The role of the polysaccharide capsule in the virulence of the Gram positive pathogen S. pneumoniae
(Winner of the Cordwainers Prize 2009)
Dr Jeremy Brown, Respiratory Medicine
Astor & GSK
Description of Project:
The Gram positive pathogen Streptococcus pneumoniae is the commonest cause of pneumonia and a frequently cause of other severe infections, including meningitis and septicaemia. It is the second commonest bacterial cause of death in the world, and the clinical importance of S. pneumoniae infections is compounded by increasing antibiotic resistance amongst clinical isolates and the drawbacks of the existing vaccine preparations, which only protect against a proportion of S. pneumoniae strains. Hence a comprehensive understanding of the interactions of S. pneumoniae with the host immune system is needed to allow the development of better therapeutic and preventative strategies. S. pneumoniae is surrounded by a polysaccharide capsule that is essential for virulence as it is thought to protect the bacteria from complement and phagocytosis, and also modifies the inflammatory response to infection. There are over 90 different types of S. pneumoniae capsule structures, which can be distinguished by their chemical structure and by recognition by specific antibodies. Different S. pneumoniae capsular serotypes vary in their ability to cause invasive disease, and this may reflect differences in the chemical structure of the capsule between serotypes. However, approximately 10% of non-capsular genes vary between strains expressing different capsular serotypes. Hence differences in virulence between capsular serotypes may be due to this variation in non-capsular genes rather than purely due to the structure of the capsule. Furthermore the precise effect of the capsule on complement-mediated immunity and phagocytosis has not been investigated in detail, and as the capsule is the main S. pneumoniae virulence factor and the target for the existing vaccine preparations this requires a more thorough assessment. My PhD will investigate the effect of capsular serotype on virulence of S. pneumoniae. By using a collection of S. pneumoniae strains which express different capsular serotypes in an otherwise isogenic background, the precise role of variation in capsule structure during interaction with host immunity can be investigated. The assays used will assess complement deposition, recognition of sub-capsular protein antigens by specific and natural antibodies, phagocytosis, and virulence in mouse models of infection for the different strains. The data from these studies will accurately define the role of the S. pneumoniae capsule during invasive infection with this important pathogen.
Hyams C, Opel S, Hanage WP, Yuste J, Bax K, Henriques-Normark B, Spratt BG, Brown JS. Effects of Streptococcus pneumoniae strain background on complement resistance. PLoS One. 2011 Oct. 10.1371/journal.pone.0024581
Sanchez CJ, Hinojosa CA, Shivshankar P, Hyams C, Camberlein E, Brown JS, Orihuela CJ. Changes in capsular serotype alter the surface exposure of pneumococcal adhesins and impact virulence. PLoS One. 2011 Oct. 10.1371/journal.pone.0026587
Cohen JM, Khandavilli S, Camberlein E, Hyams C, Baxendale HE, Brown JS. Protective contributions against invasive Streptococcus pneumoniae pneumonia of antibody and Th17-cell responses to nasopharyngeal colonisation. PLoS One. 2011 Oct. 10.1371/journal.pone.0025558
Wilkosz S, Edwards LA, Bielsa S, Hyams C, Taylor A, Davies RJ, Laurent GJ, Chambers RC, Brown JS, Lee YC. Characterization of a new mouse model of empyema and the mechanism of pleural invasion of Streptococcus pneumoniae. Am J Respir Cell Mol Biol. 2011 Sept.
Stables M J, Newson J, Ayoub S, Brown JS, Hyams C, Gilroy D. Priming innate immune responses to infection by cyclooxygenase inhibition kills antibiotic susceptible and resistant bacteria. Blood. 2010 Jul 6.
Yuste J, Sen A, Truedsson L, Jönsson G, Hyams C, Cohen JM, Camberlein E, Sriskandan S, Brown JS. Impaired opsonization with complement and phagocytosis of Streptococcus pyogenes in sera from subjects with inherited C2 deficiency. Microbes Infect. 2010 Apr 21.
Hyams C, Yuste J, Bax K, Camberlein E, Wesier JN and Brown JS. Streptococcus pneumoniae resistance to complement-mediated immunity is dependent on capsular serotype. Infect Immun. 2010 Feb;78(2):716-25.
Hyams C, Camberlein E, Cohen JM, Bax K and Brown JS. The Streptococcus pneumoniae capsule has multiple effects on complement activity and bacterial interactions with neutrophils. Infect Immun. 2010 Feb;78(2):704-15.
Hyams C, Tan JCH, Brown JS and Gordon SB. C3b/iC3b deposition on Streptococcus pneumoniae is not affected by HIV infection. PLoS One. 2010 Jan 26. 5(1): e8902. doi:10.1371/journal.pone.0008902
Yuste J, Khandavilli S, Ansari N, Muttardi K, Ismail L, Hyams C, Weiser JN, Mitchell T and Brown JS. Inhibition of complement-mediated immunity to Streptococcus pneumoniae by PspC vary with strain background and capsular serotype. Infect Immun. 2010 Jan;78(1):283-92.
Yuste J, Sen A, Truedsson L, Jönsson G, Tay LS, Hyams C, Baxendale HE, Goldblatt F, Botto M, Brown JS. Impaired opsonisation with C3b and phagocytosis of Streptococcus pneumoniae in serum from subjects with defects in the classical complement pathway. Infect Immun. 2008 Jun 9
Yuste J, Ali S, Sriskandan S, Hyams C, Botto M and Brown JS. Roles of the alternative complement pathway and C1q during innate immunity to Streptococcus pyogenes. J Immunol. 2006 May 15;176(10):6112-20