Importance of the pro-inflammatory effects of the capsule during invasive Streptococcus pneumoniae infection

Streptococcus pneumoniae is the second most common cause of fatal bacterial infection world wide, causing half of all pneumonias and is also a frequent cause of meningitis and septicaemia. While the body's immune response results in the recruitment of white blood cells allowing the killing of the foreign organisms, the resulting inflammation can also cause damage to the body's own tissues. The pneumococcus is surrounded by a capsule made of sugars, which is important for the bacteria to evade being killed by white blood cells. However recent data from Drs Brown and Noursadeghi's laboratories has shown the capsule also affects the inflammatory response to pneumococcus, surprisingly resulting in increased pro-inflammatory responses. This effect could critically affect the development of invasive disease and inflammatory complications of severe infection such as septic shock. Furthermore, there are over 90 variations in pneumococcal capsule (serotypes), which are known to vary in severity and type of disease. These variations could be partially mediated by differences between serotypes in their effects on inflammation. By examining the affects of the capsule on the inflammatory response and the mechanisms underpinning it I hope to identify potential targets for therapeutic intervention and to improve our understanding of disease development, and thus reduce the morbidity and mortality of pneumococcus.

Streptococcus pneumoniae pneumonia is one of the commonest causes of severe infection in adults and children both in developed and developing countries. Although inflammation is required to control bacterial replication, an excess inflammatory response contributes to the complications of severe S. pneumoniae infection including septic shock, acute lung injury, and brain damage during meningitis. Recently the inflammatory response has also been implicated in tight junction downregulation allowing bacterial invasion across epithelial layers, so promoting bacterial invasion. Hence the factors that influence the inflammatory response to are critical mediators of severe infection and potentially could be new therapeutic targets to improve the high mortality and morbidity of severe S. pneumoniae infections. Recent data from Drs Brown and Noursadeghi's laboratories has shown that unexpectedly unencapsulated S. pneumoniae induce a weaker macrophage pro-inflammatory response than encapsulated bacteria. Although the capsule inhibited translocation of NFKB into the nucleus, encapsulated strains stimulated increased transcription of various cytokines and a greater release of TNFa, IL-6 and IL-1B. The purpose of this project is to (a) characterize whether these affects of the capsule on inflammation affect disease development using rodent models of septic shock and acute lung injury and cell culture models of tissue invasion, (b) to use bacterial mutants and inhibitors of inflammatory pathways to identify the mechanisms underpinning the increased inflammatory response to encapsulated bacteria; and (c) to further investigate the clinical relevance of capsule on inflammation by using capsular switched mutant strains and well characterised clinical isolates to assess whether variations in inflammatory responses between S. pneumoniae strains are related to capsular serotype, and hence could contribute towards serotype-dependent differences in disease phenotypes.

Despite effective antibiotics and a successful vaccination campaign S. pneumoniae continues to cause a significant burden worldwide. The experiments detailed above should bring advances to the understanding of how S. pneumoniae causes such morbidity and mortality. By understanding these processes in more detail, we will hopefully be able to modify the inflammatory reaction without causing increased bacterial presence. As such the following will have a beneficial impact from the planned project:

The wide range of state of the art scientific techniques that I will learn and exposure to the wider scientific community while completing this PhD will contribute to my academic development and hopefully form the platform for a future career.

The academic community involved in respiratory infection, bacterial disease pathogenesis, or inflammation. Advances in the knowledge base of the capsule's role in inflammation will hopefully add to the understanding of disease processes of other groups in our and closely related fields. The central role of inflammation in many disease processes will hopefully allow a broader impact in academic circles.

Clinicians involved in the treatment of respiratory infection from GPs to Intensivists will benefit from any advances in pneumonia care that result from an improved understanding of its pathogenesis.

Downstream translational research may lead to the identification of inflammatory processes that can be affected. The development of drugs targeting these processes will have multiple benefits. This would firstly have a positive impact on the pharmaceutical companies involved and hence national economic benefits.

On the larger scale any intervention that reduces the mortality rates associated with a pathogen that affects such large numbers particularly in under 5s or the elderly could have direct benefits for future patients suffering from severe S. pneumoniae infection.