Streptococcus pneumoniae (the pneumococcus) is responsible for diseases such as pneumonia, invasive disease (IPD), and otitis media, and is the leading cause of death in children in the world. The pneumococcus is a particularly significant cause of mortality and morbidity in remote Indigenous Australian communities. Whilst the pneumococcus is a clinically significant pathogen, the organism is more likely to be carried asymptomatically in the nasopharynx. However, the mechanisms that underlie the transition from carriage to disease are poorly understood. Therefore, the present study seeks to better understand this process by using natural strain to strain variation in virulence between serotype 1 clinical isolates as a model for understanding why some strains are more likely to cause disease than others. Serotype 1 clinical isolates responsible for unusually severe IPD in humans, were found to rapidly invade and survive in the lungs, pleural cavity and blood of mice, whereas serotype 1 human carriage isolates were rapidly cleared from the lungs and not detected in the pleural cavity or blood of mice. Furthermore, stronger induction of the type I IFN response in the lungs was found to facilitate early invasion of the pleural cavity by the highly virulent strains. Genomic sequencing identified 8 accessory regions that were present in strains responsible for unusually severe disease in humans, but absent from less virulent strains. In particular, the variable region of the pneumococcal pathogenicity island 1 (PPI-1) was responsible for survival within the lungs and rapid invasion of the pleural cavity and blood. Moreover, PPI-1 was found to influence the early immune response to the pneumococcus in the lungs. This work documents rare insights into the molecular interactions between clinically significant isolates of S. pneumoniae and the host, which are ultimately essential for the development of novel therapeutic interventions.