scholarly journals Toll-Like Receptor 4-Mediated Activation of p38 Mitogen-Activated Protein Kinase Is a Determinant of Respiratory Virus Entry and Tropism

2010 ◽  
Vol 84 (21) ◽  
pp. 11359-11373 ◽  
Author(s):  
David Marchant ◽  
Gurpreet K. Singhera ◽  
Soraya Utokaparch ◽  
Tillie L. Hackett ◽  
John H. Boyd ◽  
...  
Keyword(s):  
Influenza Virus ◽  
P38 Mapk ◽  
Respiratory Virus ◽  
Respiratory Viruses ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Virus Infections ◽  
Toll Like Receptor 4 ◽  
Mitogen Activated Protein ◽  
Respiratory Virus Infections

ABSTRACT Respiratory viruses exert a heavy toll of morbidity and mortality worldwide. Despite this burden there are few specific treatments available for respiratory virus infections. Since many viruses utilize host cell enzymatic machinery such as protein kinases for replication, we determined whether pharmacological inhibition of kinases could, in principle, be used as a broad antiviral strategy for common human respiratory virus infections. A panel of green fluorescent protein (GFP)-expressing recombinant respiratory viruses, including an isolate of H1N1 influenza virus (H1N1/Weiss/43), was used to represent a broad range of virus families responsible for common respiratory infections (Adenoviridae, Paramyxoviridae, Picornaviridae, and Orthomyxoviridae). Kinase inhibitors were screened in a high-throughput assay that detected virus infection in human airway epithelial cells (1HAEo-) using a fluorescent plate reader. Inhibition of p38 mitogen-activated protein kinase (MAPK) signaling was able to significantly inhibit replication by all viruses tested. Therefore, the pathways involved in virus-mediated p38 and extracellular signal-regulated kinase (ERK) MAPK activation were investigated using bronchial epithelial cells and primary fibroblasts derived from MyD88 knockout mouse lungs. Influenza virus, which activated p38 MAPK to approximately 10-fold-greater levels than did respiratory syncytial virus (RSV) in 1HAEo- cells, was internalized about 8-fold faster and more completely than RSV. We show for the first time that p38 MAPK is a determinant of virus infection that is dependent upon MyD88 expression and Toll-like receptor 4 (TLR4) ligation. Imaging of virus-TLR4 interactions showed significant clustering of TLR4 at the site of virus-cell interaction, triggering phosphorylation of downstream targets of p38 MAPK, suggesting the need for a signaling receptor to activate virus internalization.

scholarly journals COVID-19 mitigation strategies were associated with decreases in other respiratory virus infections

2021 ◽  
Author(s):  
Sinha Pranay ◽  
Katherine Reifler ◽  
Michael Rossi ◽  
Manish Sagar
Keyword(s):  
Respiratory Virus ◽  
Respiratory Infections ◽  
Respiratory Viruses ◽  
Mitigation Strategies ◽  
Virus Infections ◽  
Time Period ◽  
Viral Respiratory Infections ◽  
Respiratory Virus Infections ◽  
Viral Respiratory

Abstract Detection of diverse respiratory viruses in Boston was around 80% lower after practices were instituted to limit COVID-19 spread compared to the same time period during the previous five years. Continuing the strategies that lower COVID-19 dissemination may be useful in decreasing the incidence of other viral respiratory infections.

scholarly journals Endotoxin Tolerance Inhibits Lyn and c-Src Phosphorylation and Association with Toll-Like Receptor 4 but Increases Expression and Activity of Protein Phosphatases

2015 ◽  
Vol 8 (2) ◽  
pp. 171-184 ◽  
Author(s):  
Yanbao Xiong ◽  
Michael Murphy ◽  
Tissa T. Manavalan ◽  
Goutham Pattabiraman ◽  
Fu Qiu ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Protein Phosphatase ◽  
Tyrosine Phosphatase ◽  
Endotoxin Tolerance ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Mitogen Activated Protein ◽  
Ptp 1B

Endotoxin tolerance protects the host by limiting excessive 'cytokine storm' during sepsis, but compromises the ability to counteract infections in septic shock survivors. It reprograms Toll-like receptor (TLR) 4 responses by attenuating the expression of proinflammatory cytokines without suppressing anti-inflammatory and antimicrobial mediators, but the mechanisms of reprogramming remain unclear. In this study, we demonstrate that the induction of endotoxin tolerance in human monocytes, THP-1 and MonoMac-6 cells inhibited lipopolysaccharide (LPS)-mediated phosphorylation of Lyn, c-Src and their recruitment to TLR4, but increased total protein phosphatase (PP) activity and the expression of protein tyrosine phosphatase (PTP) 1B, PP2A, PTP nonreceptor type (PTPN) 22 and mitogen-activated protein kinase phosphatase (MKP)-1. Chemical PP inhibitors, okadaic acid, dephostatin and cantharidic acid markedly decreased or completely abolished LPS tolerance, indicating the importance of phosphatases in endotoxin tolerization. Overexpression of PTPN22 decreased LPS-mediated nuclear factor (NF)-κB activation, p38 phosphorylation and CXCL8 gene expression, while PTPN22 ablation upregulated LPS-induced p65 NF-κB and p38 phosphorylation and the expression of TNF-a and pro-IL-1ß mRNA, indicating PTPN22 as an inhibitor of TLR4 signaling. Thus, LPS tolerance interferes with TLR4 signaling by inhibiting Lyn and c-Src phosphorylation and their recruitment to TLR4, while increasing the phosphatase activity and expression of PP2A, PTPN22, PTP1B and MKP1.

scholarly journals Inhibition of LPS-Induced Activation of Coagulation by p38 MAPK Inhibitor

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Lutz Koch ◽  
Stefan Hofer ◽  
Markus A. Weigand ◽  
David Frommhold ◽  
Johannes Poeschl ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Sandwich Elisa ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Inhibitory Effects ◽  
Coagulation Activation ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

During Gram-negative sepsis, lipopolysaccharide (LPS) activates toll-like receptor (TLR) 4 and induces complex responses of immune system and coagulation. However, the underlying LPS signalling mechanism on coagulation activation remains complex. To determine the role of the intracellular signalling factors p38 mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), and c-Jun N-terminal kinase (JNK) in the procoagulant response to LPS, coagulation process of human whole blood exposed to specific inhibitors was measured by thrombelastography. Samples were stimulated with LPS (100 μg/mL) after preincubation with BAY117082 (specific NF-κB inhibitor), SP600125 (specific JNK inhibitor), SB203580 (specific p38 MAPK inhibitor), or vehicle. SB203580 strongly inhibited LPS-induced coagulation activation, whereas BAY117082 and SP600125 showed no significant effect. Activation of p38 MAPK, NF-κB, and JNK and respective inhibitory effects were confirmed by Multi-Target Sandwich ELISA. In conclusion, activation of p38 MAPK is crucial for early LPS-induced activation of coagulation.

scholarly journals The anti-inflammatory effect and potential mechanism of cardamonin in DSS-induced colitis

2015 ◽  
Vol 309 (7) ◽  
pp. G517-G527 ◽  
Author(s):  
Gaiyan Ren ◽  
Aning Sun ◽  
Chao Deng ◽  
Jingjing Zhang ◽  
Xiaojun Wu ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Protein Kinase ◽  
Bowel Disease ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Mitogen Activated Protein ◽  
Inflammatory Bowel

Cardamonin is a naturally occurring chalcone with strong anti-inflammatory activity. However, the direct effect of cardamonin on intestinal inflammation remains elusive. In the present study, we found that cardamonin markedly ameliorated dextran sulfate sodium-induced mouse body weight loss, diarrhea, colon shortening, spleen swelling, and histological damage, which correlated with a decline in the activity of myeloperoxidase and the production of nitric oxide, tumor necrosis factor-α and interleukin-6 in the colon. The upregulation of toll-like receptor 4 after dextran sulfate sodium treatment was associated with an increase in the activation of myeloid differentiation factor 88, interleukin-1 receptor-associated kinase-1, nuclear factor-κB (NF-κB) p65, inhibitor κBα, and inhibitor κB kinase-α/β, as well as the mitogen-activated protein kinase molecules of extracellular signal-regulated kinase and c-Jun NH2-terminal kinase, and this upregulation was reversed by cardamonin administration. Moreover, cardamonin blocked the nuclear translocation of NF-κB p65, inhibited NF-κB-luciferase activity, and downregulated NF-κB target genes expression. The present study clearly demonstrates a beneficial effect of cardamonin on experimental inflammatory bowel disease via a mechanism associated with suppression of toll-like receptor 4 expression and inactivation of NF-κB and mitogen-activated protein kinase pathways. This study may give insight into the further evaluation of the therapeutic potential of cardamonin or its derivatives for human inflammatory bowel disease.

scholarly journals Sex differences in innate anti-viral immune responses to respiratory viruses and in their clinical outcomes in a birth cohort study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eteri Regis ◽  
Sara Fontanella ◽  
Lijing Lin ◽  
Rebecca Howard ◽  
Sadia Haider ◽  
...  
Keyword(s):  
Sex Differences ◽  
Immune Responses ◽  
Birth Cohort ◽  
Respiratory Virus ◽  
Respiratory Infections ◽  
Respiratory Viruses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Virus Infections ◽  
Respiratory Virus Infections

AbstractThe mechanisms explaining excess morbidity and mortality in respiratory infections among males are poorly understood. Innate immune responses are critical in protection against respiratory virus infections. We hypothesised that innate immune responses to respiratory viruses may be deficient in males. We stimulated peripheral blood mononuclear cells from 345 participants at age 16 years in a population-based birth cohort with three live respiratory viruses (rhinoviruses A16 and A1, and respiratory syncytial virus) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2) and investigated sex differences in interferon (IFN) responses. IFN-α responses to all viruses and stimuli were 1.34–2.06-fold lower in males than females (P = 0.018 −  < 0.001). IFN-β, IFN-γ and IFN-induced chemokines were also deficient in males across all stimuli/viruses. Healthcare records revealed 12.1% of males and 6.6% of females were hospitalized with respiratory infections in infancy (P = 0.017). In conclusion, impaired innate anti-viral immunity in males likely results in high male morbidity and mortality from respiratory virus infections.

scholarly journals Nfa34810 Facilitates Nocardia farcinica Invasion of Host Cells and Stimulates Tumor Necrosis Factor Alpha Secretion through Activation of the NF-κB and Mitogen-Activated Protein Kinase Pathways via Toll-Like Receptor 4

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Xingzhao Ji ◽  
Xiujuan Zhang ◽  
Heqiao Li ◽  
Lina Sun ◽  
Xuexin Hou ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Host Cells ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The mechanism underlying the pathogenesis of Nocardia is not fully known. The Nfa34810 protein of Nocardia farcinica has been predicted to be a virulence factor. However, relatively little is known regarding the interaction of Nfa34810 with host cells, specifically invasion and innate immune activation. In this study, we aimed to determine the role of recombinant Nfa34810 during infection. We demonstrated that Nfa34810 is an immunodominant protein located in the cell wall. Nfa34810 protein was able to facilitate the uptake and internalization of latex beads coated with Nfa34810 protein into HeLa cells. Furthermore, the deletion of the nfa34810 gene in N. farcinica attenuated the ability of the bacteria to infect both HeLa and A549 cells. Moreover, stimulation with Nfa34810 triggered macrophages to produce tumor necrosis factor alpha (TNF-α), and it also activated mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways by inducing the phosphorylation of ERK1/2, p38, JNK, p65, and AKT in macrophages. Specific inhibitors of ERK1/2, JNK, and NF-κB significantly reduced the expression of TNF-α, which demonstrated that Nfa34810-mediated TNF-α production was dependent upon the activation of these kinases. We further found that neutralizing antibodies against Toll-like receptor 4 (TLR4) significantly inhibited TNF-α secretion. Taken together, our results indicated that Nfa34810 is a virulence factor of N. farcinica and plays an important role during infection. Nfa34810-induced production of TNF-α in macrophages also involves ERK, JNK, and NF-κB via the TLR4 pathway.

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