Molecular characterization of pneumococcal surface protein K, a potential pneumococcal vaccine antigen

Abstract

The pneumococcal capsule is indispensable for pathogenesis in systemic infections; however, many pneumococcal diseases, including conjunctivitis, otitis media, and some systemic infections in immunocompromised patients, are caused by nonencapsulated Streptococcus pneumoniae (NESp). Null capsule clade 1 (NCC1), found in group 2 NESp, expresses pneumococcal surface protein K (PspK) and is becoming prevalent among pneumococcal organisms owing to the widespread use of pneumococcal conjugate vaccines. Despite its clinical importance, the molecular mechanisms underlying the prevalence of NCC1 have not been fully elucidated. Here, we investigated the role of the R3 domain of PspK in the epithelial cell adherence of NCC1. We found that the R3 domain of PspK mediated NCC1 adherence via its direct interaction with the epithelial surface protein annexin A2. Additionally, neutralization with purified recombinant PspK-R3 or rabbit anti-UD:R3 IgG inhibited binding of NESp to lung epithelial cells in vitro. Immunization with the 'repeat' domain of PspK-R3 or PspK-UD:R3 effectively elicited mucosal and systemic immune responses against PspK-R3 and provided protection against nasopharyngeal, lung, and middle ear colonization of NESp in mice. Additionally, we found that rabbit anti-UD:R3 IgG bound to PspC-R1 of the encapsulated TIGR4 strain and that UD:R3 immunization provided protection against nasopharyngeal and lung colonization of TIGR4 and deaths by TIGR4 and D39 in mice. Further studies using 68 pneumococcal clinical isolates showed that 79% of clinical isolates showed cross-reactivity to rabbit anti-UD:R3 IgG. About 87% of serotypes in the 13-valent pneumococcal conjugate vaccine (PCV) and 68% of nonvaccine serotypes were positive for cross-reactivity with rabbit anti-UD:R3 IgG. Thus, the R3 domain of PspK may be an effective vaccine candidate for both NESp and encapsulated Sp.

Pneumococcal surface adhesion A protein (PsaA) interacts with human Annexin A2 on airway epithelial cells

“…ANXA2 has been shown to be involved in efficient bacterial invasion of epithelial cells by pathogens such as Rickettisa, Mycoplasma pneumoniae, and Pseudomonas aeruginosa [52,53]. In addition to our findings, another group also demonstrated that pneumococcal surface protein K (PspK) interacts with ANXA2 and promotes adherence to lung epithelial cells [54]. Furthermore, a previous study demonstrated that PsaA also interacts with E-cadherin expressed on nasopharyngeal epithelial cells [18].…”

Non-encapsulatedStreptococcus pneumoniae, vaccination as a measure to interfere with horizontal gene transfer

“…In conclusion, the study of Jang et al. shows the potential of PspK as vaccinate candidate, 11 thereby also confirming earlier work from Keller et al. (2015).…”

“…showed furthermore that vaccination with R3 induced protection, showing the strongest effects measured after intranasal immunization. 11 Despite the variability of PspK, antibodies raised against this protein cross-reacted with 79% of the encapsulated strains not containing PspK. This cross-reactivity is likely due to recognition of domains of distantly related proteins, such as PspC and PspA, therefore much higher cross-reactivity is expected with PspK containing NESp.…”

“…studied one of the most important proteins involved in capsule-independent persistence of carriage, the pneumococcal surface protein Korea (PspK), as potential vaccine antigen. 11 The pspK gene is widely spread in NESp group II strains in Asia. 12 Mature PspK, an LPxTG-anchored protein, consists of an undefined domain (UD), an R3 domain, showing homology with the R1 domain of PspC and both containing α-helical structures and a more conserved part containing stretches of 7 amino acid repeats.…”

Pneumococcal Choline-Binding Proteins Involved in Virulence as Vaccine Candidates

“…Regarding nasopharyngeal colonization and the importance of NE Sp in this niche, Jang and colleagues demonstrated that R3 domain of PspK may be an effective vaccine candidate for both NE Sp and encapsulated S. pneumoniae . The immunization with R3 or UD: R3 of PspK elicited effective humoral and mucosal immune responses against nasopharyngeal colonization and the subsequent development of AOM and pulmonary infection in mice [ 75 ].…”