Effects of the Streptococcus pneumoniae capsule on interactions with macrophages and during early lung infection

Streptococcus pneumoniae (also known as the pneumococcus) is a bacteria that is a common cause of severe diseases like pneumonia and meningitis. One reason why pneumococcus is able to cause severe infections is that it is coated with a layer of material made of sugars that is called the capsule. This capsule seems to act like a coat of armour, preventing the immune system from killing the bacteria and thereby allowing the bacteria to successfully invade the body. Although it is thought the capsule prevents white cells from getting rid of the pneumococcus, surprisingly little is known on exactly how the capsule disguises or protects the pneumococcus from different aspects of the bodies immune system. The aim of this project is to investigate precisely how the capsule helps the pneumococcus cause disease in particular pneumonia, the commonest severe disease it causes. We will identify which proteins on the white cell surface are prevented from recognising the pneumococcus by the capsule, and what are the consequences of this failure to identify properly the bacteria for the immune response and development of lung infection. As all vaccines against the pneumococcus that are in use at present rely on using the capsule, more detailed information on the functions of the capsule during infection will be helpful. Furthermore, the information obtained may allow the design of new effective therapies against the pneumococcus, and will provide more detailed information on how the pneumococcus is able to cause pneumonia even in previously healthy individuals.

The polysaccharide capsule is a major virulence determinant of Streptococcus pneumoniae as well as the target of the vaccines presently in use. The capsule is thought to aid virulence by preventing phagocytosis, but the exact mechanisms involved are surprisingly poorly understood considering the importance of the capsule for S. pneumoniae disease. Furthermore little is known about how the effects of the capsule on interactions with phagocytes can affect disease development. The existing data on the S. pneumoniae capsule and preliminary data from Dr Brown?s laboratory indicate that the capsule can prevent neutrophil phagocytosis by reducing opsonisation of S. pneumoniae with complement. Furthermore, during early lung infection phagocytosis of unencapsulated S. pneumoniae by alveolar macrophages is considerably more efficient than that of encapsulated bacteria. However, phagocytosis can be mediated by interactions between the pathogen and a range of possible phagocyte cell surface receptors, including complement receptors, antibody receptors, lectins, integrins and scavenger receptors, and how the S. pneumoniae capsule affects these interactions with macrophages is poorly defined. We propose to use encapsulated and unencapsulated strains of two S. pneumoniae capsular serotypes to investigate the effect of the capsule on S. pneumoniae interactions with macrophages in more detail. In addition, we will also investigate how the capsule affects S. pneumoniae interactions with the alveolar macrophage in vivo and aids the development of lung infection. By using Dr Brown?s experience in investigating S. pneumoniae immunity and Dr Caron?s expertise in the molecular mechanisms of phagocyosis, we will addresses the hypothesis that the S. pneumoniae capsule increases virulence during the develpment of lung infection mainly by preventing complement opsonisation of the bacteria and thereby indirectly inhibiting phagocytosis by alveolar macrophages. In particular we will use a combination of recent advances in techniques for investigating macrophage cell biology and in the use of animal models to characterise the development of infection to assess the effects of the S. pneumoniae capsule on: (a) the distribution and nature of complement deposition on S. pneumoniae: (b) complement-dependent and -independent interactions of S. pneumoniae with macrophages; (c) which receptors and mechanism(s) are responsible for S. pneumoniae recognition and phagocytosis by macrophages; and (d) how these capsule-dependent effects alter the development of early lung infection. The data obtained will improve our fundamental understanding of the function of the capsule, a major virulence determinant and therapeutic target of S. pneumoniae, and may lead to improved therapies against this important pathogen.