Pneumococcal polysaccharide-based vaccines are effective in preventing pneumococcus infection; however, some drawbacks preclude their widespread use in developing and undeveloped countries. Here, we evaluated the protective effects of ATP-dependent caseinolytic protease (ClpP), pneumolysin mutant (⌬A146 Ply), putative lipoate-protein ligase (Lpl), or combinations thereof against pneumococcal infections in mice. Vaccinated mice were intraperitoneally and/or intranasally challenged with different pneumococcal strains. In intraperitoneal challenge models with pneumococcal strain D39 (serotype 2), the most striking protection was obtained with the combination of the three antigens. Similarly, with the intranasal challenge models, (i) additive clearance of bacteria in lungs was observed for the combination of the three antigens and (ii) a combination vaccine conferred complete protection against intranasal infections of three of the four most common pneumococcal strains (serotypes 14, 19F, and 23F) and 80% protection for pneumococcal strain 6B. Even so, immunity to this combination could confer protection against pneumococcal infection with a mixture of four serotypes. Our results showed that the combination vaccine was as effective as the currently used vaccines (PCV7 and PPV23). These results indicate that system immunization with the combination of pneumococcal antigens could provide an additive and broad protection against Streptococcus pneumoniae in pneumonia and sepsis infection models.Streptococcus pneumoniae (pneumococcus) commonly colonizes the upper respiratory tract asymptomatically and was estimated, in 2005, to kill 1.6 million people every year, most of whom were children aged Ͻ5 years in developing and undeveloped countries (36). As far as we know, 91 capsular polysaccharide serotypes have been identified in S. pneumoniae (33); among these, serotypes 23F, 19F, 14, and 6B are the four most epidemic strains worldwide (2,5,15,17,25,26,29). Moreover, and of recent concern, the widespread use of antibiotics, leading to the development of antibiotic resistance or multidrug resistance against S. pneumoniae, is increasing (9,12,26).Heptavalent protein-polysaccharide conjugate vaccine (PCV7) and 23-valent pneumococcal polysaccharide vaccine (PPV23) are the two vaccines currently being used against S. pneumoniae. Both of these vaccines are polysaccharide-based formulations and effective in preventing invasive pneumococcal infections; however, some drawbacks, such as high cost, the limited polysaccharides covered, poor immunogenicity in the very young and the very old, and serotype replacement (22,24,26,36), limit their wider use.Alternatively, in an attempt to overcome the disadvantages of polysaccharide-based vaccines, a number of studies have been focusing on the screening and evaluation of proteinbased vaccine candidates. Pneumococcal protein vaccine candidates, such as nontoxic pneumolysin derivates, pneumococcal surface proteins (PspA and PspC), pneumococcal surface adhesin (PsaA), and ATP-dependent caseino...
IL-27 is involved in inflammatory reactions. CXCL10 is an important chemokine contributing to airway inflammatory disease. In this study, we investigated whether IL-27 modulated the synthesis of CXCL10 in primary human lung fibroblasts (HLFs). HLFs were activated by IL-27 alone, or in combination with other cytokines. CXCL10 synthesis was measured by real-time PCR and ELISA. An examination of transcriptional regulation was performed via the transient transfection of promoter constructs, whereas mRNA stability was assessed by actinomycin D chase and real-time PCR. The underlying signaling pathways were studied by Western blotting and intracellular staining, using flow cytometry. Our results demonstrated that IL-27 induced and synergized with TNF-α to up-regulate CXCL10 mRNA and protein concentrations in a steroid-insensitive manner. This synergistic CXCL10 production was dependent on the transcriptional regulation of CXCL10 gene promoter activity and the enhanced stability of CXCL10 mRNA because of IL-27 and TNF-α, and this synergism was regulated by the activation of p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-OH kinase (PI3K)-Akt dominantly, and in small part via NF-κB. Interestingly, IL-27 promoted the basal and enhanced TNF-α-induced phosphorylation of p38 MAPK and Akt, but not IκBα. Moreover, enhanced CXCL10 mRNA stability occurred via a p38 MAPK-dependent pathway. Finally, clinical analysis showed that IL-27 was detected in the bronchoalveolar lavage of patients with asthma, chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (PTB), and increased IL-27 concentrations were correlated with increased CXCL10 concentrations in patients with COPD and PTB. Our findings suggest that IL-27 has the potential to amplify airway inflammation via the induction of CXCL10 from HLFs, in combination with TNF-α.
bMucosal immunization with attenuated vaccine can protect against pneumococcal invasion infection, but the mechanism was unknown. Our study found that mucosal delivery with the live attenuated SPY1 vaccine strain can confer T cell-and B cell-dependent protection against pneumococcal colonization and invasive infection; yet it is still unclear which cell subsets contribute to the protection, and their roles in pneumococcal colonization and invasion remain elusive. Adoptive transfer of anti-SPY1 antibody conferred protection to naive MT mice, and immune T cells were indispensable to protection examined in nude mice. A critical role of interleukin 17A (IL-17A) in colonization was demonstrated in mice lacking IL-17A, and a vaccine-specific Th2 immune subset was necessary for systemic protection. Of note, we found that SPY1 could stimulate an immunoregulatory response and that SPY1-elicited regulatory T cells participated in protection against colonization and lethal infection. The data presented here aid our understanding of how live attenuated strains are able to function as effective vaccines and may contribute to a more comprehensive evaluation of live vaccines and other mucosal vaccines. Vaccination is an indispensable strategy to prevent infection caused by Streptococcus pneumoniae (S. pneumoniae), which is estimated to lead to a mortality rate of more than 50 deaths in every 1,000 births in children under 5 years of age in some countries (1). The commercially available 23-valent polysaccharide vaccine contains the most common serotypes that cause pneumococcal infection and is effective in adults but fails to protect children of less than 2 years of age, who are most vulnerable to pneumococcal infection. The recent extensive introduction of conjugated capsular polysaccharide vaccine (PCV) has drastically decreased the child morbidity and mortality caused by strains of S. pneumoniae expressing capsular serotypes included in the vaccine. However, the serotype coverage of PCV is limited, and a growing body of evidence showed that PCV could induce selective pressure and gradual replacement with nonvaccine serotypes (serotype replacement) (2, 3). The conjugated vaccine is also very expensive and is complex in design, making more difficult its application in the low-income countries that have the highest burden of S. pneumoniae infections (4).As a consequence of these shortcomings with the commercially available S. pneumoniae vaccines, other approaches have been explored, including protein antigen vaccines, killed whole-cell S. pneumoniae vaccines, or attenuated live S. pneumoniae vaccines (5, 6). The wide range of antigenic molecules present in live attenuated vaccines promises that the immune responses they induce are likely to be multiple and powerful and may also more closely mimic those obtained in natural infection than immune responses to a vaccine using a subcomponent or killed bacteria (7). Some live bacterial vaccines have been clinically used, including the Mycobacterium bovis BCG (8) and vaccines for prev...
Our findings provide new insight for immunopathologic mechanisms of sepsis-induced secondary bacterial pneumonia.
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