IbeA is an important invasion determinant contributing to Escherichia coli K1 entry into brain microvascular endothelial cells (BMEC) that is a key step in the pathogenesis of E. coli meningitis. Our previous studies ...IbeA is an important invasion determinant contributing to Escherichia coli K1 entry into brain microvascular endothelial cells (BMEC) that is a key step in the pathogenesis of E. coli meningitis. Our previous studies have shown that IbeA-induced signaling and E. coli K1 invasion is mediated by two IbeA-binding proteins, vimentin, which is constitutively present in the surface of human BMECs (HBMECs), and PSF, which is inducibly expressed in both mesenchymal (endothelium) and non-mesenchymal (epithelium) cells. However, it is unknown whether p54nrb, a PSF partner protein, could contribute to the pathogenesis of E. coli K1 meningitis. Here, we reported that a 54-kDa protein was identified by copurification with PSF through IbeA-affinity chromatography as an IbeA-binding protein, which is identical to p54nrb. Both p54nrb and PSF are RNA-binding proteins and share significant sequence homology. The specific interaction between IbeA and p54nrb was confirmed by Western blot and ligand overlay assays. Recombinant p54nrb blocked E. coli K1 invasion of human BMEC very effectively. Overexpressed p54nrb as a GFP fusion protein in the transfected 293T cells significantly enhanced E. coli K1 invasion. Furthermore, higher levels of surface p54nrb in the transfected 293T cells were detected by flow cytometry. These results suggest that the IbeA invasion protein of E. coli K1 interacts with p54nrb for bacterial invasion of human BMEC.展开更多
The human immunodeficiency virus-1(HIV-1)envelope protein gp120 is the major contributor to the pathogenesis of HIVassociated neurocognitive disorder(HAND).Neuroinflammation plays a pivotal role in gp120-induced neuro...The human immunodeficiency virus-1(HIV-1)envelope protein gp120 is the major contributor to the pathogenesis of HIVassociated neurocognitive disorder(HAND).Neuroinflammation plays a pivotal role in gp120-induced neuropathology,but how gp120 triggers neuroinflammatory processes and subsequent neuronal death remains unknown.Here,we provide evidence that NLRP3 is required for gp120-induced neuroinflammation and neuropathy.Our results showed that gp120-induced NLRP3-dependent pyroptosis and IL-1βproduction in microglia.Inhibition of microglial NLRP3 inflammasome activation alleviated gp120-mediated neuroinflammatory factor release and neuronal injury.Importantly,we showed that chronic administration of MCC950,a novel selective NLRP3 inhibitor,to gp120 transgenic mice not only attenuated neuroinflammation and neuronal death but also promoted neuronal regeneration and restored the impaired neurocognitive function.In conclusion,our data revealed that the NLRP3 inflammasome is important for gp120-induced neuroinflammation and neuropathology and suggest that NLRP3 is a potential novel target for the treatment of HAND.展开更多
文摘IbeA is an important invasion determinant contributing to Escherichia coli K1 entry into brain microvascular endothelial cells (BMEC) that is a key step in the pathogenesis of E. coli meningitis. Our previous studies have shown that IbeA-induced signaling and E. coli K1 invasion is mediated by two IbeA-binding proteins, vimentin, which is constitutively present in the surface of human BMECs (HBMECs), and PSF, which is inducibly expressed in both mesenchymal (endothelium) and non-mesenchymal (epithelium) cells. However, it is unknown whether p54nrb, a PSF partner protein, could contribute to the pathogenesis of E. coli K1 meningitis. Here, we reported that a 54-kDa protein was identified by copurification with PSF through IbeA-affinity chromatography as an IbeA-binding protein, which is identical to p54nrb. Both p54nrb and PSF are RNA-binding proteins and share significant sequence homology. The specific interaction between IbeA and p54nrb was confirmed by Western blot and ligand overlay assays. Recombinant p54nrb blocked E. coli K1 invasion of human BMEC very effectively. Overexpressed p54nrb as a GFP fusion protein in the transfected 293T cells significantly enhanced E. coli K1 invasion. Furthermore, higher levels of surface p54nrb in the transfected 293T cells were detected by flow cytometry. These results suggest that the IbeA invasion protein of E. coli K1 interacts with p54nrb for bacterial invasion of human BMEC.
基金This project was financially supported by the Key Program of the Natural Science Foundation of Guangdong,China(No.2017B030311017)the National Natural Science Foundation of China(No.81370740)+1 种基金the Program of the Natural Science Foundation of Guangdong,China(No.2018A030313845)the China Postdoctoral Science Foundation(No.2018M633076).
文摘The human immunodeficiency virus-1(HIV-1)envelope protein gp120 is the major contributor to the pathogenesis of HIVassociated neurocognitive disorder(HAND).Neuroinflammation plays a pivotal role in gp120-induced neuropathology,but how gp120 triggers neuroinflammatory processes and subsequent neuronal death remains unknown.Here,we provide evidence that NLRP3 is required for gp120-induced neuroinflammation and neuropathy.Our results showed that gp120-induced NLRP3-dependent pyroptosis and IL-1βproduction in microglia.Inhibition of microglial NLRP3 inflammasome activation alleviated gp120-mediated neuroinflammatory factor release and neuronal injury.Importantly,we showed that chronic administration of MCC950,a novel selective NLRP3 inhibitor,to gp120 transgenic mice not only attenuated neuroinflammation and neuronal death but also promoted neuronal regeneration and restored the impaired neurocognitive function.In conclusion,our data revealed that the NLRP3 inflammasome is important for gp120-induced neuroinflammation and neuropathology and suggest that NLRP3 is a potential novel target for the treatment of HAND.
