Understanding the relationship between central metabolism and virulence in the human pathogen Streptococcus pneumoniae

Abstract

Streptococcus pneumoniae is a normal inhabitant of the human nasopharynx, but it is better known for its role in a plethora of human diseases. Growing emergence of antibiotic-resistant streptococci and non-type vaccine strains increases the urgency of finding new targets for the development of novel therapeutic and preventive drugs. As a major concern for global public health, S. pneumoniae has always attracted great attention from the scientific community, which has translated into knowledge on pathogenesis and virulence and the development of a considerable “toolbox” for genetic manipulation and genomic analysis, as well as a large number of deciphered genome sequences. Interestingly, genome-wide studies have consistently pinpointed genes involved in carbohydrate uptake and metabolism as essential for the virulence of S. pneumoniae. These global studies offered the opportunity to investigate in greater depth the potential connections between basic physiology, and in particular central metabolism, and pneumococcal virulence and pathogenesis. The general goal of this thesis is to achieve a deeper understanding of the molecular mechanisms underlying sugar metabolism and their relation to virulence factors in S. pneumoniae, with a special focus on capsule production. In the present work, glucose (Glc) and galactose (Gal) were used as carbon sources for the study of pneumococcal sugar metabolism. This choice was made for two reasons: Firstly, Glc is a common preferred sugar and is also found as a major carbon source in niches potentially occupied by S. pneumoniae during host inflammation or hyperglycaemia. Secondly, Gal, generally a slowly metabolized non-preferred sugar, is a major carbohydrate in the human nasopharynx, the non-pathological colonization niche of S. pneumoniae.