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111.
Sarah A. Barr Emily N. Kennedy Liliana S. McKay Richard M. Johnson Ryan J. Ohr Peggy A. Cotter Robert B. Bourret 《Molecular microbiology》2023,119(2):174-190
Bordetella species cause lower respiratory tract infections in mammals. B. pertussis and B. bronchiseptica are the causative agents of whooping cough and kennel cough, respectively. The current acellular vaccine for B. pertussis protects against disease but does not prevent transmission or colonization. Cases of pertussis are on the rise even in areas of high vaccination. The PlrSR two-component system, is required for persistence in the mouse lung. A partial plrS deletion strain and a plrS H521Q strain cannot survive past 3 days in the lung, suggesting PlrSR works in a phosphorylation-dependent mechanism. We characterized the biochemistry of B. bronchiseptica PlrSR and found that both proteins function as a canonical two-component system. His521 was essential and Glu522 was critical for PlrS autophosphorylation. Asn525 was essential for phosphatase activity. The PAS domain was critical for both PlrS autophosphorylation and phosphatase activities. PlrS could both phosphotransfer to and exert phosphatase activity toward PlrR. Unexpectedly, PlrR formed a tetramer when unphosphorylated and a dimer upon phosphorylation. Finally, we demonstrated the importance of PlrS phosphatase activity for persistence within the murine lung. By characterizing PlrSR we hope to guide future in vivo investigation for development of new vaccines and therapeutics. 相似文献
112.
Proinflammatory M1 activation of hepatic macrophages (HM) is critical in pathogenesis of hepatitis, but its mechanisms are still elusive. Our earlier work demonstrates the role of ferrous iron (Fe(2+)) as a pathogen-associated molecular pattern-independent agonist for activation of IκB kinase (IKK) and NF-κB in HM via activation and interaction of p21(ras), transforming growth factor β-activated kinase-1 (TAK1), and phosphatidylinositol 3-kinase (PI3K) in caveosomes. However, iron-induced signaling upstream of these kinases is not known. Here we show that Fe(2+) induces generation of superoxide anion (O(2)()) in endosomes, reduces protein-tyrosine phosphatase (PTP) activity, and activates Src at 2~10 min of Fe(2+) addition to rat primary HM culture. Superoxide dismutase (SOD) blocks O(2)() generation, PTP inhibition, and Src activation. Fe(2+)-induced p21(ras) activity is abrogated with the Src inhibitor PP2 and SOD. Fe(2+) stimulates Lys(63)-linked polyubiquitination (polyUb) of TRAF6 in caveosomes, and a dominant negative K63R mutant of ubiquitin or SOD prevents iron-induced TRAF6 polyUb and TAK1 activation. These results demonstrate that Fe(2+)-generated O(2)() mediates p21(ras) and TAK1 activation via PTP inhibition and Lys(63)-polyUb of TRAF6 in caveosomes for proinflammatory M1 activation in HM. 相似文献
113.
Cao S Al-Rehaily AJ Brodie P Wisse JH Moniz E Malone S Kingston DG 《Phytochemistry》2008,69(2):553-557
7-(2'-Hydroxy-3'-chloroprenyloxy)-4,8-dimethoxyfuroquinoline (1) and 6-(2'-hydroxy-3'-chloroprenyloxy)-4,7-dimethoxyfuroquinoline (2), together with ten known compounds, have been isolated from the aerial parts of Ertela (Monnieria) trifolia (L.) Kuntze. All the isolates were tested for antiproliferative activity against the A2780 human ovarian cancer cell line. 相似文献
114.
Ebensen T Link C Riese P Schulze K Morr M Guzmán CA 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(4):2065-2073
The glycolipid alpha-galactosylceramide (alphaGalCer) has immunomodulatory properties, which have been exploited to combat cancer, chronic inflammatory diseases, and infections. However, its poor solubility makes alphaGalCer a suboptimal compound for in vivo applications. In this study, a pegylated derivative of alphaGalCer is characterized, which exhibits improved physical and biological properties. The new compound, alphaGalCerMPEG, is water-soluble and retains the specificity for the CD1d receptor of alphaGalCer. The in vitro stimulatory properties on immune cells (e.g., dendritic cells and splenocytes) are maintained intact, even when tested at a 33-fold lower concentration of the active moiety than alphaGalCer. NK cells isolated from mice treated with alphaGalCerMPEG also had stronger cytotoxic activity on YAC-1 cells than those obtained from animals receiving either alphaGalCer or CpG. Intranasal immunization studies performed in mice showed that alphaGalCerMPEG exerts stronger adjuvant activities than the parental compound alphaGalCer when tested at 0.35 vs 11.7 nM/dose. Coadministration of beta-galactosidase with alphaGalCerMPEG resulted not only in high titers of Ag-specific Abs in serum (i.e., 1:512,000), but also in the stimulation of stronger Th2 and secretory IgA responses, both at local and remote mucosal effector sites (i.e., nose, lung, and vagina). The new synthetic derivative alphaGalCerMPEG represents a promising tool for the development of immune interventions against infectious and noninfectious diseases. 相似文献
115.
Characterization of fusion determinants points to the involvement of three discrete regions of both E1 and E2 glycoproteins in the membrane fusion process of hepatitis C virus 总被引:1,自引:0,他引:1 下载免费PDF全文
Lavillette D Pécheur EI Donot P Fresquet J Molle J Corbau R Dreux M Penin F Cosset FL 《Journal of virology》2007,81(16):8752-8765
Infection of eukaryotic cells by enveloped viruses requires the merging of viral and cellular membranes. Highly specific viral surface glycoproteins, named fusion proteins, catalyze this reaction by overcoming inherent energy barriers. Hepatitis C virus (HCV) is an enveloped virus that belongs to the genus Hepacivirus of the family Flaviviridae. Little is known about the molecular events that mediate cell entry and membrane fusion for HCV, although significant progress has been made due to recent developments in infection assays. Here, using infectious HCV pseudoparticles (HCVpp), we investigated the molecular basis of HCV membrane fusion. By searching for classical features of fusion peptides through the alignment of sequences from various HCV genotypes, we identified six regions of HCV E1 and E2 glycoproteins that present such characteristics. We introduced conserved and nonconserved amino acid substitutions in these regions and analyzed the phenotype of HCVpp generated with mutant E1E2 glycoproteins. This was achieved by (i) quantifying the infectivity of the pseudoparticles, (ii) studying the incorporation of E1E2 and their capacity to mediate receptor binding, and (iii) determining their fusion capacity in cell-cell and liposome/HCVpp fusion assays. We propose that at least three of these regions (i.e., at positions 270 to 284, 416 to 430, and 600 to 620) play a role in the membrane fusion process. These regions may contribute to the merging of viral and cellular membranes either by interacting directly with lipid membranes or by assisting the fusion process through their involvement in the conformational changes of the E1E2 complex at low pH. 相似文献
116.
Carter PH Brown GD Friedrich SR Cherney RJ Tebben AJ Lo YC Yang G Jezak H Solomon KA Scherle PA Decicco CP 《Bioorganic & medicinal chemistry letters》2007,17(19):5455-5461
A new series of CCR2 antagonists has been discovered that incorporates intramolecular hydrogen bonding as a strategy for rigidifying the scaffold. The structure-activity relationship was established through initial systematic modification of substitution pattern and chain length, followed by independent optimization of three different substituents (benzylamine, carboxamide, and benzamide). Several of the acyclic compounds display 10-30 nM binding affinity for CCR2. Moreover, these antagonists are able to block both MCP-1-induced Ca(2+) flux and monocyte chemotaxis, and are selective for binding to CCR2 over CCR1 and CCR3. 相似文献
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Peggy S. M. Hill 《Ethology : formerly Zeitschrift fur Tierpsychologie》1999,105(6):531-545
Gryllotalpa major is a rare, burrowing insect native to the tallgrass prairie of the south-central United States and is known to exhibit 'lek-like' behavior during mating. Here I report on a study carried out in the field that demonstrates that the prairie mole cricket meets all criteria defining a classical lekking species. Males construct specialized acoustic burrows from which they call to attract females for mating. I show that these burrows, which seem to serve no purpose other than for sexual advertisement and mating, are aggregated spatially on at least three scalar levels. Females fly through the aggregation of burrows and drop to the ground in the vicinity of calling males, and are, thus, not constrained in choosing a mate. Females enter the males' acoustic burrows, but I argue that the burrows are not used as oviposition sites, and that the males do not otherwise sequester resources important to females. Although the term 'lek' is useful for the discussion of mating systems, its definition remains ambiguous. I discuss the current usage of the term and suggest extensions. 相似文献