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Infection and Immunity, October 2004, p. 5646-5653, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5646-5653.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The ClpP Protease of Streptococcus pneumoniae Modulates Virulence Gene Expression and Protects against Fatal Pneumococcal Challenge

Hyog-Young Kwon,1,{dagger} A. David Ogunniyi,2,{dagger} Moo-Hyun Choi,1 Suhk-Neung Pyo,1 Dong-Kwon Rhee,1* and James C. Paton2

College of Pharmacy, Sungkyunkwan University, Suwon, Korea,1 School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia2

Received 23 December 2003/ Returned for modification 6 May 2004/ Accepted 7 July 2004

Streptococcus pneumoniae usually colonizes the nasopharynx of humans asymptomatically but occasionally translocates from this niche to the lungs, the brain, and the blood, causing potentially fatal infections. Spread to other host tissues requires a significant morphological change and the expression of virulence factors, such as capsular polysaccharide, and virulence proteins, such as pneumolysin (Ply), PspA, and CbpA. Modulation of the expression of pneumococcal virulence genes by heat shock and by heat shock proteins ClpL and ClpP, as well as the attenuation of virulence of a clpP mutant in a murine intraperitoneal infection model, was demonstrated previously. In this study, we further investigated the underlying mechanism of virulence attenuation by the clpP mutation. The half-lives of the mRNAs of ply and of the first gene of the serotype 2 capsule synthesis locus [cps(2)A] in the clpP mutant were more than twofold longer than those of the parent after heat shock, suggesting that the mRNA species were regulated posttranscriptionally by ClpP. In addition, the clpP mutant was defective in colonization of the nasopharynx and survival in the lungs of mice after intranasal challenge. The mutant was also killed faster than the parent in the murine macrophage RAW264.7 cell line, indicating that ClpP is required for colonization and intracellular survival in the host. Furthermore, fractionation studies demonstrated that ClpP was translocated into the cell wall after heat shock, and immunization of mice with ClpP elicited a protective immune response against fatal systemic challenge with S. pneumoniae D39, making ClpP a potential vaccine candidate for pneumococcal disease.

* Corresponding author. Mailing address: College of Pharmacy, Sungkyunkwan University, Suwon 440-746, South Korea. Phone: 82 31 2907707. Fax: 82 31 2928800. E-mail: dkrhee{at}skku.edu.

Editor: V. J. DiRita

{dagger} H.-Y.K. and A.D.O. contributed equally to this work.

Infection and Immunity, October 2004, p. 5646-5653, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5646-5653.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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