scholarly journals mRNA-lncRNA Co-Expression Network Analysis Reveals the Role of lncRNAs in Immune Dysfunction during Severe SARS-CoV-2 Infection

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 402
Author(s):  
Sumit Mukherjee ◽  
Bodhisattwa Banerjee ◽  
David Karasik ◽  
Milana Frenkel-Morgenstern
Keyword(s):  
Network Analysis ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Lavage Fluid ◽  
Cytokine Signaling ◽  
Respiratory Disorder ◽  
Cytokine Storm ◽  
Global Public Health ◽  
Aberrant Expression

The recently emerged SARS-CoV-2 virus is responsible for the ongoing COVID-19 pandemic that has rapidly developed into a global public health threat. Patients severely affected with COVID-19 present distinct clinical features, including acute respiratory disorder, neutrophilia, cytokine storm, and sepsis. In addition, multiple pro-inflammatory cytokines are found in the plasma of such patients. Transcriptome sequencing of different specimens obtained from patients suffering from severe episodes of COVID-19 shows dynamics in terms of their immune responses. However, those host factors required for SARS-CoV-2 propagation and the underlying molecular mechanisms responsible for dysfunctional immune responses during COVID-19 infection remain elusive. In the present study, we analyzed the mRNA-long non-coding RNA (lncRNA) co-expression network derived from publicly available SARS-CoV-2-infected transcriptome data of human lung epithelial cell lines and bronchoalveolar lavage fluid (BALF) from COVID-19 patients. Through co-expression network analysis, we identified four differentially expressed lncRNAs strongly correlated with genes involved in various immune-related pathways crucial for cytokine signaling. Our findings suggest that the aberrant expression of these four lncRNAs can be associated with cytokine storms and anti-viral responses during severe SARS-CoV-2 infection of the lungs. Thus, the present study uncovers molecular interactions behind the cytokine storm activation potentially responsible for hyper-inflammatory responses in critical COVID-19 patients.

scholarly journals Lung biopsy cells transcriptional landscape from COVID-19 patient stratified lung injury in SARS-CoV-2 infection through impaired pulmonary surfactant metabolism

2020 ◽  
Author(s):  
Abul Bashar Mir Md. Khademul Islam ◽  
Md. Abdullah-Al-Kamran Khan
Keyword(s):  
Gene Expression ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Biopsy ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Gene Expression Pattern ◽  
Viral Proteins ◽  
Cytokine Signaling ◽  
Surfactant Metabolism

AbstractClinical management of COVID-19 is still complicated due to the lack of therapeutic interventions to reduce the breathing problems, respiratory complications and acute lung injury – which are the major complications of most of the mild to critically affected patients and the molecular mechanisms behind these clinical features are still largely unknown. In this study, we have used the RNA-seq gene expression pattern in the COVID-19 affected lung biopsy cells and compared it with the effects observed in typical cell lines infected with SARS-CoV-2 and SARS-CoV. We performed functional overrepresentation analyses using these differentially expressed genes to signify the processes/pathways which could be deregulated during SARS-CoV-2 infection resulting in the symptomatic impairments observed in COVID-19. Our results showed that the significantly altered processes include inflammatory responses, antiviral cytokine signaling, interferon responses, and interleukin signaling etc. along with downmodulated processes related to lung’s functionality like-responses to hypoxia, lung development, respiratory processes, cholesterol biosynthesis and surfactant metabolism. We also found that the viral protein interacting host’s proteins involved in similar pathways like: respiratory failure, lung diseases, asthma, and hypoxia responses etc., suggesting viral proteins might be deregulating the processes related to acute lung injury/breathing complications in COVID-19 patients. Protein-protein interaction networks of these processes and map of gene expression of deregulated genes revealed that several viral proteins can directly or indirectly modulate the host genes/proteins of those lung related processes along with several host transcription factors and miRNAs. Surfactant proteins and their regulators SPD, SPC, TTF1 etc. which maintains the stability of the pulmonary tissue are found to be downregulated through viral NSP5, NSP12 that could lead to deficient gaseous exchange by the surface films. Mitochondrial dysfunction owing to the aberration of NDUFA10, NDUFAF5, SAMM50 etc. by NSP12; abnormal thrombosis in lungs through atypical PLAT, EGR1 functions by viral ORF8, NSP12; dulled hypoxia responses due to unusual shift in HIF-1 downstream signaling might be the causative elements behind the acute lung injury in COVID-19 patients. Our study put forward a distinct mechanism of probable virus induced lung damage apart from cytokine storm and advocate the need of further research for alternate therapy in this direction.

Mechanisms by which fatty acids regulate leucocyte function

2007 ◽  
Vol 113 (2) ◽  
pp. 65-77 ◽  
Author(s):  
Thais Martins de Lima ◽  
Renata Gorjão ◽  
Elaine Hatanaka ◽  
Maria Fernanda Cury-Boaventura ◽  
Erica Paula Portioli Silva ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Substantial Improvement ◽  
Lipid Mediators ◽  
Control Of Gene Expression ◽  
Intracellular Signalling Pathways ◽  
Activation Of Transcription ◽  
Associated Proteins

Fatty acids (FAs) have been shown to alter leucocyte function and thus to modulate inflammatory and immune responses. In this review, the effects of FAs on several aspects of lymphocyte, neutrophil and macrophage function are discussed. The mechanisms by which FAs modulate the production of lipid mediators, activity of intracellular signalling pathways, activity of lipid-raft-associated proteins, binding to TLRs (Toll-like receptors), control of gene expression, activation of transcription factors, induction of cell death and production of reactive oxygen and nitrogen species are described in this review. The rationale for the use of specific FAs to treat patients with impaired immune function is explained. Substantial improvement in the therapeutic usage of FAs or FA derivatives may be possible based on an improvement in the understanding of the precise molecular mechanisms of action with respect to the different leucocyte types and outcome with respect to the inflammatory responses.

scholarly journals Silibinin and SARS-CoV-2: Dual Targeting of Host Cytokine Storm and Virus Replication Machinery for Clinical Management of COVID-19 Patients

2020 ◽  
Vol 9 (6) ◽  
pp. 1770 ◽  
Author(s):  
Joaquim Bosch-Barrera ◽  
Begoña Martin-Castillo ◽  
Maria Buxó ◽  
Joan Brunet ◽  
José Antonio Encinar ◽  
...  
Keyword(s):  
Virus Replication ◽  
Drug Candidate ◽  
Cytokine Signaling ◽  
Central Component ◽  
Cytokine Storm ◽  
Global Public Health ◽  
Replication Machinery ◽  
Open Label ◽  
Open Label Phase ◽  
Novel Coronavirus

COVID-19, the illness caused by infection with the novel coronavirus SARS-CoV-2, is a rapidly spreading global pandemic in urgent need of effective treatments. Here we present a comprehensive examination of the host- and virus-targeted functions of the flavonolignan silibinin, a potential drug candidate against COVID-19/SARS-CoV-2. As a direct inhibitor of STAT3—a master checkpoint regulator of inflammatory cytokine signaling and immune response—silibinin might be expected to phenotypically integrate the mechanisms of action of IL-6-targeted monoclonal antibodies and pan-JAK1/2 inhibitors to limit the cytokine storm and T-cell lymphopenia in the clinical setting of severe COVID-19. As a computationally predicted, remdesivir-like inhibitor of RNA-dependent RNA polymerase (RdRp)—the central component of the replication/transcription machinery of SARS-CoV-2—silibinin is expected to reduce viral load and impede delayed interferon responses. The dual ability of silibinin to target both the host cytokine storm and the virus replication machinery provides a strong rationale for the clinical testing of silibinin against the COVID-19 global public health emergency. A randomized, open-label, phase II multicentric clinical trial (SIL-COVID19) will evaluate the therapeutic efficacy of silibinin in the prevention of acute respiratory distress syndrome in moderate-to-severe COVID-19-positive onco-hematological patients at the Catalan Institute of Oncology in Catalonia, Spain.

scholarly journals Cytokines mediated hyperinflammation in SARS-CoV2: An Overview

2020 ◽  
Vol 1 (supplement) ◽  
pp. 7
Author(s):  
Liaqat Ali
Keyword(s):  
Middle East ◽  
Severe Acute Respiratory Syndrome ◽  
Immune Responses ◽  
T Lymphocyte ◽  
Lymphoid Tissue ◽  
Inflammatory Responses ◽  
Cytokine Storm ◽  
Host Immune Responses ◽  
Lymphocyte Responses

Hyperinflammation induced by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV2) is a major cause of disease severity and mortality in infected patients. The immunopathogenesis of SARS-CoV2 infection is similar to the previous Middle East Respiratory Syndrome-related coronavirus (MERS-CoV) and SARS-CoV coronavirus with severe inflammatory responses. Therefore, severity of this viral infection is not only associated with the virus but also due to host immune responses. Hyperinflammatory responses due to cytokine storm are a centerpiece of SARS-CoV2 pathogenesis with overwhelming consequences for the host. Virus infected monocyte derived macrophages produce cytokines and this contributes to damage of lymphoid tissue and limits the lymphocyte responses. Blocking the deadly cytokine storm and T lymphocyte stimulation is a vital defense for treating SARS-CoV2. Here, we will describe the role of hyperinflamation and the involvement of cytokines in severe SARS-CoV2 infection.

scholarly journals Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6

2008 ◽  
Vol 205 (5) ◽  
pp. 1077-1086 ◽  
Author(s):  
Fabiana S. Machado ◽  
Lísia Esper ◽  
Alexandra Dias ◽  
Rajat Madan ◽  
YuanYuan Gu ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Proteasomal Degradation ◽  
Innate Immune ◽  
Cytokine Signaling ◽  
Immune Signaling ◽  
Innate Immune Signaling

Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key counterregulatory roles during infection. The molecular mechanisms underlying LX-mediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2–dependent ubiquitinylation and proteasome-mediated degradation of TNF receptor–associated factor (TRAF) 2 and TRAF6, which are adaptor molecules that couple TNF and interleukin-1 receptor/Toll-like receptor family members to intracellular signaling events. LX-mediated degradation of TRAF6 inhibits proinflammatory cytokine production by dendritic cells. This restraint of innate immune signaling can be ablated by inhibition of proteasome function. In vivo, this leads to dysregulated immune responses, accompanied by increased mortality during infection. Proteasomal degradation of TRAF6 is a central mechanism underlying LX-driven immune counterregulation, and a hitherto unappreciated mechanism of action of ASA. These findings suggest a new molecular target for drug development for diseases marked by dysregulated inflammatory responses.

scholarly journals Reduced inflammatory responses to SARS-CoV-2 infection in children presenting to hospital with COVID19 in China

2020 ◽  
Author(s):  
Guoqing Qian ◽  
Yong Zhang ◽  
Yang Xu ◽  
Weihua Hu ◽  
Ian P Hall ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Immune Responses ◽  
Tumour Necrosis Factor ◽  
Proinflammatory Cytokines ◽  
Tumour Necrosis ◽  
Inflammatory Responses ◽  
Severe Disease ◽  
Hubei Province ◽  
Cytokine Storm ◽  
Necrosis Factor

SummaryBackgroundInfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children is associated with better outcomes than in adults. The inflammatory response to COVID-19 infection in children remains poorly characterised.MethodsWe retrospectively analysed the medical records of 127 laboratory-confirmed COVID-19 patients aged 1 month to 16 years from Wuhan and Jingzhou of Hubei Province. Patients presented between January 25th and March 24th 2020. Information on clinical features, laboratory results, plasma cytokines/chemokines and lymphocyte subsets were analysed.FindingsChildren admitted to hospital with COVID-19 were more likely to be male (67.7%) and the median age was 7.3 [IQR 4.9] years. All but one patient with severe disease was aged under 2 and the majority (5/7) had significant co-morbidities. Despite 53% having viral pneumonia on CT scanning only 2 patients had low lymphocyte counts and no differences were observed in the levels of plasma proinflammatory cytokines, including interleukin (IL)-2, IL-4, IL-6, tumour necrosis factor (TNF)-α, and interferon (IFN)-γ between patients with mild, moderate or severe disease.InterpretationsWe demonstrated that the immune responses of children to COVID-19 infection is significantly different from that seen in adults. Our evidence suggests that SARS-CoV-2 does not trigger a robust inflammatory response or ‘cytokine storm’ in children with COVID-19, and this may underlie the generally better outcomes seen in children with this disease. These data also imply anti-cytokine therapies may not be effective in children with moderate COVID-19.FundingThis study was funded by National Natural Foundation of China (No. 81970653).Research in contextEvidence before this studyWe searched PubMed without language restriction for studies published until June 25, 2020, using the search terms “SARS-CoV-2” or “novel coronavirus” or “COVID-19” and “immune responses” or “innate immunity” or “cytokine” or “subset of lymphocyte” and “children” or “adolescent”. Previously published research describes that severe and fatal cases in children are relatively rare. However, the inflammatory responses to COVID-19 infection in children remains poorly characterised.Added value of this studyWe analysed data from 127 laboratory-confirmed COVID-19 patients aged 1 month to 16 years in Hubei province to explore the immune responses to SARS-CoV-2 infection presenting to hospital with COVID-19. Cell numbers of CD3+, CD4+, CD8+ and natural killer T cells were within mostly normal limits even in more severe cases, and the levels of immunoglobulins, and proinflammatory cytokines, including interleukin (IL)-2, IL-4, IL-6, tumour necrosis factor (TNF)-α, and interferon (IFN)-γ were not generally elevated regardless of disease severity.Implications of all the available evidenceThe immune response to SARS-CoV-2 infection of children is significantly different from that seen in adults. The inflammatory responses seen even in children with viral pneumonia on CT are relatively mild and do not trigger the “cytokine storm” seen in some adults with COVID-19. This implies anti-cytokine therapies may not be effective in children with COVID-19.

scholarly journals Effect of JAK-STAT pathway in regulation of fatty liver hemorrhagic syndrome in chickens

2021 ◽  
Vol 34 (1) ◽  
pp. 143-153 ◽  
Author(s):  
Yaling Zhu ◽  
Huirong Mao ◽  
Gang Peng ◽  
Qingjie Zeng ◽  
Qing Wei ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Immune Response ◽  
Fatty Liver ◽  
Molecular Mechanisms ◽  
Laying Hens ◽  
Inflammatory Responses ◽  
Differentially Expressed ◽  
Cytokine Signaling ◽  
Tissue Destruction ◽  
Stat Pathway

Objective: To explore the molecular mechanisms of fatty liver hemorrhagic syndrome (FLHS) in laying hens, an experiment was conducted to reveal the differences in histopathological observation and gene expression between FLHS group and normal group.Methods: We compared the histopathological difference using hematoxylin and eosin staining and proceeded with RNA sequencing of adipose tissue to search differentially expressed genes and enriched biological processes and pathways. Then we validated the mRNA expression levels by real-time polymerase chain reaction and quantified protein levels in the circulation by enzyme-linked immunosorbent assay.Results: We identified 100 differentially expressed transcripts corresponding to 66 genes (DEGs) were identified between FLHS-affected group and normal group. Seven DEGs were significantly enriched in the immune response process and lipid metabolic process, including phospholipase A2 group V, WAP kunitz and netrin domain containing 2, delta 4-desaturase sphingolipid 2, perilipin 3, interleukin-6 (<i>IL-6</i>), ciliary neurotrophic factor (<i>CNTF</i>), and suppressor of cytokine signaling 3 (<i>SOCS3</i>). And these genes could be the targets of immune response and be involved in metabolic homeostasis during the process of FLHS in laying hens. Based on functional categories of the DEGs, we further proposed a model to explain the etiology and pathogenesis of FLHS. <i>IL-6</i> and <i>SOCS3</i> mediate inflammatory responses and the satiety hormone of leptin, induce dysfunction of Jak-STAT signaling pathway, leading to insulin resistance and lipid metabolic disorders. Conversely, <i>CNTF</i> may reduce tissue destruction during inflammatory attacks and confer protection from inflammation-induced insulin resistance in FLHS chickens.Conclusion: These findings highlight the therapeutic implications of targeting the JAK-STAT pathway. Inhibition of <i>IL6</i> and <i>SOCS3</i> and facilitation of <i>CNTF</i> could serve as a favorable strategy to enhance insulin action and improve glucose homoeostasis, which are of importance for treating obesity-related disorders for chickens.

Phytochemical profiles and their anti-inflammatory responses against influenza from Traditional Chinese medicine or herbs

2020 ◽  
Vol 20 ◽  
Author(s):  
Huihui Ti
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Influenza Viruses ◽  
Pharmacological Mechanism ◽  
Influenza Activity ◽  
Underlying Mechanisms ◽  
Phytochemical Profiles

: Traditional Chinese medicine (TCM) or herbs are widely used in the prevention and treatment of viral infectious diseases. However, the underlying mechanisms of TCMs remain largely obscure due to complicated material basis and multi-target therapeutics. TCMs have been reported to display anti-influenza activity associated with immunoregulatory mechanisms by enhancing host anti-influenza immune responses. Previous studies have helped us understanding the direct harm caused by the virus itself. In this review, we have tried to summarize recent progress in TCM-based anti-influenza research the indirect harmful immune responses caused by influenza viruses. In particular, the phytochemicals from TCMs responsible for molecular mechanisms of action belonging to different classes, including phenolic compounds, flavonoids, alkaloids and polysaccharides, have been identified and demonstrated. In addition, this review focuses on the pharmacological mechanism, e.g., inflammatory responses and the interferon (IFN) signaling pathway, which can provide a theoretical basis and approaches for TCM based anti-influenza treatment.

scholarly journals Vitamin D Promotes Pneumococcal Killing and Modulates Inflammatory Responses in Primary Human Neutrophils

2017 ◽  
Vol 9 (4) ◽  
pp. 375-386 ◽  
Author(s):  
Karthik Subramanian ◽  
Peter Bergman ◽  
Birgitta Henriques-Normark
Keyword(s):  
Vitamin D ◽  
Pattern Recognition ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Pattern Recognition Receptors ◽  
Human Neutrophils ◽  
Cytokine Signaling ◽  
Dependent Manner ◽  
Bacterial Killing ◽  
Tract Infections

Streptococcus pneumoniae is a major human pathogen and a leading cause of pneumonia, septicemia, and meningitis worldwide. Despite clinical studies linking vitamin D deficiency and pneumonia, molecular mechanisms behind these observations remain unclear. In particular, the effects of vitamin D on neutrophil responses remain unknown. Using pneumococcal strains, primary neutrophils isolated from human blood, and sera from patients with frequent respiratory tract infections (RTIs), we investigated the effects of vitamin D on neutrophil bactericidal and inflammatory responses, including pattern recognition receptors, antimicrobial peptides, and cytokine regulation. We found that vitamin D upregulated pattern recognition receptors, TLR2, and NOD2, and induced the antimicrobial human neutrophil peptides (HNP1-3) and LL-37, resulting in increased killing of pneumococci in a vitamin D receptor-dependent manner. Antibodies targeting HNP1-3 inhibited bacterial killing. Vitamin D supplementation of serum from patients with bacterial RTIs enhanced neutrophil killing. Moreover, vitamin D lowered inflammatory cytokine production by infected neutrophils via IL-4 production and the induction of suppressor of cytokine signaling (SOCS) proteins SOCS-1 and SOCS-3, leading to the suppression of NF-κB signaling. Thus, vitamin D enhances neutrophil killing of S. pneumoniae while dampening excessive inflammatory responses and apoptosis, suggesting that vitamin D could be used alongside antibiotics when treating pneumococcal infections.

scholarly journals Evaluation of Immunostimulant Activity and Inhibition of Cytokine Storm Activity of Proprietary Herbal Formulation Virulina®

2020 ◽  
Vol 11 (3) ◽  
pp. 10482-10492
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Cytokine Storm ◽  
Rat Serum ◽  
Storm Activity ◽  
Synthetic Drugs ◽  
Polycytidylic Acid ◽  
Factor Α

Immunostimulation is the strengthening of the immune system through the induction of non-specific immune responses. Synthetic drugs have harmful side effects, enormous costs, and are ineffectual in controlling several pathological disorders. Therefore, nowadays, herbal immunostimulants have been considered as a superior and less toxic opportunity for the management of disorders as well as their complications. The objective of the current investigation is the formulation of Virulina®-Natural Solutions (VL®-NS) polyherbal formulation and its evaluation for immunostimulant and cytokine storm inhibition activity. The immunostimulant & anti-inflammatory potential of Virulina® were determined by using in-vitro phagocytosis through polymorphonuclear analysis, indicating the invasion of leukocytes. In-vitro cytokine storm inhibitory activity was also performed using mouse macrophage cells (RAW264.7) treated with polyinosinic-polycytidylic acid to test the ability of Virulina® to attenuate the immune responses. The inflammatory responses were evaluated by the endotoxin-lipopolysaccharide (LPS) model following the endotoxin challenges of aggravating the inflammatory mediators (cytokines); thereby, the LPS derived from E. coli as antigen at a dose of 10 mgkg-1, i.p was used for the systemic inflammation. VL®-NS exhibited enhanced phagocytic efficacy at 100 mgml-1 in PMN function test. VL®-NS significantly decreases the expression of a cytokine such as interleukin-6, tumor necrosis factor-α & vascular endothelial growth factor in RAW264.7 cell culture. The increase in LPS-induced cytokine levels in rat serum was dose-dependently & significantly (p<0.05) inhibited by VL®-NS treatment. VL®-NS tend to be potent immunostimulant therapy as a superior and less toxic opportunity for the strengthening of the immune system for the management of several inflammatory disorders.

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