Streptococcus pneumoniae Interacts with pIgR Expressed by the Brain Microvascular Endothelium but Does Not Co-Localize with PAF Receptor

Abstract

Streptococcus pneumoniae is thought to adhere to the blood-brain barrier (BBB) endothelium prior to causing meningitis. The platelet activating factor receptor (PAFR) has been implicated in this adhesion but there is a paucity of data demonstrating direct binding of the bacteria to PAFR. Additionally, studies that inhibit PAFR strongly suggest that alternative receptors for pneumococci are present on the endothelium. Therefore, we studied the roles of PAFR and pIgR, an established epithelial pneumococcal receptor, in pneumococcal adhesion to brain endothelial cells in vivo. Mice were intravenously infected with pneumococci and sacrificed at various time points before meningitis onset. Co-localization of bacteria with PAFR and pIgR was investigated using immunofluorescent analysis of the brain tissue. In vitro blocking with antibodies and incubation of pneumococci with endothelial cell lysates were used to further probe bacteria-receptor interaction. In vivo as well as in vitro pneumococci did not co-localize with PAFR. On the other hand the majority of S. pneumoniae co-localized with endothelial pIgR and pIgR blocking reduced pneumococcal adhesion to endothelial cells. Pneumococci physically interacted with pIgR in endothelial cell lysates. In conclusion, bacteria did not associate with PAFR, indicating an indirect role of PAFR in pneumococcal adhesion to endothelial cells. In contrast, pIgR on the BBB endothelium may represent a novel pneumococcal adhesion receptor.

Platelet Endothelial Cell Adhesion Molecule-1, a Putative Receptor for the Adhesion of Streptococcus pneumoniae to the Vascular Endothelium of the Blood-Brain Barrier

“…Blocking of PAFR leads to a significant reduction of pneumococcal adhesion to endothelial cells in vitro, and complete absence of PAFR leads to less invasive pneumococcal disease in mouse models (4,7). However, we recently obtained data suggesting that a physical interaction between S. pneumoniae and PAFR is not likely to occur, as we did not observe colocalization between the receptor and the bacteria in the brain tissue of intravenously infected mice (10). Orihuela et al showed that the laminin receptor can initiate the contact of S. pneumoniae with the brain vascular endothelium in vivo (11).…”

“…Orihuela et al showed that the laminin receptor can initiate the contact of S. pneumoniae with the brain vascular endothelium in vivo (11). The polyimmunoglobulin receptor (pIgR) can mediate binding of pneumococci to the epithelium of the upper respiratory tract (5,12), and we recently showed new evidence that pIgR is also implicated in binding of S. pneumoniae to brain endothelial cells (10). At the moment the extent of their contribution is unclear, and it remains to be established whether more receptors are involved in pneumococcal adherence to the blood-brain endothelium.…”

Pneumococcal meningitis is promoted by single cocci expressing pilus adhesin RrgA

“…Next, we used a bacteremia-derived meningitis mouse model (6,7,15) to study the role played by pilus-1 in meningitis development. Bacterial counts from brain homogenates demonstrated that mice infected with piliated invasive BHN191 had approximately 80% more pneumococci in the brain than did mice infected with the nonpiliated carriage isolate BHN460 ( Figure 1A).…”

“…Meningitis is usually caused by bacteria crossing from the bloodstream into the brain through the blood-brain barrier (BBB) (4). Pneumococcal translocation through the BBB is facilitated by receptor-mediated binding to the plasma membrane of endothelial cells (5)(6)(7). Previous reports have shown that the surface-anchored neuraminidase A (NanA) protein promotes pneumococcal invasion of brain endothelial cells (8) and that pneumolysin and choline-binding protein A (CbpA) are important for the development of invasive pneumococcal disease, including meningitis (9).…”

Temporal upregulation of host surface receptors provides a window of opportunity for bacterial adhesion and disease

“…Pneumococci utilize a similar set of host surface receptors, including PAFR, for both adherence to the respiratory epithelium and for penetrating the endothelial lining of the blood-brain barrier [34]. In addition, poly immunoglobulin receptor (pIgR), which transports immunoglobulins across mucosal epithelium, and platelet endothelial cell adhesion molecule-1 (PECAM-1), involved in leukocyte migration and angiogenesis in the endothelium, have also been found to be utilized by pneumococci for endothelium adhesion and invasion [62,63]. It has been proposed that pneumococcal infection in itself may upregulate pIgR and PECAM-1 expression via a PAFR-mediated signalling mechanism [64].…”