Molecular Basis of Pneumococcal Adherence and Complement Evasion: Structural and Biochemical Studies of Pneumococcal Virulence Factor CbpA ByDavid Otieno AchilaStreptococcus pneumoniae is a human adapted pathogen of global importance as a leading cause of a wide spectrum of infections, such as pneumonia, bacteremia, meningitis, otitis media, and sinusitis. S. pneumoniae is highly resistant to host innate immunity during nasopharyngeal colonization and invasive infections. Because of pneumococcal strain variations, the vaccines currently available for pneumococcal infections are only effective against a subset of strains and do not provide universal protection. Promising novel antigens have been identified including CbpA, a surface protein whose gene is present in all characterized virulent S. pneumoniae strains. S. pneumoniae recruits FH, a negative regulator of complement system, to its surface and therefore evades complement-mediated clearance. CbpA binds to the human complement factor H (FH), but not to the FH proteins from other animal species that have been tested to date, including mouse and rabbit. In this study, we show for the first time that 9th domain of FH (FH CCP9) of the 20 FH domains is crucial and sufficient for its interaction with CbpA and that the interaction is very tight with a Kd of ~ 5 nM. We also present a 1 Ẳ crystal structure of the FH9 in complex with N-terminal á-helical domain of CbpA (CbpAN). We also found evidence of a hydrophobic core defined by four FH CCP9 residues and one CbpAN residue at the complex interface which may be responsible for host-specificity. These findings will enhance the understanding of the host-specificity of this host-pathogen interaction and also inform creation of better animal models for studying pneumococcal diseases. The insights gained will also benefit design of universal protein-based vaccines and novel therapeutics for the treatment and prevention of otitis medium and other infections caused by pneumococcus.
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