The success of Streptococcus pneumonia (pneumococcal) as a human pathogen is largely due to its capability to employ a polysaccharide (PS) capsule to avoid host immunity. Recent discovery and characterization of the pneumococcal serotype 11E strongly suggested that inactivation of the capsule synthesis gene wcjE8 which encodes a putative O-acetyltransferase, plays an important role in escaping a host humoral immune response to the closely related serotype 11A. Since many epidemiologically prevalent serotypes also contain the gene, discerning the effects of WcjE-mediated variable O-acetylating on the serological properties of serotypes 11A and 11E will aid in understanding pneumococcal pathology, in determining trends of emerging pneumococcal serotypes and in designing effective PS-based vaccines. Previously serotype as 11A, the true epidemiological nature of 11E is unclear. Clinical isolates originally serotype as 11A will be readdressed for the expression of 11E capsule using serospecific monoclonal antibodies. To understand the serological flexibility of these serotypes, the genetic properties that lead to seroswitching between 11A and 11E will be further studied. Additionally, the role wcjE inactivation plays in avoiding a human humoral response will be evaluated using an in vitro opsonophagocytosis killing assay (OPKA) with sera from humans vaccinated with the 23- valent polysaccharide vaccine, which includes 11A PS. Independent and competitive OPKA survival of strains expressing 11A and 11E capsule will be compared, and the capacity of purified 11A and 11E PS to inhibit functional antibodies will be determined. Finally, the capacity of serotype 11A to escape an 11A-specific humoral response through wcjE- inactivation in vivo and the effects on pathology will be verified in a murine infection model. The survival of 11A and 11E strains will be compared under naove conditions, with passive 11A-specific immunization, and with preimmunization against 11A and 11E PS. These assays will also provide preliminary information on the use of 11E as a potential vaccine against both serotypes.
Understanding how Streptococcus pneumonia serotypes escape an immune response is important for the design of interventional and preventative strategies against this significant human pathogen. This proposed research will study the effects of O-acetylating modification of S. pneumonia capsule on antibody-dependent clearance of the bacteria, in relation to the prevalent serotype 11A and the closely related serotype 11E.
|Calix, Juan J; Dagan, Ron; Pelton, Stephen I et al. (2012) Differential occurrence of Streptococcus pneumoniae serotype 11E between asymptomatic carriage and invasive pneumococcal disease isolates reflects a unique model of pathogen microevolution. Clin Infect Dis 54:794-9|
|Calix, Juan J; Saad, Jamil S; Brady, Allison M et al. (2012) Structural characterization of Streptococcus pneumoniae serotype 9A capsule polysaccharide reveals role of glycosyl 6-O-acetyltransferase wcjE in serotype 9V capsule biosynthesis and immunogenicity. J Biol Chem 287:13996-4003|
|Calix, Juan J; Nahm, Moon H; Zartler, Edward R (2011) Elucidation of structural and antigenic properties of pneumococcal serotype 11A, 11B, 11C, and 11F polysaccharide capsules. J Bacteriol 193:5271-8|