Molecular Mechanisms of Pneumococcal Adaptation to Host Environment & Stress

The gram-positive bacterium Streptococcus pneumoniae (pneumococcus) is a leading cause of lower respiratory infections worldwide and is also responsible fordiseases such as otitis media, sinusitis, meningitis, endocarditis and sepsis. The progression to this pathogenic lifestyle is preceded by colonization of the nasopharynx.In order to successfully colonize the human upper respiratory tract (URT), pneumococcus must adapt to the unpredictable and hostile conditions of the human host. To achieve this, bacterial cells must adeptly reconfigure their cellular programs to ensure their survival while continuing to evade the host immune responses. This work is aimed at understanding the different molecular mechanismsof pneumococcal adaptation to the host environment and the stresses it encounters therein. In this thesis, I focus on two distinct mechanisms that enable pneumococcalpropagation and survival in diverse conditions. First, I describe a novel intercellular communication peptide called BriC that promotes biofilm development and stimulates colonization in a murine model. BriC signaling results in enrichment of unsaturated lipids in the cell membrane via enhancing FabT-mediated regulation of fatty acid biosynthesis genes. My work reveals the existence of acomplex molecular network that regulates briC expression in the cells. BriC helps in integration of various regulatory inputs as briC levels are induced by the activationof competence and fatty acid biosynthesis pathways. The tightly controlled architecture of briC regulation highlights its importance in the ever-changing environment of the human host. Second, I explore pneumococcal stress responsepathway and show that a cell wall branching enzyme MurM modulates intracellular stress and prevents the activation of stringent response pathway. Through its ability to deacylate mischarged tRNAs, MurM can calibrate stress response withconsequences to host-pathogen interactions. This work expands our understanding of the bacterial cell wall: cell wall modification that impart structural rigidity to the cell are interlinked to the cell’s ability to signal intracellularly and mount responses to environmental stresses.