Streptococcus pneumoniae (the pneumococcus) is a major cause of pneumonia, septicaemia and meningitis, particularly in high-risk groups such as children, the elderly and the immunocompromised. Host genetic factors play a significant role in susceptibility to pneumococcal disease. We have developed a mouse model of genetic susceptibility to invasive pneumococcal disease, with the purpose of identifying candidate disease genes. A panel of nine inbred mouse strains were screened in response to pneumococcal pneumonia infection and two strains emerged showing different phenotypes to the disease, the resistant BALB/c and the susceptible CBA/Ca. On the F2 intercrosses of the mentioned strains was mapped a major quantitative trait locus named Streptococcus pneumoniae infection resistance 1 (Spir1). The Spir1 genetic interval found in chromosome 7, between D7Mit341 and D7Mit247, in an interval with 13Mb and approximately 250 genes, containing several genes that encode molecules involved in inflammation or innate immunity. Previous investigation on gene expression and protein levels in BALB/c and CBA/Ca lungs during an infection time course observed significant differences in transforming growth factor (TGF)-β1 and Ikbβ between strains in response to pneumococcal infection. Regarding the related host genetic differences, further research was done during my PhD, investigating host immune responses to pneumococcal infection and more intensely the contribution of TGF-β and its downstream targets (including T regulatory cells). I have demonstrated that Foxp3+ T regulatory cells have crucial protective functions during infection, as blocking their induction with an inhibitor of TGF-β significantly alters the BALB/c resistance phenotype to infection and aids bacterial dissemination from lungs; and conversely, adoptive transfer of T regulatory cells to CBA/Ca mice, prior to infection, prolongs survival and decreases bacterial dissemination. This novel study provides key evidence for the importance of immunomodulation during pulmonary pneumococcal infection. Within this genomic region located in chromosome 7, it was found in the pneumococcal-susceptible CBA/Ca strain a novel polymorphism in the cd22 gene, predicted to prevent synthesis of the protein almost completely, whereas pneumococcal-resistant BALB/c mice have no impairment in the B-cell receptor CD22. Strikingly, CD22-deficient mice (C57BL/6J background) evidenced reduced survival and increased bacterial dissemination from lungs to blood and spleen, not observed in control mice. This study provides enthusing new indication for the contribution of B-cell receptor CD22 during invasive pneumococcal disease. Together, these studies indicate that the Spir1 region contains a cluster of genes contributing to susceptibility to pneumococcal disease.