Pattern of Accessory Regions and Invasive Disease Potential in<i>Streptococcus pneumoniae</i>

Blomberg, Christel; Dagerhamn, Jessica; Dahlberg, Sofia; Browall, Sarah; Fernebro, Josefin; Albiger, Barbara; Morfeldt, Eva; Normark, Staffan; Henriques‐Normark, Birgitta

doi:10.1086/597205

Cited by 58 publications

(92 citation statements)

References 36 publications

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“…Instead, we have sought additional support for the hypothesis by comparing median FH binding to clinical strains when divided by serotype into highly or weakly invasive groups. Invasive potential varies between strains with the same capsular serotype, which will partially confound these comparisons (34). Despite this, there was still a significantly higher level of FH binding to clinical isolates expressing more invasive serotypes.…”

Section: Discussionmentioning

confidence: 99%

Streptococcus pneumoniae Capsular Serotype Invasiveness Correlates with the Degree of Factor H Binding and Opsonization with C3b/iC3b

Hyams¹,

Trzciński

Camberlein³

et al. 2013

Infect Immun

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e Different capsular serotypes of Streptococcus pneumoniae vary markedly in their ability to cause invasive infection, but the reasons why are not known. As immunity to S. pneumoniae infection is highly complement dependent, variations in sensitivity to complement between S. pneumoniae capsular serotypes could affect invasiveness. We have used 20 capsule-switched variants of strain TIGR4 to investigate whether differences in the binding of the alternative pathway inhibitor factor H (FH) could be one mechanism causing variations in complement resistance and invasive potential between capsular serotypes. Flow cytometry assays were used to assess complement factor binding and complement-dependent neutrophil association for the TIGR4 capsuleswitched strains. FH binding varied with the serotype and inversely correlated with the results of factor B binding, C3b/iC3b deposition, and neutrophil association. Differences between strains in FH binding were lost when assays were repeated with pspC mutant strains, and loss of PspC also reduced differences in C3b/iC3b deposition between strains. Median FH binding was high in capsule-switched mutant strains expressing more invasive serotypes, and a principal component analysis demonstrated a strong correlation between serotype invasiveness, high FH binding, and resistance to complement and neutrophil association. Further data obtained with 33 clinical strains also demonstrated that FH binding negatively correlated with C3b/iC3b deposition and that median FH binding was high in strains expressing more invasive serotypes. These data suggest that variations in complement resistance between S. pneumoniae strains and the association of a serotype with invasiveness could be related to capsular serotype effects on FH binding.

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Section: Discussionmentioning

confidence: 99%

Streptococcus pneumoniae Capsular Serotype Invasiveness Correlates with the Degree of Factor H Binding and Opsonization with C3b/iC3b

Hyams¹,

Trzciński

Camberlein³

et al. 2013

Infect Immun

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“…Several strategies have been employed to screen in vivo-induced genes, including in vivo expression technology (IVET) (12), signature-tagged mutagenesis (STM) (13,14), differential fluorescence induction (DFI) (15)(16)(17), DNA microarray (18,19), reverse vaccinology (20,21), antigenome technology (22,23), and genomic array footprinting (GAF) (24). The availability of complete pathogen genome sequences has stimulated the development and wide-spread application of DNA arrays, which has revolutionized the study of genes that are involved in microbial pathogenesis (25).…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel pneumococcal vaccine antigen preferentially expressed during meningitis in mice

et al. 2012

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Streptococcus pneumoniae is the most common cause of severe bacterial meningitis in children, the elderly, and immunocompromised individuals. To identify virulence factors preferentially expressed during meningitis, we conducted niche-specific genome-wide in vivo transcriptomic analysis after intranasal infection of mice with serotype 4 or 6A pneumococci. The expression of 34 bacterial genes was substantially altered in brain tissue of mice infected with either of the 2 strains. Ten upregulated genes were common to both strains, 7 of which were evaluated for their role in the development of meningitis. One previously uncharacterized protein, α-glycerophosphate oxidase (GlpO), was cytotoxic for human brain microvascular endothelial cells (HBMECs) via generation of H 2 O 2 . A glpO deletion mutant was defective in adherence to HBMECs in vitro as well as in progression from the blood to the brain in vivo. Mutant bacteria also induced markedly reduced meningeal inflammation and brain pathology compared with wild type, despite similar levels of bacteremia. Immunization of mice with GlpO protected against invasive pneumococcal disease and provided additive protection when formulated with pneumolysin toxoid. Our results provide the basis of a strategy that can be adapted to identify genes that contribute to the development of meningitis caused by other pathogens.

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“…IPD is defined as the recovery of S. pneumoniae from a normally sterile site such as the blood or brain (7,12,13). To date, 97 distinct serotypes have been described based on the unique chemical and immunogenic properties of their capsule (10,14), and these serotypes can be divided into invasive as well as noninvasive/carrier serotypes (15,16). Otherwise noninvasive serotypes are able to lethally infect immunocompromised patients, reflecting the impact of host immunity on the IPD potential (8,17).…”

mentioning

confidence: 99%

Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

et al. 2016

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e Influenza A virus (IAV) and Streptococcus pneumoniae are major causes of respiratory tract infections, particularly during coinfection. The synergism between these two pathogens is characterized by a complex network of dysregulated immune responses, some of which last until recovery following IAV infection. Despite the high serotype diversity of S. pneumoniae and the serotype replacement observed since the introduction of conjugate vaccines, little is known about pneumococcal strain dependency in the enhanced susceptibility to severe secondary S. pneumoniae infection following IAV infection. Thus, we studied how preinfection with IAV alters host susceptibility to different S. pneumoniae strains with various degrees of invasiveness using a highly invasive serotype 4 strain, an invasive serotype 7F strain, and a carrier serotype 19F strain. A murine model of pneumococcal coinfection during the acute phase of IAV infection showed a significantly increased degree of pneumonia and mortality for all tested pneumococcal strains at otherwise sublethal doses. The incidence and kinetics of systemic dissemination, however, remained bacterial strain dependent. Furthermore, we observed strain-specific alterations in the pulmonary levels of alveolar macrophages, neutrophils, and inflammatory mediators ultimately affecting immunopathology. During the recovery phase following IAV infection, bacterial growth in the lungs and systemic dissemination were enhanced in a strain-dependent manner. Altogether, this study shows that acute IAV infection predisposes the host to lethal S. pneumoniae infection irrespective of the pneumococcal serotype, while the long-lasting synergism between IAV and S. pneumoniae is bacterial strain dependent. These results hold implications for developing tailored therapeutic treatment regimens for dual infections during future IAV outbreaks. Infection with secondary bacterial pathogens is attributed to be the major cause of excessive mortality during influenza A virus (IAV) outbreaks. This lethal synergism has been recognized as early as during the 1918-1919 IAV pandemic with an estimated global death toll of 50 to 100 million (1, 2). Retrospective studies disclosed that 71% of the fatal cases during this pandemic were positive for Streptococcus pneumoniae (also called pneumococcus), providing the first epidemiological evidence for viral-bacterial coinfections (2). A clear predisposition to bacterial disease was also evident in all of the succeeding influenza pandemics, including the more recent 2009 H1N1 outbreak, which had a 10 to 55% higher incidence of hospitalizations and mortality due to bacterial pneumonia (3). Pneumococcal colonization is transient and asymptomatic in immunocompetent individuals and most commonly occurs in early childhood (4). At the same time, however, pneumococci are able to cause a variety of diseases ranging from mild sinusitis and otitis media to more-severe infections like sepsis and meningitis. Even though the introduction of the polyvalent pneumococcal conjugate vaccines...

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Pattern of Accessory Regions and Invasive Disease Potential inStreptococcus pneumoniae

Cited by 58 publications

References 36 publications

Streptococcus pneumoniae Capsular Serotype Invasiveness Correlates with the Degree of Factor H Binding and Opsonization with C3b/iC3b

Streptococcus pneumoniae Capsular Serotype Invasiveness Correlates with the Degree of Factor H Binding and Opsonization with C3b/iC3b

Identification of a novel pneumococcal vaccine antigen preferentially expressed during meningitis in mice

Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

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