
Zhikui Cheng ◽  
Gang Xu ◽  
Xiaodan Yang ◽  
...  
Keyword(s):  
Viral Infection ◽  
Interleukin 6 ◽  
Underlying Mechanism ◽  
Antiviral Response ◽  
Type I ◽  
Interleukin 6 Receptor ◽  
Important Regulator ◽  
Membrane Bound ◽  
Host Antiviral Response

MicroRNA (miR)-590-5p has been identified as an important regulator of some signaling pathways such as cell proliferation and tumorigenesis. However, little is known about its role during viral infection. Here, we report that miR-590-5p was significantly induced by various viruses and effectively potentiated virus replication in different viral infection systems. Furthermore, miR-590-5p substantially attenuated the virus-induced expression of type I and type III interferons (IFNs) and inflammatory cytokines, resulting in impaired downstream antiviral signaling. Interleukin-6 receptor (IL6R) was identified as a target of miR-590-5p. Interestingly, the role of miR-590-5p in virus-triggered signaling was abolished in IL6R knockout cells, and this could be rescued by restoring the expression of the soluble IL6R (sIL6R) but not the membrane-bound IL6R (mIL6R), suggesting that sIL6R is indispensable for miR-590-5p in modulating the host antiviral response. Furthermore, miR-590-5p down-regulated endogenous sIL6R and mIL6R expression through a translational repression mechanism. These findings thus uncover a previously uncharacterized role and the underlying mechanism of miR-590-5p in the innate immune response to viral infection.

scholarly journals Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses

2019 ◽  
Vol 216 (9) ◽  
pp. 1986-1998 ◽  
Author(s):  
Sarah Spencer ◽  
Sevgi Köstel Bal ◽  
William Egner ◽  
Hana Lango Allen ◽  
Syed I. Raza ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Interleukin 6 ◽  
Inflammatory Responses ◽  
Recurrent Infections ◽  
Potential Toxicity ◽  
Inflammatory Conditions ◽  
Genes Encoding ◽  
Interleukin 6 Receptor ◽  
Homozygous Mutations ◽  
Toxicity Of Drugs

IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R. We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.

scholarly journals Interleukin 6 in inflammation, autoimmunity and cancer

2020 ◽  
Author(s):  
Toshio Hirano
Keyword(s):  
Chronic Inflammation ◽  
Immune Cells ◽  
Positive Feedback ◽  
Interleukin 6 ◽  
Feedback Loop ◽  
Inflammatory Responses ◽  
Virus Disease ◽  
Cytokine Storm ◽  
Necrosis Factor Alpha ◽  
Positive Feedback Loop

Abstract Interleukin 6 (IL-6) is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune cells and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is a NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6–STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6–STAT3 axis is a critical target for treating diseases.

scholarly journals In vitro selection of an RNA aptamer yields an interleukin-6/interleukin-6 receptor interaction inhibitor

2021 ◽  
Author(s):  
Takehiro Ando ◽  
Mizuki Yamamoto ◽  
Yukio Takamori ◽  
Keita Tsukamoto ◽  
Daisuke Fuji ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
In Vitro Selection ◽  
Receptor Interaction ◽  
Rna Aptamer ◽  
Cytokine Storm ◽  
Interleukin 6 Receptor ◽  
Systematic Evolution ◽  
Exponential Enrichment ◽  
Selection Of

ABSTRACT Interleukin-6 (IL-6) binds to IL-6 receptor (IL-6R) subunit, related to autoimmune diseases and cytokine storm in COVID-19. In this study we performed Systematic Evolution of Ligands by Exponential enrichment (SELEX) and identified a novel RNA aptamer. This RNA aptamer not only bound to IL-6R with a dissociation constant of 200 nM, but also inhibited the interaction of IL-6R with IL-6.

scholarly journals Interleukin-6 receptor genetic variation and tocilizumab treatment response to COVID-19

2021 ◽  
Author(s):  
Ammar Ali Almarzooq
Keyword(s):  
Genetic Variation ◽  
Interleukin 6 ◽  
Treatment Efficacy ◽  
European Ancestry ◽  
Asian Populations ◽  
Inflammatory Conditions ◽  
African Populations ◽  
Interleukin 6 Receptor ◽  
Membrane Bound ◽  
Sub Saharan

ABSTRACTInterleukin-6 receptor (IL6R) stimulates the inflammatory pathways as part of the acute-phase response to infection. Tocilizumab is a monoclonal antibody that inhibits both membrane-bound and soluble IL6R and is used to treat inflammatory conditions, including COVID-19. Despite the disproportionate incidence of COVID-19 among underserved, racial, and ethnic minority populations, the efficacy of tocilizumab in hospitalized COVID-19 patients from these populations is unclear. In this work, three genetic markers for the IL6R gene were analyzed across diverse ethnic backgrounds to identify population differences in response to tocilizumab treatment. Genetic structure analyses showed that African populations were significantly different from other described populations. In addition, mapped frequencies of these alleles showed that Sub-Saharan African populations were 3.4x more likely to show an impaired response to tocilizumab than East Asian populations, and 1.8x more likely than European ancestry populations. Existing IL6R genotype results may identify populations at increased therapeutic failure risk. As results from current clinical trials on the efficacy of tocilizumab treatment for extreme COVID-19 infections are conflicting, more studies are needed across diverse patient backgrounds to better understand the genetic factors necessary to predict treatment efficacy. This work demonstrates how pharmacogenomics studies can elucidate genetic variation on treatment efficacy on COVID-19.

scholarly journals Use of tocilizumab in the combination treatment of a COVID-19 patient with concomitant rheumatoid arthritis (a case report)

2021 ◽  
Vol 23 (5) ◽  
pp. 739-748
Author(s):  
V. A. Vizir ◽  
A. S. Sadomov ◽  
O. V. Demidenko
Keyword(s):  
Rheumatoid Arthritis ◽  
Monoclonal Antibody ◽  
Combination Treatment ◽  
Interleukin 6 ◽  
Clinical Case ◽  
Clinical Laboratory ◽  
Cytokine Storm ◽  
X Ray ◽  
Interleukin 6 Receptor ◽  
Receptor Monoclonal Antibody

The aim is to familiarize practitioners with the clinical case of tocilizumab use in the combination treatment of the coronavirus disease (COVID-19) patient with concomitant rheumatoid arthritis. Materials and methods. The clinical case shows our own follow-up of COVID-19 clinical course in the patient with concomitant rheumatoid arthritis during combination treatment with the use of a recombinant humanized anti-interleukin-6 receptor monoclonal antibody tocilizumab. Results. The patient with a severe COVID-19 course, whose examination and treatment results are given in the article, was comorbid for rheumatoid arthritis. The cytokine storm development at the hospital stage was confirmed by an increase in markers of systemic inflammation: C-reactive protein, D-dimer, fibrinogen, an almost 50-fold increase in serum interleukin-6 level, as well as absolute and relative lymphocytopenia. Despite the anti-inflammatory therapy administered with systemic corticosteroids, the patient’s condition progressively worsened. After assessing the indications and contraindications, it was decided to use the interleukin-6 receptor inhibitor tocilizumab, followed by rapid clinical, laboratory and X-ray positive response to the treatment. The understanding of tocilizumab use in patients with COVID-19 at the current stage was formed based on the comparative analysis of our own clinical case data and the results of relevant clinical trials, world recommendations and guidelines. Conclusions. The use of recombinant humanized anti-interleukin-6 receptor monoclonal antibody tocilizumab in the combination treatment of severe COVID-19 with concomitant rheumatoid arthritis is pathogenetically based and decreases the main clinical and laboratory signs of cytokine storm, respiratory failure, improves chest x-ray findings and reduces the length of hospital stay. Further large randomized placebo-controlled trials including the population of patients with various comorbid conditions are needed to clarify conclusively the place and role of anti-cytokine drugs in the treatment of COVID-19 patients.

Membrane-bound and Soluble Interleukin-6 Receptor: Studies on Structure, Regulation of Expression, and Signal Transductiona

2006 ◽  
Vol 762 (1) ◽  
pp. 222-237 ◽  
Author(s):  
PETER C. HEINRICH ◽  
LUTZ GRAEVE ◽  
STEFAN ROSE-JOHN ◽  
JENS SCHNEIDER-MERGENER ◽  
ELKE DITTRICH ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Regulation Of Expression ◽  
Interleukin 6 Receptor ◽  
Membrane Bound ◽  
Structure Regulation

scholarly journals In Silico Studies on Psilocybin Drug Derivatives Against SARS-CoV-2 and Cytokine Storm of Human Interleukin-6 Receptor

2022 ◽  
Vol 12 ◽  
Author(s):  
Faez Iqbal Khan ◽  
Fakhrul Hassan ◽  
Dakun Lai
Keyword(s):  
Free Energy ◽  
Structural Dynamics ◽  
Interleukin 6 ◽  
In Silico ◽  
Chemotherapeutic Agents ◽  
Cytokine Storm ◽  
Anticancer Properties ◽  
In Silico Studies ◽  
Interleukin 6 Receptor ◽  
Different Sources

Various metabolites identified with therapeutic mushrooms have been found from different sources and are known to have antibacterial, antiviral, and anticancer properties. Over thousands soil growth-based mushroom metabolites have been discovered, and utilized worldwide to combat malignancy. In this study, psilocybin-mushroom that contains the psychedelic compounds such as psilacetin, psilocin, and psilocybine were screened and found to be inhibitors of SARS-CoV-2 Mprotease. It has been found that psilacetin, psilocin, and psilocybine bind to Mprotease with −6.0, −5.4, and −5.8 kcal/mol, respectively. Additionally, the psilacetin was found to inhibit human interleukin-6 receptors to reduce cytokine storm. The binding of psilacetin to Mprotease of SARS-CoV-2 and human interleukin-6 receptors changes the structural dynamics and Gibbs free energy patterns of proteins. These results suggested that psilocybin-mushroom could be utilized as viable potential chemotherapeutic agents for SARS-CoV-2.

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