In addition, we also demonstrated that pIgR present in human endothelial cell lysates binds to the bacteria, implicating that pIgR may also be involved in bacterial transcytosis of endothelial cells and thus contribute to the development of meningitis. Several studies show that PspC is a natural ligand for pIgR and is necessary and sufficient for pneumococcal adherence to epithelial cells. Subsequent in vitro studies reported that the interaction with PspC was specific for human pIgR. In these studies the interaction between pIgR and PspC was investigated using purified PspC, while we used intact bacteria. The latter might be more relevant and keep the protein in a natural conformation as PspC is normally non-covalently attached to the cell wall through its choline NBD 556 binding motif. Additionally, either isolated soluble component derived from murine pIgR, or transiently transfected cells were used, while we specifically detected membrane bound mouse pIgR in endothelial in mouse brain slides and human endothelial cells. Our finding that S. pneumoniae co-localized with mouse pIgR is based on the unambiguous analysis of our in vivo immunofluorescence and confocal data. Furthermore, the study by Zhang et al. clearly showed that absence of pIgR in vivo leads to less lung invasion and sepsis, indicating that also in the mouse, interaction between S. pneumoniae and pIgR is part of pathogenesis. Further support for a role of pIgR comes from studies that show that pneumococci lacking PspC are less adherent to rat BMEC than wild-type, and PspC was shown to be involved in the transition from the lungs to the blood and from the blood into the cerebrospinal fluid. This indicates that interaction of PspC to pIgR might be important for the development of meningitis. Alternatively, the interaction between S. pneumoniae and endothelial pIgR is mediated through other bacterial proteins. After intranasal challenge, mice lacking pIgR showed less nasal colonization and decreased levels of bacteremia compared to wildtype mice but, unfortunately, no data was provided on the presence of the bacteria in the brain and or CSF. To definitely assess whether the absence of pIgR significantly reduces bacterial translocation into the brain in vivo, intravenous NBQX administration of pneumococci in pIgR2/2 and WT mice should be performed. In conclusion, PAFR is unlikely to physically interact with the bacteria in vivo. On the other hand, we have shown that pIgR is expressed by brain endothelial cells and may act as a novel receptor for S. pneumoniae adhesion to the BBB endothelium. The results presented in this study provide a better understanding of the events preceding pneumococcal meningitis and, in particular, of S. pneumoniae receptor-mediated adhesion to the brain microvascular endothelium.