The Virulence Function of <i>Streptococcus pneumoniae</i> Surface Protein A Involves Inhibition of Complement Activation and Impairment of Complement Receptor-Mediated Protection

Ren, Bin; McCrory, Mark A.; Pass, Christina; Bullard, Daniel C.; Ballantyne, Christie M.; Xu, Yuanyuan; Briles, David E.; Szalai, Alexander J.

doi:10.4049/jimmunol.173.12.7506

Cited by 106 publications

(89 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Combined, these findings demonstrate that the classical and the alternative pathways are both required for efficient opsonophagocytosis of S. pneumoniae (in nonimmunized hosts). The latter pathway amplifies pneumococcal opsonization by C3, which the former pathway initiated (42,43). Second, the results of our reconstitution experiments, when combined with the finding that pneumococcal infection induces complement expression in the CNS, show that the inability of the host immune response to overcome S. pneumoniae infection within the CSF (44) does not seem to be due to the lack of C proteins.…”

Section: Discussionmentioning

confidence: 66%

Complement C1q and C3 Are Critical for the Innate Immune Response to Streptococcus pneumoniae in the Central Nervous System

Rupprecht

Angele

Klein

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

Previous studies suggest that the complement system can contribute to limiting pneumococcal outgrowth within the CNS. In this study, we evaluated the role of the complement system in the activation of the innate immune response and the development of the prognosis-relevant intracranial complications in a murine model of pneumococcal meningitis. Thereby, we used mice deficient in C1q, lacking only the classical pathway, and C3, lacking all three complement activation pathways. At 24 h after intracisternal infection, bacterial titers in the CNS were almost 12- and 20-fold higher in C1q- and C3-deficient-mice, respectively, than in wild-type mice. Mean CSF leukocyte counts were reduced by 47 and 73% in C1q- and C3-deficient-mice, respectively. Intrathecal reconstitution with wild-type serum in C3-deficient mice restored both the ability of mice to combat pneumococcal infection of the CSF and the ability of leukocytes to egress into the CSF. The altered recruitment of leukocytes into the CSF of C3-deficient mice was paralleled by a strong reduction of the brain expression of cytokines and chemokines. The dampened immune response in C3-deficient mice was accompanied by a reduction of meningitis-induced intracranial complications, but, surprisingly, also with a worsening of short-term outcome. The latter seems to be due to more severe bacteremia (12- and 120-fold higher in C1q- and C3-deficient-mice, respectively) and, consecutively, more severe systemic complications. Thus, our study demonstrated for the first time that the complement system plays an integral role in mounting the intense host immune response to Streptococcus pneumoniae infection of the CNS.

show abstract

Section: Discussionmentioning

confidence: 66%

Complement C1q and C3 Are Critical for the Innate Immune Response to Streptococcus pneumoniae in the Central Nervous System

Rupprecht

Angele

Klein

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…This can be compounded by the use of control mice that are not heterozygous littermates but may occur even when control mice are littermates. LFA-1 2/-mice, although more susceptible to infection in a variety of models, have enhanced clearance of pneumococci after intravenous infection because the gene knockout is associated with greater numbers of neutrophils and greater levels of pneumococcus-specific antibody (32). However, understanding these compensatory changes can be informative and it is possible that other approaches, such as the use of small molecular inhibitors, may also trigger these changes.…”

Section: Discussionmentioning

confidence: 95%

Reactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia

Marriott

Jackson

Wilkinson³

et al. 2008

Am J Respir Crit Care Med

View full text Add to dashboard Cite

Rationale: The role of NADPH oxidase activation in pneumonia is complex because reactive oxygen species contribute to both microbial killing and regulation of the acute pulmonary infiltrate. The relative importance of each role remains poorly defined in communityacquired pneumonia. Objectives: We evaluated the contribution of NADPH oxidasederived reactive oxygen species to the pathogenesis of pneumococcal pneumonia, addressing both the contribution to microbial killing and regulation of the inflammatory response. Methods: Mice deficient in the gp91 phox component of the phagocyte NADPH oxidase were studied after pneumococcal challenge. Measurements and Main Results: gp91 phox2/-mice demonstrated no defect in microbial clearance as compared with wild-type C57BL/6 mice. A significant increase in bacterial clearance from the lungs of gp91 phox2/-mice was associated with increased numbers of neutrophils in the lung, lower rates of neutrophil apoptosis, and enhanced activation. Marked alterations in pulmonary cytokine/ chemokine expression were also noted in the lungs of gp91 phox2/-mice, characterized by elevated levels of tumor necrosis factor-a, KC, macrophage inflammatory protein-2, monocyte chemotactic protein-1, and IL-6. The greater numbers of neutrophils in gp91 phox2/-mice were not associated with increased lung injury. Levels of neutrophil elastase in bronchoalveolar lavage were not decreased in gp91 phox2/-mice. Conclusions: During pneumococcal pneumonia, NADPH oxidasederived reactive oxygen species are redundant for host defense but limit neutrophil recruitment and survival. Decreased NADPH oxidasedependent reactive oxygen species production is well tolerated and improves disease outcome during pneumococcal pneumonia by removing neutrophils from the tight constraints of reactive oxygen species-mediated regulation.

show abstract

“…The main function of PspA is preventing the deposition of complement on the surface of the bacterium thereby inhibiting opsonization and phagocytosis (Ren et al, 2004a;Ren et al, 2004b). PspA was also shown to inhibit death by apolactoferrin at mucosal sites (Shaper et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Pulmonary dry powder vaccine of pneumococcal antigen loaded nanoparticles

Kunda

Alfagih

Miyaji

et al. 2015

International Journal of Pharmaceutics

View full text Add to dashboard Cite

Pneumonia, caused by Streptococcus pneumoniae, mainly affects the immune compromised, the very young and the old, and remains one of the leading causes of death.A steady rise in disease numbers from non-vaccine serotypes necessitates a new vaccine formulation that ideally has better antigen stability and integrity, does not require cold-chain and can be delivered non-invasively. In this study, a dry powder vaccine containing an important antigen of S. pneumoniae, pneumococcal surface protein A (PspA) that has shown cross-reactivity amongst serotypes to be delivered via the pulmonary route has been formulated. The formulation contains the antigen PspA adsorbed onto the surface of polymeric nanoparticles encapsulated in L-leucine microparticles that can be loaded into capsules and delivered via an inhaler. We have successfully synthesized particles of ~150 nm and achieved ~ 20 µg of PspA adsorption per mg of NPs. In addition, the spray-dried powders displayed a FPF of 74.31±1.32% and MMAD of 1.70±0.03 μm suggesting a broncho-alveolar lung deposition facilitating the uptake of the nanoparticles by dendritic cells. Also, the PspA released from the dry powders maintained antigen stability (SDS-PAGE), integrity (Circular dichroism) and activity (lactoferrin binding assay). Moreover, the released antigen also maintained its antigenicity as determined by ELISA.

show abstract

The Virulence Function of Streptococcus pneumoniae Surface Protein A Involves Inhibition of Complement Activation and Impairment of Complement Receptor-Mediated Protection

Cited by 106 publications

References 31 publications

Complement C1q and C3 Are Critical for the Innate Immune Response to Streptococcus pneumoniae in the Central Nervous System

Complement C1q and C3 Are Critical for the Innate Immune Response to Streptococcus pneumoniae in the Central Nervous System

Reactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia

Pulmonary dry powder vaccine of pneumococcal antigen loaded nanoparticles

Contact Info

Product

Resources

About