The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
David E Briles - One of the best experts on this subject based on the ideXlab platform.
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importance of phosphoinositide 3 kinase γ in the host defense against Pneumococcal Infection
American Journal of Respiratory and Critical Care Medicine, 2007Co-Authors: Ulrich A Maus, James C. Paton, David E Briles, Myriam Backi, Christine C Winter, Mrigank Srivastava, Matthias Schwarz, Thomas Ruckle, Matthias Mack, Tobias WelteAbstract:Rationale: The pivotal role of phosphoinositide 3-kinase γ (PI3Kγ) in leukocyte recruitment makes it an attractive target for immunomodulatory therapy. However, interfering with PI3Kγ signaling might increase the risk of bacterial Infections in humans.Objectives: We hypothesized that deletion or pharmacologic inhibition of PI3Kγ would impair the lung inflammatory response to the prototypic gram-positive bacterial pathogen Streptococcus pneumoniae.Methods: PI3Kγ knockout (KO) and wild-type mice were infected with S. pneumoniae or challenged with the Pneumococcal virulence factor pneumolysin (PLY), and inflammatory leukocyte recruitment, bacterial pathogen elimination, and resolution/repair processes were determined.Measurements and Main Results: PI3Kγ KO mice challenged with PLY responded with lung edema and neutrophilic alveolitis, but showed a drop in alveolar macrophages and failed to recruit exudate macrophages when compared with wild-type mice. S. pneumoniae–infected PI3Kγ KO mice and wild-type mice p...
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the virulence function of streptococcus pneumoniae surface protein a involves inhibition of complement activation and impairment of complement receptor mediated protection
Journal of Immunology, 2004Co-Authors: Bing Ren, David E Briles, Mark A Mccrory, Christina Pass, Daniel C Bullard, Christie M Ballantyne, Alexander J SzalaiAbstract:Complement is important for elimination of invasive microbes from the host, an action achieved largely through interaction of complement-decorated pathogens with various complement receptors (CR) on phagocytes. Pneumococcal surface protein A (PspA) has been shown to interfere with complement deposition onto pneumococci, but to date the impact of PspA on CR-mediated host defense is unknown. To gauge the contribution of CRs to host defense against pneumococci and to decipher the impact of PspA on CR-dependent host defense, wild-type C57BL/6J mice and mutant mice lacking CR types 1 and 2 (CR1/2−/−), CR3 (CR3−/−), or CR4 (CR4−/−) were challenged with WU2, a PspA+ capsular serotype 3 pneumococcus, and its PspA− mutant JY1119. Pneumococci also were used to challenge factor D-deficient (FD−/−), LFA-1-deficient (LFA-1−/−), and CD18-deficient (CD18−/−) mice. We found that FD−/−, CR3−/−, and CR4−/− mice had significantly decreased longevity and survival rate upon Infection with WU2. In comparison, PspA− pneumococci were virulent only in FD−/− and CR1/2−/− mice. Normal mouse serum supported more C3 deposition on pneumococci than FD−/− serum, and more iC3b was deposited onto the PspA− than the PspA+ strain. The combined results confirm earlier conclusions that the alternative pathway of complement activation is indispensable for innate immunity against Pneumococcal Infection and that PspA interferes with the protective role of the alternative pathway. Our new results suggest that complement receptors CR1/2, CR3, and CR4 all play important roles in host defense against Pneumococcal Infection.
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characterization of the dihydrolipoamide dehydrogenase from streptococcus pneumoniae and its role in Pneumococcal Infection
Molecular Microbiology, 2002Co-Authors: Alexander W Smith, Hazeline Roche, Marieclaude Trombe, David E Briles, Anders HakanssonAbstract:In the present study, we have characterized the dihydrolipoamide dehydrogenase (DLDH) of Strepto-coccus pneumoniae and its role during Pneumococcal Infection. We have also demonstrated that a lack of DLDH results in a deficiency in alpha-galactoside metabolism and galactose transport. DLDH is an enzyme that is classically involved in the three-step conversion of 2-oxo acids to their respective acyl-CoA derivatives, but DLDH has also been shown to have other functions. The dldh gene was virtually identical in three Pneumococcal strains examined. Besides the functional domains and motifs associated with this enzyme, analysis of the Pneumococcal dldh gene sequence revealed the presence of an N-terminal lipoyl domain. DLDH-negative bacteria totally lacked DLDH activity, indicating that this gene encodes the only DLDH in S. pneumoniae. These DLDH-negative bacteria grew normally in vitro but were avirulent in sepsis and lung Infection models in mice, indicating that DLDH activity is necessary for the survival of pneumococci within the host. The lack of virulence was not associated with a loss of 2-oxo acid dehydrogenase activity, as the wild-type Pneumococcal strains did not contain activity of any of the known 2-oxo acid enzyme complexes. Instead, studies of carbohydrate utilization demonstrated that the DLDH-negative bacteria were impaired for alpha-galactoside and galactose metabolism. The DLDH mutants lost their ability to oxidize or grow with galactose or melibiose as sole carbon source and showed reduced oxidation and growth on raffinose or stachyose. The bacteria had an 85% reduction in alpha-galactosidase activity and showed virtually no transport of galactose into the cells, which can explain these phenotypic changes. The DLDH-negative bacteria produced only 50% of normal capsular polysaccharide, a phenotype that may be associated with impaired carbohydrate metabolism.
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natural development of antibodies to Pneumococcal surface protein a Pneumococcal surface adhesin a and pneumolysin in relation to Pneumococcal carriage and acute otitis media
The Journal of Infectious Diseases, 2000Co-Authors: Satu Rapola, James C. Paton, David E Briles, Virva Jantti, Raili Haikala, Ritva Syrjanen, George M Carlone, Jacquelyn S Sampson, Aino K Takala, Terhi KilpiAbstract:Pneumococcal surface protein A (PspA), Pneumococcal surface adhesin A (PsaA), and pneumolysin (Ply) are common to virtually all Streptococcus pneumoniae isolates. They are immunogenic and protective against Pneumococcal challenge in animals and are the major candidates for a protein-based Pneumococcal vaccine for humans. However, little is known of the natural development of antibodies to these proteins in humans. The objective of this study was to evaluate the natural development of antibodies to PspA, PsaA, and Ply in relation to Pneumococcal Infection and carriage in young children. Serum antibodies to these proteins were measured by EIA in children at ages 6, 12, 18, and 24 months and in their mothers. All age groups were capable of producing antibodies to the 3 proteins. The antibody concentrations increased with age and were strongly associated with Pneumococcal exposure, whether by carriage or Infection (acute otitis media).
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the potential to use pspa and other Pneumococcal proteins to elicit protection against Pneumococcal Infection
Vaccine, 2000Co-Authors: David E Briles, Susan K Hollingshead, Alexis Brookswalter, Gary S Nabors, Laura Ferguson, Margo Schilling, Stephan Gravenstein, Pat Braun, Janice King, Amy SwiftAbstract:Pneumococcal proteins, alone, in combination with each other, or in combination with capsular polysaccharide-protein conjugates may be useful Pneumococcal vaccine components. Four proteins with a potential for use in vaccines are PspA, pneumolysin, PsaA, and PspC. In a mouse model of carriage, PsaA and PspC were the most efficacious vaccine proteins. Of these, PsaA was the best at eliciting protection against carriage. However, a combination of PspA and pneumolysin may elicit stronger immunity to pulmonary Infection and possibly sepsis than either protein alone. Recently, a phase one trial of a recombinant family 1 PspA was completed in man. PspA was observed to be safe and immunogenic. Injection of 0.1 ml of immune serum diluted to 1/400 was able to protect mice from fatal Infection with S. pneumoniae. Under these conditions, pre-immune serum was not protective. The immune human serum protected mice from Infections with pneumococci expressing either of the major PspA families (1 and 2) and both of the Pneumococcal capsular types tested: 3 and 6.
Birgitta Henriquesnormark - One of the best experts on this subject based on the ideXlab platform.
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tlr7 contributes to the rapid progression but not to the overall fatal outcome of secondary Pneumococcal disease following influenza a virus Infection
Journal of Innate Immunity, 2013Co-Authors: Sabine Stegemannkoniszewski, Shizuo Akira, Marcus Gereke, Sofia Orrskog, Stefan Lienenklaus, Bastian Pasche, Sophie R Bader, Achim D Gruber, Siegfried Weiss, Birgitta HenriquesnormarkAbstract:Increased risk for bacterial superInfections substantially contributes to the mortality caused by influenza A virus (IAV) epidemics. While the mechanistic basis for this lethal synergism is still insufficiently understood, immune modulation through the viral Infection has been shown to be involved. Since the pattern-recognition receptor (PRR) toll-like receptor 7 (TLR7) is a major sensor for the viral genome, we studied how IAV recognition by TLR7 influences the development of secondary Pneumococcal Infection. In a mouse model of IAV, TLR7-deficient hosts induced a potent antiviral response and showed unchanged survival. In secondary Pneumococcal Infection during acute influenza, TLR7ko mice showed a fatal outcome similar to wild-type (WT) hosts, despite significantly delayed disease progression. Also, when bacterial superInfection occurred after virus clearance, WT and TLR7-deficient hosts showed similar mortality, even though we found the phagocytic activity of alveolar macrophages isolated from IAV-pre-infected hosts to be enhanced in TLR7ko over WT mice. Thus, we show that a virus-sensing PRR modulates the progression of secondary Pneumococcal Infection following IAV. However, the fatal overall outcome in WT as well as TLR7ko hosts suggests that processes distinct from TLR7-triggering override the contribution of this single PRR.
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toll like receptor 9 acts at an early stage in host defence against Pneumococcal Infection
Cellular Microbiology, 2007Co-Authors: Barbara Albiger, Sofia Dahlberg, Andreas Sandgren, Florian Wartha, Katharina Beiter, Hiroaki Katsuragi, Shizuo Akira, Staffan Normark, Birgitta HenriquesnormarkAbstract:Toll-like receptor 9 (TLR9) induces an inflammatory response by recognition of unmethylated CpG dinucleotides, mainly present in prokaryotic DNA. So far, TLR9-deficient mice have been shown to be more sensitive than wild-type mice to viral, but not to bacterial Infections. Here, we show that mice deficient in TLR9 but not in TLR1, TLR2, TLR4 and TLR6 or IL-1R/IL-18R are more susceptible to a respiratory tract bacterial Infection caused by Streptococcus pneumoniae. Intranasal challenge studies revealed that TLR9 plays a protective role in the lungs at an early stage of Infection prior to the entry of circulating inflammatory cells. Alveolar as well as bone marrow-derived macrophages deficient in either TLR9 or the myeloid adaptor differentiation protein MyD88 were impaired in Pneumococcal uptake and in Pneumococcal killing. Our data suggest that in the airways, Pneumococcal Infection triggers a TLR9 and MyD88-dependent activation of phagocytic activity from resident macrophages leading to an early clearance of bacteria from the lower respiratory tract.
Daniel M Musher - One of the best experts on this subject based on the ideXlab platform.
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emergence of macrolide resistance during treatment of Pneumococcal pneumonia
The New England Journal of Medicine, 2002Co-Authors: Daniel M Musher, Mark E Dowell, Virginia D Shortridge, Robert K Flamm, James H Jorgensen, Pierre Le Magueres, Kurt L KrauseAbstract:To the Editor: The emergence of antibiotic resistance during treatment for Pneumococcal Infection is exceedingly rare.1 To our knowledge, there is no previous report of a genetically characterized,...
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bacteremic and nonbacteremic Pneumococcal pneumonia a prospective study
Medicine, 2000Co-Authors: Daniel M Musher, Hoang M Phan, Irene Alexandraki, Edward A Graviss, Nasser Yanbeiy, Ahmad Eid, Luzmin A Inderias, Eric SolomonAbstract:We prospectively identified cases of Pneumococcal pneumonia and used stringent criteria to stratify them into bacteremic and nonbacteremic cases. Although patients were distributed among racial groups in proportion to all patients seen at this medical center, the proportion of African-Americans with bacteremic disease was significantly increased. All patients had at least 1 underlying condition predisposing to Pneumococcal Infection, and most had several. Although the mean number of predisposing factors was greater among bacteremic patients than nonbacteremic patients, only alcohol ingestion was significantly more common. Nearly one-third of patients had substantial anemia (hemoglobin < or = 10 g/dL) on admission, which may have predisposed to Infection. In the case of other laboratory abnormalities, such as albumin, creatinine, and bilirubin, it was difficult to determine which abnormality might have predisposed to Pneumococcal Infection and which might have resulted from it. The radiologic appearance was varied. Airspace consolidation and air bronchogram on chest X-ray were highly associated with bacteremic disease, as was the presence of pleural effusion. Although the Pneumonia Patient Outcomes Research Team (PORT) risk score was a predictor of mortality, it did not help to predict the presence of bacteremia in an individual case. Most patients who died in the first week in hospital were bacteremic, and a high PORT risk score with bacteremia reliably predicted a high likelihood of a fatal outcome. Eleven patients had extrapulmonary disease with meningitis, empyema, and septic arthritis predominating; all of these patients were bacteremic. The antibiotic susceptibility of our strains correlated well with those that have been reported in the United States during the years of this study. The use of numerous antibiotics of different classes in many patients, especially those who were the most ill, precluded analysis of outcome based on antibiotic therapy. Only 17 patients had been vaccinated. Since nearly all patients had conditions for which Pneumococcal vaccine is recommended and more than one-third had been hospitalized in the preceding 6 months, the low rate of vaccination can be regarded as a missed opportunity to administer a potentially beneficial vaccine.
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association between fcγriia r131 allotype and bacteremic Pneumococcal pneumonia
Clinical Infectious Diseases, 2000Co-Authors: Arthur M F Yee, Hoang M Phan, Ricardo Zuniga, Jane E Salmon, Daniel M MusherAbstract:Human FcgammaRIIa has 2 codominantly expressed allotypes, which differ greatly in their ability to ligate immunoglobulin G2 (IgG2). Whereas FcgammaRIIa-R131 binds only weakly to IgG2, FcgammaRIIa-H131 binds to it efficiently and might be primarily responsible for the phagocytosis of IgG2-opsonized bacteria. IgG2 plays a pivotal role in defense against Pneumococcal Infection. This prospective study showed that 50% of patients with bacteremic Pneumococcal pneumonia were homozygous for FcgammaRIIa-R131, compared with 28% with nonbacteremic Pneumococcal pneumonia and 29% of uninfected controls (P<.05). The gene frequency of FcgammaRIIa-R131 was 0.67 in bacteremic patients, significantly higher than in the other groups (P<.05). All bacteremic patients who died within 1 week of hospitalization were homozygous for FcgammaRIIa-R131. Therefore, the severity of Pneumococcal Infection may, in part, be genetically mediated. Taken together with similar findings in cases of meningococcal disease, these results suggest that such genetic factors may be generalizable to Infections caused by encapsulated bacteria.
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emergence of antibody to capsular polysaccharides of streptococcus pneumoniae during outbreaks of pneumonia association with nasopharyngeal colonization
Clinical Infectious Diseases, 1997Co-Authors: Daniel M Musher, Jean E Groover, Mary R Reichler, Francis X Riedo, Benjamin Schwartz, David A Watson, Robert E Baughn, Robert F BreimanAbstract:Antibody to Pneumococcal capsular polysaccharides (PPS) of Streptococcus pneumoniae plays a major role in protecting the host against Pneumococcal Infection. A variable proportion of healthy adults have antibody to PPS, often in the absence of recognized Pneumococcal Infection. To determine whether exposure to pneumococci or colonization by pneumococci, or both, stimulates the emergence of antibody to PPS, we studied outbreaks of pneumonia at two military camps. Of the men who were present at a military training camp during an outbreak of pneumonia due to S. pneumoniae serotype 1 but who did not develop pneumonia, 27.8% had IgG antibody to PPS 1, whereas only 3.6% of controls had this antibody. In another outbreak caused by S. pneumoniae serotypes 7F and 8, 35.9% of asymptomatic soldiers who had nasopharyngeal colonization by one of these strains had antibody to the relevant PPS, and another 30.8% who originally did not have antibody developed it within 30 days; thus, 66.7% of these soldiers had antibody to the relevant PPS. These data show that serotype-specific antibody promptly appears following exposure to an outbreak of Pneumococcal pneumonia and is probably mediated through acquisition of nasopharyngeal Pneumococcal carriage.
Luis Borderías - One of the best experts on this subject based on the ideXlab platform.
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sensitivity specificity and positivity predictors of the Pneumococcal urinary antigen test in community acquired pneumonia
Annals of the American Thoracic Society, 2015Co-Authors: Luis Molinos, Olga Rajas, Luis Borderías, Rafael Zalacain, Rosario Menendez, Soledad Reyes, Alberto Capelastegui, Catia Cilloniz, Juan J Martinvillasclaras, Salvador BelloAbstract:Rationale: Detection of the C-polysaccharide of Streptococcus pneumoniae in urine by an immune-chromatographic test is increasingly used to evaluate patients with community-acquired pneumonia.Objectives: We assessed the sensitivity and specificity of this test in the largest series of cases to date and used logistic regression models to determine predictors of positivity in patients hospitalized with community-acquired pneumonia.Methods: We performed a multicenter, prospective, observational study of 4,374 patients hospitalized with community-acquired pneumonia.Measurements and Main Results: The urinary antigen test was done in 3,874 cases. Pneumococcal Infection was diagnosed in 916 cases (21%); 653 (71%) of these cases were diagnosed exclusively by the urinary antigen test. Sensitivity and specificity were 60 and 99.7%, respectively. Predictors of urinary antigen positivity were female sex; heart rate ≥125 bpm, systolic blood pressure <90 mm Hg, and SaO2 <90%; absence of antibiotic treatment; pleuritic ...
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The role of mannose-binding lectin in Pneumococcal Infection
The European respiratory journal, 2012Co-Authors: M. Isabel García-laorden, Felipe Rodríguez De Castro, Jordi Solé-violán, Olga Rajas, José Blanquer, Luis Borderías, Javier Aspa, M. Luisa Briones, Antoni Payeras, J. Alberto Marcos-ramosAbstract:The role of mannose-binding lectin (MBL) deficiency (MBL2; XA/O and O/O genotypes) in host defences remains controversial. The surfactant proteins (SP)-A1, -A2 and -D, other collectins whose genes are located near MBL2, are part of the first-line lung defence against Infection. We analysed the role of MBL on susceptibility to Pneumococcal Infection and the existence of linkage disequilibrium (LD) among the four genes. We studied 348 patients with Pneumococcal community-acquired pneumonia (P-CAP) and 2,110 controls. A meta-analysis of MBL2 genotypes in susceptibility to P-CAP and to invasive Pneumococcal disease (IPD) was also performed. The extent of LD of MBL2 with SFTPA1, SFTPA2 and SFTPD was analysed. MBL2 genotypes did not associate with either P-CAP or bacteraemic P-CAP in the case-control study. The MBL-deficient O/O genotype was significantly associated with higher risk of IPD in a meta-analysis, whereas the other MBL-deficient genotype (XA/O) showed a trend towards a protective role. We showed the existence of LD between MBL2 and SP genes. The data do not support a role of MBL deficiency on susceptibility to P-CAP or to IPD. LD among MBL2 and SP genes must be considered in studies on the role of MBL in infectious diseases.
Olga Rajas - One of the best experts on this subject based on the ideXlab platform.
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sensitivity specificity and positivity predictors of the Pneumococcal urinary antigen test in community acquired pneumonia
Annals of the American Thoracic Society, 2015Co-Authors: Luis Molinos, Olga Rajas, Luis Borderías, Rafael Zalacain, Rosario Menendez, Soledad Reyes, Alberto Capelastegui, Catia Cilloniz, Juan J Martinvillasclaras, Salvador BelloAbstract:Rationale: Detection of the C-polysaccharide of Streptococcus pneumoniae in urine by an immune-chromatographic test is increasingly used to evaluate patients with community-acquired pneumonia.Objectives: We assessed the sensitivity and specificity of this test in the largest series of cases to date and used logistic regression models to determine predictors of positivity in patients hospitalized with community-acquired pneumonia.Methods: We performed a multicenter, prospective, observational study of 4,374 patients hospitalized with community-acquired pneumonia.Measurements and Main Results: The urinary antigen test was done in 3,874 cases. Pneumococcal Infection was diagnosed in 916 cases (21%); 653 (71%) of these cases were diagnosed exclusively by the urinary antigen test. Sensitivity and specificity were 60 and 99.7%, respectively. Predictors of urinary antigen positivity were female sex; heart rate ≥125 bpm, systolic blood pressure <90 mm Hg, and SaO2 <90%; absence of antibiotic treatment; pleuritic ...
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The role of mannose-binding lectin in Pneumococcal Infection
The European respiratory journal, 2012Co-Authors: M. Isabel García-laorden, Felipe Rodríguez De Castro, Jordi Solé-violán, Olga Rajas, José Blanquer, Luis Borderías, Javier Aspa, M. Luisa Briones, Antoni Payeras, J. Alberto Marcos-ramosAbstract:The role of mannose-binding lectin (MBL) deficiency (MBL2; XA/O and O/O genotypes) in host defences remains controversial. The surfactant proteins (SP)-A1, -A2 and -D, other collectins whose genes are located near MBL2, are part of the first-line lung defence against Infection. We analysed the role of MBL on susceptibility to Pneumococcal Infection and the existence of linkage disequilibrium (LD) among the four genes. We studied 348 patients with Pneumococcal community-acquired pneumonia (P-CAP) and 2,110 controls. A meta-analysis of MBL2 genotypes in susceptibility to P-CAP and to invasive Pneumococcal disease (IPD) was also performed. The extent of LD of MBL2 with SFTPA1, SFTPA2 and SFTPD was analysed. MBL2 genotypes did not associate with either P-CAP or bacteraemic P-CAP in the case-control study. The MBL-deficient O/O genotype was significantly associated with higher risk of IPD in a meta-analysis, whereas the other MBL-deficient genotype (XA/O) showed a trend towards a protective role. We showed the existence of LD between MBL2 and SP genes. The data do not support a role of MBL deficiency on susceptibility to P-CAP or to IPD. LD among MBL2 and SP genes must be considered in studies on the role of MBL in infectious diseases.