It was recently shown that bacterial thymus-independent (TI) antigens confer long-lasting immunity and generate memory B lymphocytes. However, reactivation of TI memory B cells is repressed in immunocompetent mice, thus raising the issue of the mechanism whereby TI vaccines confer immune protection. Here, we propose an explanation to this apparent paradox by showing that a Streptococcus pneumoniae capsular polysaccharide (PS) generates long-lived bone marrow (BM) plasma cells which frequency can be increased by CpG oligodeoxynucleotides (ODNs). The adjuvant effect of CpG ODNs on the PS3 Ab response is directly targeted to B cells and does not involve B-1a cells. We also demonstrated that BM plasma cells generated in response to the thymus-dependent (TD) form of the PS vaccine have a higher secretion capacity than those produced after immunization with the CpGadjuvanted PS vaccine. Finally, we show that the PS-specific BM plasma cell compartment is sufficient to confer full protection of vaccinated mice against S pneumoniae infection. Altogether, our results show that TI antigens like their TD counterparts can generate both the lymphoid and the plasma cell component of B-cell memory. They also provide a framework for the improvement and widespread usage of TI vaccines. IntroductionDespite advances in antimicrobial therapy, infections with extracellular polysaccharide (PS)-encapsulated bacteria remain an important clinical problem and a primary source of death worldwide. Pathogenic bacteria including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae express capsular PSs that behave as prototypic thymus-independent (TI) antigens (Ags). These Ags have initially been defined on the basis of their ability to elicit an antibody (Ab) response in T cell-deficient or athymic mice by a mechanism that requires expression of a functional Bruton tyrosine kinase. 1 They are mostly nonpeptidic molecules, which in their great majority, are unable to follow the conventional Agprocessing pathway leading to presentation by MHC class I and II molecules. 2 To overcome systemic infections by encapsulated extracellular bacteria such as S pneumoniae, B cells rapidly generate a protective Ab response against capsular PS. B-1 and marginal zone B cells have been envisioned as key players in the humoral response against TI Ags. 3 More recently, 2 studies, using Borrelia hermsii or capsular PSs from S pneumoniae as immunogens, have shown that B-1b cells are critically involved in bacterial clearance in vaccinated mice. 4,5 It has long been thought that the generation of memory B cells is restricted to thymus-dependent (TD) responses. However, the recent observation that adoptive transfer of B-1b cells from donor mice immunized with whole bacteria can confer long-lasting TI immunity to immunodeficient mice shows that TI Ags generate B-cell memory and that this function can be assigned to the B-1b-cell subset. 5 Nonetheless, the concept of TI B-cell memory is at odds with the fact that, unlike TD Ags, TI Ags fail to...
Toll-like receptors (TLRs) are considered as potential targets for vaccine adjuvants. Here, we explored the impact of TLR agonists on the B cell response to a prototypic thymus-independent (TI) antigen: a Streptococcus pneumoniae capsular polysaccharide (PS). In adult mice, all TLR agonists (and CpG oligodeoxynucleotides [ODN] in particular) enhance the PS antibody response, provided that their administration is delayed until the second day after PS vaccination. In infant mice, CpG ODN not only potentiated the PS3 antibody response but also restored responsiveness to PS3 vaccination. Moreover, the immune protection induced by the plain PS3 vaccine adjuvanted by CpG ODN was comparable to that conferred by the conjugate vaccine in terms of efficiency and longevity. CpG ODN exert their adjuvant effect by increasing the survival rate of antigen-stimulated B cells as well as the output of plasmablasts. Our results provide a rationale for broader application of polysaccharidic vaccines.
No specific treatment for nonalcoholic hepatic fatty liver disease has been defined. We followed the spontaneous evolution of liver steatosis and tested the therapeutic usefulness of metformin and fenofibrate in a model of steatosis, the Zucker diabetic fatty (ZDF) rat. ZDF and control rats were studied at 7, 14, and 21 weeks. After initial study at 7 weeks, ZDF rats received no treatment, metformin or fenofibrate until studies at 14 or 21 weeks. ZDF rats were obese, hypertriglyceridemic, insulin resistant at 7 weeks, type 2 diabetic at 14, diabetic with insulin deficiency at 21. They had steatosis at 7 weeks with increased hepatic expression and activity of lipogenesis. Steatosis was unchanged at 14 and 21 weeks despite lower expression and activity of lipogenesis. Metformin and fenofibrate did not modify energy intake or expenditure or the evolution of diabetes. Both compounds decreased plasma triacylglycerol (TAG) concentrations. Hepatic TAG content was reduced by fenofibrate at 14 and 21 weeks but only at 21 weeks by metformin. Metformin had no significant effects on the expression in liver of genes of fatty acids metabolism. The beneficial effect of fenofibrate occurred despite increased expression of genes involved in the uptake and activation of fatty acids. Acyl‐CoA oxidase (ACO) and carnitine palmitoyltransferase I (CPTI) mRNA levels were increased by fenofibrate showing evidence of increased lipid oxidation. To conclude, metformin had only moderate effects on liver steatosis. The effects of fenofibrate was more marked but remained mild.
During the budding process, influenza A viruses (IAVs) incorporate multiple host cell membrane proteins. However, for most of them, their significance in viral morphogenesis and infectivity remains unknown. We demonstrate here that the expression of annexin V (A5) is upregulated at the cell surface upon IAV infection and that a substantial proportion of the protein is present in lipid rafts, the site of virus budding. Western blotting and immunogold analysis of highly purified IAV particles showed the presence of A5 in the virion. Significantly, gamma interferon (IFN-␥)-induced Stat phosphorylation and IFN-␥-induced 10-kDa protein (IP-10) production in macrophage-derived THP-1 cells was inhibited by purified IAV particles. Disruption of the IFN-␥ signaling pathway was A5 dependent since downregulation of its expression or its blockage reversed the inhibition and resulted in decreased viral replication in vitro. The functional significance of these results was also observed in vivo. Thus, IAVs can subvert the IFN-␥ antiviral immune response by incorporating A5 into their envelope during the budding process. IMPORTANCEMany enveloped viruses, including influenza A viruses, bud from the plasma membrane of their host cells and incorporate cellular surface proteins into viral particles. However, for the vast majority of these proteins, only the observation of their incorporation has been reported. We demonstrate here that the host protein annexin V is specifically incorporated into influenza virus particles during the budding process. Importantly, we showed that packaged annexin V counteracted the antiviral activity of gamma interferon in vitro and in vivo. Thus, these results showed that annexin V incorporated in the viral envelope of influenza viruses allow viral escape from immune surveillance. Understanding the role of host incorporated protein into virions may reveal how enveloped RNA viruses hijack the host cell machinery for their own purposes.
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