Identification and Characterization of a Novel Family of Pneumococcal Proteins That Are Protective against Sepsis

Adamou, John E.; Heinrichs, Jon H.; Erwin, Alice L.; Walsh, William T.; Gayle, Tony; Dormitzer, Melissa; Dagan, Ron; Brewah, Yambasu A.; Barren, Philip; Lathigra, Raju; Langermann, Solomon; Koenig, Scott; Johnson, Syd

doi:10.1128/iai.69.2.949-958.2001

Cited by 198 publications

(202 citation statements)

References 41 publications

Supporting

Mentioning

193

Contrasting

Unclassified

Order By: Relevance

“…1A). The same motif, for which no function has been identified, has been described for several surface proteins of Streptococcus pneumoniae (1,64). Together, the similarities between Blr and Slr demonstrate that these two proteins are members of a family of streptococcal proteins with LRRs.…”

Section: Resultsmentioning

confidence: 78%

The Streptococcal Blr and Slr Proteins Define a Family of Surface Proteins with Leucine-Rich Repeats: Camouflaging by Other Surface Structures

et al. 2006

View full text Add to dashboard Cite

Regions with tandemly arranged leucine-rich repeats (LRRs) have been found in many prokaryotic and eukaryotic proteins, in which they provide a remarkably versatile framework for the formation of ligandbinding sites. Bacterial LRR proteins include the recently described Slr protein of Streptococcus pyogenes, which is related to internalin A of Listeria monocytogenes. Here, we show that strains of the human pathogen Streptococcus agalactiae express a protein, designated Blr, which together with Slr defines a family of internalin A-related streptococcal LRR proteins. Analysis with specific antibodies demonstrated that Blr is largely inaccessible on S. agalactiae grown in vitro, but surface exposure was increased ϳ100-fold on mutants lacking polysaccharide capsule. In S. pyogenes, surface exposure of Slr was not affected in a mutant lacking hyaluronic acid capsule but was increased >20-fold in mutants lacking M protein or protein F. Thus, both Blr and Slr are efficiently camouflaged by other surface structures on bacteria grown in vitro. When Blr and Slr exposed on the bacterial surface were compared, they exhibited only little immunological cross-reactivity, in spite of extensive residue identity, suggesting that their surface-exposed parts have been under evolutionary pressure to diverge functionally and/or antigenically. These data identify a family of immunologically diverse streptococcal LRR proteins that show unexpected complexity in their interactions with other bacterial surface components.

show abstract

Section: Resultsmentioning

confidence: 78%

The Streptococcal Blr and Slr Proteins Define a Family of Surface Proteins with Leucine-Rich Repeats: Camouflaging by Other Surface Structures

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Dis.). Immunization of mice with members of the BVH-11 family, i.e., PhtA (BVH-11-3), PhtB/PhpA (BVH-11), or PhtD (BVH-11-2), generated protection against S. pneumoniae (1,31), while a truncated version of BVH-3 (PhtE) was shown to be ineffective (1).…”

mentioning

confidence: 99%

Prevention of Pneumococcal Disease in Mice Immunized with Conserved Surface-Accessible Proteins

et al. 2004

View full text Add to dashboard Cite

The development of a vaccine against Streptococcus pneumoniae has been complicated by the existence of at least 90 antigenically distinct capsular serotypes. Common protein-based vaccines could represent the best strategy to prevent pneumococcal infections, regardless of serotype. In the present study, the immunoscreening of an S. pneumoniae genomic library allowed the identification of a novel immune protein target, BVH-3. We demonstrate that immunization of mice with BVH-3 elicits protective immunity against experimental sepsis and pneumonia. Sequence analysis revealed that the bvh-3 gene is highly conserved within the species. Since the BVH-3 protein shows homology at its amino-terminal end with other pneumococcal proteins, it was of interest to determine if protection was due to the homologous or to the protein-specific regions. Immunoprotection studies using recombinant BVH-3 and BVH-3-related protein fragments as antigens allowed the localization of surface-exposed and protective epitopes at the protein-specific carboxyl termini, thus establishing that BVH-3 is distinct from other previously reported protective protein antigens. Immunization with a chimeric protein comprising the carboxyl-terminal regions of BVH-3 and of a BVH-3-related protein improved the protection by targeting two surface pneumococcal components. Thus, BVH-3 and the chimeric protein hold strong promise as vaccine components to control pneumococcal disease.

show abstract

“…Several functions have been proposed for these proteins, including promoting adherence to host cell surfaces (9), protection against complement deposition (12), and scavenging of zinc ions (13). PhtD protein has been shown to elicit protection in a mouse model against S. pneumoniae systemic infection caused by different serotypes (11,14). Human anti-PhtD antibodies have been detected in children during NP colonization and invasive diseases caused by S. pneumoniae, indicating that PhtD is expressed and recognized by the host immune system during infection (10,15,16).…”

mentioning

confidence: 99%

Human Antibodies to PhtD, PcpA, and Ply Reduce Adherence to Human Lung Epithelial Cells and Murine Nasopharyngeal Colonization by Streptococcus pneumoniae

et al. 2014

View full text Add to dashboard Cite

bStreptococcus pneumoniae adherence to human epithelial cells (HECs) is the first step in pathogenesis leading to infections. We sought to determine the role of human antibodies against S. pneumoniae protein vaccine candidates PhtD, PcpA, and Ply in preventing adherence to lung HECs in vitro and mouse nasopharyngeal (NP) colonization in vivo. Human anti-PhtD, -PcpA, and -Ply antibodies were purified and Fab fragments generated. Fabs were used to test inhibition of adherence of TIGR4 and nonencapsulated strain RX1 to A549 lung HECs. The roles of individual proteins in adherence were tested using isogenic mutants of strain TIGR4. Anti-PhtD, -PcpA, and -Ply human antibodies were assessed for their ability to inhibit NP colonization in vivo by passive transfer of human antibody in a murine model. Human antibodies generated against PhtD and PcpA caused a decrease in adherence to A549 cells (P < 0.05). Anti-PhtD but not anti-PcpA antibodies showed a protective role against mouse NP colonization. To our surprise, anti-Ply antibodies also caused a significant (P < 0.05) reduction in S. pneumoniae colonization. Our results support the potential of PhtD, PcpA, and Ply protein vaccine candidates as alternatives to conjugate vaccines to prevent non-serotype-specific S. pneumoniae colonization and invasive infection.

show abstract

Identification and Characterization of a Novel Family of Pneumococcal Proteins That Are Protective against Sepsis

Cited by 198 publications

References 41 publications

The Streptococcal Blr and Slr Proteins Define a Family of Surface Proteins with Leucine-Rich Repeats: Camouflaging by Other Surface Structures

The Streptococcal Blr and Slr Proteins Define a Family of Surface Proteins with Leucine-Rich Repeats: Camouflaging by Other Surface Structures

Prevention of Pneumococcal Disease in Mice Immunized with Conserved Surface-Accessible Proteins

Human Antibodies to PhtD, PcpA, and Ply Reduce Adherence to Human Lung Epithelial Cells and Murine Nasopharyngeal Colonization by Streptococcus pneumoniae

Contact Info

Product

Resources

About