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McNeela EA Burke A Neill DR Baxter C Fernandes VE Ferreira D Smeaton S El-Rachkidy R McLoughlin RM Mori A Moran B Fitzgerald KA Tschopp J Pétrilli V Andrew PW Kadioglu A Lavelle EC 《PLoS pathogens》2010,6(11):e1001191
Pneumolysin (PLY) is a key Streptococcus pneumoniae virulence factor and potential candidate for inclusion in pneumococcal subunit vaccines. Dendritic cells (DC) play a key role in the initiation and instruction of adaptive immunity, but the effects of PLY on DC have not been widely investigated. Endotoxin-free PLY enhanced costimulatory molecule expression on DC but did not induce cytokine secretion. These effects have functional significance as adoptive transfer of DC exposed to PLY and antigen resulted in stronger antigen-specific T cell proliferation than transfer of DC exposed to antigen alone. PLY synergized with TLR agonists to enhance secretion of the proinflammatory cytokines IL-12, IL-23, IL-6, IL-1β, IL-1α and TNF-α by DC and enhanced cytokines including IL-17A and IFN-γ by splenocytes. PLY-induced DC maturation and cytokine secretion by DC and splenocytes was TLR4-independent. Both IL-17A and IFN-γ are required for protective immunity to pneumococcal infection and intranasal infection of mice with PLY-deficient pneumococci induced significantly less IFN-γ and IL-17A in the lungs compared to infection with wild-type bacteria. IL-1β plays a key role in promoting IL-17A and was previously shown to mediate protection against pneumococcal infection. The enhancement of IL-1β secretion by whole live S. pneumoniae and by PLY in DC required NLRP3, identifying PLY as a novel NLRP3 inflammasome activator. Furthermore, NLRP3 was required for protective immunity against respiratory infection with S. pneumoniae. These results add significantly to our understanding of the interactions between PLY and the immune system. 相似文献
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Zbinden KG Obst-Sander U Hilpert K Kühne H Banner DW Böhm HJ Stahl M Ackermann J Alig L Weber L Wessel HP Riederer MA Tschopp TB Lavé T 《Bioorganic & medicinal chemistry letters》2005,15(23):5344-5352
We describe the structure-based design and synthesis of highly potent, orally bioavailable tissue factor/factor VIIa inhibitors which interfere with the coagulation cascade by selective inhibition of the extrinsic pathway. 相似文献
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In the frame of the largest French project of artificial production reefs, initiated by the city of Marseilles in 2001, the present study aimed at describing the hydrodynamic pattern of the coastal area considered, by the use of a 3D numerical modelling. Results were local wind statistics, bottom current fields and drifting particle maps. The knowledge of the hydrodynamic connexions between particle (such as larvae) sources or targeted areas linked to the reefs, allows us to explain the success or failure of the reefs' colonizing. Moreover, the study confirms the wind spatial variability and demonstrates the error resulting from the use of an average but locally absent wind direction. 相似文献
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Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival 总被引:19,自引:0,他引:19
Many pathogenic organisms produce pore-forming toxins as virulence factors. Target cells however mount a response to such membrane damage. Here we show that toxin-induced membrane permeabilization leads to a decrease in cytoplasmic potassium, which promotes the formation of a multiprotein oligomeric innate immune complex, called the inflammasome, and the activation of caspase-1. Further, we find that when rendered proteolytic in this context caspase-1 induces the activation of the central regulators of membrane biogenesis, the Sterol Regulatory Element Binding Proteins (SREBPs), which in turn promote cell survival upon toxin challenge possibly by facilitating membrane repair. This study highlights that, in addition to its well-established role in triggering inflammation via the processing of the precursor forms of interleukins, caspase-1 has a broader role, in particular linking the intracellular ion composition to lipid metabolic pathways, membrane biogenesis, and survival. 相似文献
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Cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) was originally identified as an inhibitor of death-receptor signalling through competition with caspase-8 for recruitment to FAS-associated via death domain (FADD). More recently, it has been determined that both cFLIP and caspase-8 are required for the survival and proliferation of T cells following T-cell-receptor stimulation. This paradoxical finding launched new investigations of how these molecules might connect with signalling pathways that link to cell survival and growth following antigen-receptor activation. As discussed in this Review, insight gained from these studies indicates that cFLIP and caspase-8 form a heterodimer that ultimately links T-cell-receptor signalling to activation of nuclear factor-kappaB through a complex that includes B-cell lymphoma 10 (BCL-10), mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1) and receptor-interacting protein 1 (RIP1). 相似文献
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Rebuma Firdessa Rea Tschopp Alehegne Wubete Melaku Sombo Elena Hailu Girume Erenso Teklu Kiros Lawrence Yamuah Martin Vordermeier R. Glyn Hewinson Douglas Young Stephen V. Gordon Mesfin Sahile Abraham Aseffa Stefan Berg 《PloS one》2012,7(12)