Anticapsular Polysaccharide Antibodies and Nasopharyngeal Colonization with<i>Streptococcus pneumoniae</i>in Infant Rats

Malley, Richard; Stack, Anne M.; Ferretti, Michelle L; Thompson, Claudette M.; Saladino, Richard A.

doi:10.1086/597600

Cited by 41 publications

(24 citation statements)

References 15 publications

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“…Anticapsular Abs not only prevent invasion but, as shown by active and passive immunization (5,24), are sufficient to prevent pneumococcal colonization; however, they may not be neces- WCV͞CT and subsequently treated with rat IgG or anti-CD8 Ab were significantly protected against nasopharyngeal colonization compared with mice that were immunized with CT alone (P Ͻ 0.05 for each comparison) and were indistinguishable from mice that received WCV͞CT with no additional treatment (P Ͼ 0.5). In contrast, mice treated with anti-CD4 Ab were not protected (P ϭ 0.46 vs. CT group) and were significantly more colonized than mice in the three other WCV͞CT immunized groups (P Ͻ 0.05).…”

Section: Discussionmentioning

confidence: 98%

CD4⁺T cells mediate antibody-independent acquired immunity to pneumococcal colonization

Malley

Trzciński

Srivastava

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Acquired immunity to Streptococcus pneumoniae (pneumococcus) has long been assumed to depend on the presence of anticapsular antibodies. We found, however, that colonization with live pneumococci of serotypes 6B, 7F, or 14 protected mice against recolonization by any of the serotypes and that protection from acquisition of a heterologous or homologous strain did not depend on anticapsular antibody. Further, intranasal immunization by live pneumococcal colonization or by a killed, nonencapsulated wholecell vaccine protected antibody-deficient mice against colonization, suggesting independence of antibodies to any pneumococcal antigens. Protection by intranasal immunization with whole-cell vaccine was completely abrogated in T cell-deficient mice, and in mice that were congenitally deficient in CD4 ؉ T cells or depleted of these cells at the time of challenge. In contrast, mice congenitally deficient in, or depleted of, CD8 ؉ T cells were fully protected. Protection in this model was observed beyond 2 months after immunization, arguing against innate or nonspecific immune mechanisms. Thus, we find that immunity to pneumococcal colonization can be induced in the absence of antibody, independent of the capsular type, and this protection requires the presence of CD4 ؉ T cells at the time of challenge.Streptococcus pneumoniae ͉ cell-mediated immunity ͉ vaccine A lmost 1 million children in the developing world die of infections due to Streptococcus pneumoniae (pneumococcus) each year (1). Pneumococcus is considered an ''extracellular'' bacterial pathogen, i.e., it is killed upon ingestion by phagocytic cells. Ingestion is facilitated by antibody (Ab) to its capsular polysaccharides (PS), of which there are at least 90 different serotypes. The two existing pneumococcal vaccines are based on injected mixtures of PS. Plain (unconjugated) PS vaccine contains 23 serotypes but is not efficacious in children Ͻ2 years old and therefore fails to protect those at highest risk. Protein-conjugated PS contains seven serotypes and protects infants (2), but it is difficult to manufacture (resulting in repeated shortages), is expensive, needs refrigeration, requires multiple injections, and does not include many of the capsular serotypes that cause pneumococcal disease in the developing world. Furthermore, serotype replacement, whereby pneumococcal serotypes not included in the conjugate vaccine become more prevalent causes of colonization and disease, has already been observed in clinical trials (3) and in epidemiologic studies (4) after implementation of conjugate vaccine immunization programs. Therefore, despite the success of the capsule-based vaccines, alternative strategies are urgently needed.The success of serum therapy (passive transfer of anticapsular Ab from hyperimmune animals) and the efficacy of PS and PS-protein conjugate vaccines have clearly demonstrated that anticapsular Ab alone is sufficient to treat or prevent pneumococcal disease. Furthermore, studies in animals (5) and humans (6) clearly demonstrate that antica...

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Section: Discussionmentioning

confidence: 98%

CD4⁺T cells mediate antibody-independent acquired immunity to pneumococcal colonization

Malley

Trzciński

Srivastava

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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306

283

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“…Il1r1 ؊/؊ mice do not have altered adaptive immunity to the pneumococcus. Although there is a contribution of type-specific antibody to protection induced by either vaccination or prior exposure (29,30), effective clearance of primary colonization requires Th17-dependent cellular immunity rather than humoral responses (8,31). Il-1␤ is a known driver of Th17 responses (32), which contribute to macrophage recruitment during colonization (8).…”

Section: Weeks After Inoculation There Was a Significantly Higher Bacmentioning

confidence: 99%

Sensing of Interleukin-1 Cytokines during Streptococcus pneumoniae Colonization Contributes to Macrophage Recruitment and Bacterial Clearance

2015

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Streptococcus pneumoniae (the pneumococcus), a leading cause of bacterial disease, is most commonly carried in the human nasopharynx. Colonization induces inflammation that promotes the organism's growth and transmission. This inflammatory response is dependent on intracellular sensing of bacterial components that access the cytosolic compartment via the pneumococcal pore-forming toxin pneumolysin. In vitro, cytosolic access results in cell death that includes release of the proinflammatory cytokine interleukin-1␤ (IL-1␤). IL-1 family cytokines, including IL-1␤, are secreted upon activation of inflammasomes, although the role of this activation in the host immune response to pneumococcal carriage is unknown. Using a murine model of pneumococcal nasopharyngeal colonization, we show that mice deficient in the interleukin-1 receptor type 1 (Il1r1 ؊/؊ ) have reduced numbers of neutrophils early after infection, fewer macrophages later in carriage, and prolonged bacterial colonization. Moreover, intranasal administration of Il-1␤ promoted clearance. Macrophages are the effectors of clearance, and characterization of macrophage chemokines in colonized mice revealed that Il1r1 ؊/؊ mice have lower expression of the C-C motif chemokine ligand 6 (CCL6), correlating with reduced macrophage recruitment to the nasopharynx. IL-1 family cytokines are known to promote adaptive immunity; however, we observed no difference in the development of humoral or cellular immunity to pneumococcal colonization between wild-type and Il1r1 ؊/؊ mice. Our findings show that sensing of IL-1 cytokines during colonization promotes inflammation without immunity, which may ultimately benefit the pneumococcus. Streptococcus pneumoniae (the pneumococcus) is an opportunistic bacterial pathogen that is responsible for over 1 million deaths annually, mostly in children under the age of 5 years (1). The pneumococcus serially colonizes the mucosal surfaces of the human upper respiratory tract, and carriage of the organism provides the reservoir for all pneumococcal disease (2). Colonization induces airway inflammation that is characterized by a suppurative rhinitis and increased mucus secretion. These secretions promote bacterial growth (3), and inflammation is important for bacterial transmission in a viral coinfection model (4). Human studies have demonstrated that higher bacterial burdens are correlated with a more profound rhinitis (5); however, as a result of this inflammatory response, colonization is normally cleared by the host's immune system within several weeks (6).A well-defined murine model of pneumococcal colonization (7) has elucidated bacterial and host factors that are critical to immune recognition of the pneumococcus, which drives the eventual resolution of the carrier state. Although early colonization triggers the recruitment of neutrophils, these are ineffective at resolving the infection. Clearance of pneumococci from the upper airway over a period of weeks requires a sustained presence of macrophages in the nasopharynx (8). Althou...

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“…A role for the capsule in colonization has not been described, and in vitro studies have suggested that it may interfere with this process (1,17,32,42,44,48). The ability of capsule-specific antibodies to reduce carriage, however, suggests that the capsule is expressed during nasopharyngeal colonization (18,34,36). Moreover, the varied ability of encapsulated strains of different serotypes to colonize the nasopharynx suggests some influence of the capsule on colonization (2,14,49,50,56).…”

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confidence: 99%

Requirement for Capsule in Colonization by Streptococcus pneumoniae

2001

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Nasopharyngeal colonization is a necessary first step in the pathogenesis of Streptococcus pneumoniae. Using isolates containing defined mutations in the S. pneumoniae capsule locus, we found that expression of the capsular polysaccharide is essential for colonization by the type 2 strain D39 and the type 3 strains A66 and WU2. Nonencapsulated derivatives of each of these strains were unable to colonize BALB/cByJ mice. Similarly, type 3 mutants that produced <6% of the parental amounts of capsule could not colonize. Capsule production equivalent to that of the parent strain was not required for efficient colonization, however, as type 3 mutants producing approximately 20% of the parental amounts of capsule colonized as effectively as the parent. This 80% reduction in capsule level had only a minimal effect on intraperitoneal virulence but caused a significant reduction in virulence via the intravenous route. In the X-linked immunodeficient CBA/N mouse, the type 3 mutant producing ϳ20% of the parental amount of capsule (AM188) was diminished in its ability to cause invasive disease and death following intranasal inoculation. Following intravenous or intraperitoneal challenge, however, only extended survival times were observed. Our results demonstrate an additional role for capsule in the pathogenesis of S. pneumoniae and show that isolates producing reduced levels of capsule can remain highly virulent.

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Anticapsular Polysaccharide Antibodies and Nasopharyngeal Colonization withStreptococcus pneumoniaein Infant Rats

Cited by 41 publications

References 15 publications

CD4⁺T cells mediate antibody-independent acquired immunity to pneumococcal colonization

CD4⁺T cells mediate antibody-independent acquired immunity to pneumococcal colonization

Sensing of Interleukin-1 Cytokines during Streptococcus pneumoniae Colonization Contributes to Macrophage Recruitment and Bacterial Clearance

Requirement for Capsule in Colonization by Streptococcus pneumoniae

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Anticapsular Polysaccharide Antibodies and Nasopharyngeal Colonization withStreptococcus pneumoniaein Infant Rats

Cited by 41 publications

References 15 publications

CD4+T cells mediate antibody-independent acquired immunity to pneumococcal colonization

CD4+T cells mediate antibody-independent acquired immunity to pneumococcal colonization

Sensing of Interleukin-1 Cytokines during Streptococcus pneumoniae Colonization Contributes to Macrophage Recruitment and Bacterial Clearance

Requirement for Capsule in Colonization by Streptococcus pneumoniae

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CD4⁺T cells mediate antibody-independent acquired immunity to pneumococcal colonization

CD4⁺T cells mediate antibody-independent acquired immunity to pneumococcal colonization