scholarly journals Dendritic Cell-Derived Exosomes Express a Streptococcus pneumoniae Capsular Polysaccharide Type 14 Cross-Reactive Antigen That Induces Protective Immunoglobulin Responses against Pneumococcal Infection in Mice

2006 ◽  
Vol 75 (1) ◽  
pp. 220-230 ◽  
Author(s):  
Jesus Colino ◽  
Clifford M. Snapper

ABSTRACT Exosomes activate T cells in vivo, but whether exosomes are able to induce humoral immune responses is still unknown. We found that dendritic cells, but not other immune cells, constitutively release an exosome-associated glycoconjugate that is cross-reactive with the capsular polysaccharide of Streptococcus pneumoniae type 14 (Cps14-CRA). Cps14-CRA was localized to the cholesterol-enriched microdomains or rafts of the exosomes and was mapped to the β1→6 branched N-acetyl-lactosamine derivatives of the Cps14-CRA. Injection of CFA-primed naive mice with purified dendritic cell exosomes induced immunoglobulin (Ig) anti-Cps14 responses composed predominantly of IgM, IgG3, and IgG1. These responses were associated with protection against a lethal challenge with live S. pneumoniae type 14, but not with type 3 bacteria, and was correlated with the titer of elicited IgM and IgG3 anti-Cps14. These data show, for the first time, that exosomes can induce a humoral immune response to an associated unprocessed, autologous antigen. Although anti-Cps14 Ig responses are specifically demonstrated, these could reflect a broader mechanism that modulates both natural immunity and autoimmunity to other glycotopes.

1988 ◽  
Vol 106 (1) ◽  
pp. 101-107 ◽  
Author(s):  
Guy J.W.J. Zigterman ◽  
AndréF.M. Verheul ◽  
Erna B.H.W. Ernste ◽  
Ronald F.M. Rombouts ◽  
Marinus J. De Reuver ◽  
...  

2005 ◽  
Vol 73 (1) ◽  
pp. 298-307 ◽  
Author(s):  
Abdul Q. Khan ◽  
Quanyi Chen ◽  
Zheng-Qi Wu ◽  
James C. Paton ◽  
Clifford M. Snapper

ABSTRACT Little is known regarding the role of Toll-like receptors (TLRs) in regulating protein- and polysaccharide-specific immunoglobulin (Ig) isotype production in response to an in vivo challenge with an extracellular bacterium. In this report we demonstrate that MyD88−/−, but not TLR2−/−, mice are markedly defective in their induction of multiple splenic proinflammatory cytokine- and chemokine-specific mRNAs after intraperitoneal (i.p.) challenge with heat-killed Streptococcus pneumoniae capsular type 14 (S. pneumoniae type 14). This is correlated with analogous responses in splenic cytokine protein release in vitro following addition of S. pneumoniae type 14. Consistent with these data, naïve MyD88−/−, but not TLR2−/−, mice are more sensitive to killing following i.p. challenge with live S. pneumoniae type 14, relative to responses in wild-type mice. However, prior immunization of MyD88−/− mice with heat-killed S. pneumoniae type 14 protects against an otherwise-lethal challenge with live S. pneumoniae type 14. Surprisingly, both MyD88−/− and TLR2−/− mice exhibit striking and equivalent defects in elicitation of type 1 IgG isotypes (IgG3, IgG2b, and IgG2a), but not the type 2 IgG isotype, IgG1, specific for several protein and polysaccharide antigens, in response to i.p. challenge with heat-killed S. pneumoniae type 14. Of note, the type 1 IgG isotype titers specific for pneumococcal surface protein A are reduced in MyD88−/− mice but not TLR2−/− mice. These data suggest that distinct TLRs may differentially regulate innate versus adaptive humoral immunity to intact S. pneumoniae and are the first to implicate a role for TLR2 in shaping an in vivo type 1 IgG humoral immune response to a gram-positive extracellular bacterium.


2005 ◽  
Vol 73 (3) ◽  
pp. 1304-1312 ◽  
Author(s):  
Dennis O. Gor ◽  
Xuedong Ding ◽  
David E. Briles ◽  
Michael R. Jacobs ◽  
Neil S. Greenspan

ABSTRACT Antibodies to capsular polysaccharide (PS) are protective against systemic infection by Streptococcus pneumoniae, but the large number of pneumococcal serogroups and the age-related immunogenicity of pure PS limit the utility of PS-based vaccines. In contrast, cell wall-associated proteins from different capsular serotypes can be cross-reactive and immunogenic in all age groups. Therefore, we evaluated three pneumococcal proteins with respect to relative accessibility to antibody, in the context of intact pneumococci, and their ability to elicit protection against systemic infection by encapsulated S. pneumoniae. Sequences encoding pneumococcal surface adhesin A (PsaA), putative protease maturation protein A (PpmA), and the N-terminal region of pneumococcal surface protein A (PspA) from S. pneumoniae strain A66.1 were cloned and expressed in Escherichia coli. The presence of genes encoding PsaA, PpmA, and PspA in 11 clinical isolates was examined by PCR, and the expression of these proteins by each strain was examined by Western blotting with antisera raised to the respective recombinant proteins. We used flow cytometry to demonstrate that PspA was readily detectable on the surface of the pneumococcal strains analyzed, whereas PsaA and PpmA were not. Consistent with these observations, mice with passively or actively acquired antibodies to PspA or type 3 PS were equivalently protected from homologous systemic challenge with type 3 pneumococci, whereas mice with passively or actively acquired antibodies to PsaA or PpmA were not effectively protected. These experiments support the hypothesis that the extent of protection against systemic pneumococcal infection is influenced by target antigen accessibility to circulating host antibodies.


2010 ◽  
Vol 17 (5) ◽  
pp. 713-721 ◽  
Author(s):  
Kevin Fabrizio ◽  
Catherine Manix ◽  
Allan J. Guimaraes̃ ◽  
Joshua D. Nosanchuk ◽  
Liise-anne Pirofski

ABSTRACT Acquired antibody immunity to Streptococcus pneumoniae (pneumococcus) has been linked to serotype (ST)-specific opsonic antibodies to the relevant pneumococcal capsular polysaccharide (PPS) that mediate protection by enhancing the bactericidal effect of host phagocytes. Despite the well-recognized role of opsonic IgG in host defense against pneumococcus, PPS-specific monoclonal antibodies (MAbs) that mediate protection against lethal challenge with ST3 pneumococcus in mice but do not promote phagocytic killing in vitro (nonopsonic antibodies) have been described. In this study, we sought to determine the biological activity of one such MAb, A7 (a human PPS3-specific IgM), and the mechanism by which it mediates protection. In vitro studies demonstrated that coincubation of A7 with ST3 in the absence of phagocytes or a complement source resulted in a reduction in CFU on blood agar plates that was largely reversible by sonication. A chromogenic cellular proliferation assay demonstrated that A7 did not affect replication of ST3 in liquid culture. The ability of A7 to induce aggregation of ST3 was confirmed by fluorescence microscopy and flow cytometry: A7 induced aggregation of ST3, and in the presence of a complement source, A7 promoted deposition of complement component 3 (C3) on aggregated bacteria in a dose-dependent fashion. Similarly, administration of preincubated mixtures of A7 and ST3 intraperitoneally to mice protected them from the lethality of ST3 in a dose-dependent fashion. These findings suggest that A7-mediated aggregation enhances resistance to ST3, most likely by enhancing C3 deposition on the ST3 capsule, thereby promoting host antipneumococcal activity in vivo.


2009 ◽  
Vol 16 (10) ◽  
pp. 1413-1419 ◽  
Author(s):  
Anoop S. Pulickal ◽  
Samir Gautam ◽  
Elizabeth A. Clutterbuck ◽  
Stephen Thorson ◽  
Buddha Basynat ◽  
...  

ABSTRACT Typhoid fever is a major public health problem in developing countries, conservatively estimated to occur in 17 million cases and be responsible for 200,000 deaths annually. We investigated the acquisition of natural immunity to Salmonella enterica serovar Typhi in a region where typhoid is endemic by testing sera from an age-stratified sample of 210 healthy participants in Kathmandu, Nepal, for bactericidal activity toward S. Typhi and for anti-Vi capsular polysaccharide antibodies. Bactericidal titers in children were significantly lower than those in newborns and adults (P < 0.0001). Anti-S. Typhi bactericidal geometric mean titers were age dependent, increasing 10-fold during childhood. Anti-Vi polysaccharide antibody geometric mean concentrations were also lower in children than in adults. Data presented here indicate the possibility of a relationship between low levels of bactericidal activity toward S. Typhi in serum and susceptibility to disease, as observed for other polysaccharide-encapsulated bacteria. Bactericidal antibody may be a marker of protective immunity against S. Typhi.


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