Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice

Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. quantitate specific antibody isotype responses and the ability of antibody and various proteins to inhibit epithelial cell adhesion. Host cytokine response was not reduced by PspK. NESp was able to colonize the mouse nasopharynx as effectively as encapsulated pneumococci. Systemic and mucosal immunization provided protection from colonization by PspK-positive (PspK+) NESp. Anti-PspK antibodies were recovered from immunized mice and significantly reduced the ability of NESp to adhere to human epithelial cells. A protein-based pneumococcal vaccine is needed to provide broad protection against encapsulated and nonencapsulated pneumococci in an era of increasing antibiotic resistance and vaccine escape mutants. We demonstrate that PspK may serve as an NESp target for next-generation pneumococcal vaccines. Immunization with PspK guarded against pneumococcal colonization, which is usually requisite for pneumococcal disease. INTRODUCTION Vaccination has been the single most effective means of preventing death by infectious organisms (1). (pneumococcus) is the etiological agent of several human diseases such as pneumonia, sinusitis, otitis media (OM), meningitis, Mouse monoclonal antibody to Keratin 7. The protein encoded by this gene is a member of the keratin gene family. The type IIcytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratinchains coexpressed during differentiation of simple and stratified epithelial tissues. This type IIcytokeratin is specifically expressed in the simple epithelia ining the cavities of the internalorgans and in the gland ducts and blood vessels. The genes encoding the type II cytokeratinsare clustered in a region of chromosome 12q12-q13. Alternative splicing may result in severaltranscript variants; however, not all variants have been fully described and septicemia (2). The prevalence of invasive pneumococcal disease (IPD) was significantly reduced after the introduction of currently licensed pneumococcal vaccines (3). Pneumococcal vaccines target specific pneumococcal polysaccharide serotypes, 23 in Pneumovax (Pneumovax 23 [PPSV23]; Merck, Whitehouse Station, NJ, USA) and 13 in Prevnar (Prevnar 13 [PCV13]; Pfizer [formerly Wyeth Pharmaceuticals], New York, NY, USA). With over 90 known antigenically distinct pneumococcal serotypes, there is a significant deficit in vaccine coverage of the serological diversity expressed by the species (4). This coverage gap is usually widened by the increase in nonencapsulated (NESp) carriage since the introduction of the pneumococcal conjugate vaccine (PCV) (5). Pneumococcal disease is usually predicated by carriage, and NESp is usually associated with cases of OM and conjunctivitis (6,C8). NESp cannot be guarded against by current vaccine formulations due to the lack of the capsular polysaccharide. Vaccination with a pneumococcal protein antigen can provide broader pneumococcal protection and be more BGJ398 (NVP-BGJ398) cost-effective to produce, but a suitable candidate that covers the majority of pneumococci has yet to be developed. While numerous protein-based candidates have been tested, such as PspA, PspC, and PcpA, they have been found to be effective to various degrees based on pneumococcal strain (9,C12). Combinations of proteins have been found to be more effective and to have broader coverage (13, 14). NESp does not contain the aforementioned proteins, increasing the need for a protein target effective against NESp (15, 16). Pneumococcal surface proteins are potential targets for immunization due to accessibility and the BGJ398 (NVP-BGJ398) function of the protein during colonization. Pneumococcal surface proteins are classified by means of surface attachment and BGJ398 (NVP-BGJ398) include choline binding proteins (CBPs), LPxTG binding proteins, lipoproteins, and nonclassical surface proteins (17, 18). Some of the most well characterized surface proteins are CBP and LPxTG binding proteins (17). These proteins are immunogenic and aid in colonization. Colonization is usually requisite for pneumococcal disease in encapsulated and nonencapsulated strains (2, 17). Pneumococcal surface protein K (PspK), an LPxTG-anchored surface protein, has been shown to be necessary for colonization in a subset (null capsule clade I) of NESp and plays a role in virulence during experimental OM (19,C21). The role of PspK in colonization makes it a potential vaccine target. While we have previously exhibited an increase in epithelial cell adherence due to PspK, it is unknown if there are other effects PspK exerts during colonization (20). Pneumococcal surface protein C (PspC), a CBP, shares some sequence identity with PspK (21). PspC has been reported to aid in epithelial cell adhesion, recruitment of immune factors, and regulation of specific cytokines (22, 23). All of these functions are important for initial colonization and persistence in the nasopharynx. The pneumococcus must attach to epithelial cells to effectively colonize the nasopharynx. Once.