title: Streptococcus pneumoniae invades endothelial host cells via multiple pathways and is killed in a lysosome dependent manner.
abstract: Streptococcus pneumoniae is one of the major causative agents of pneumonia, sepsis, meningitis and other morbidities. In spite of its heavy disease burden, surprisingly little is known about the mechanisms involved in the switch of life style, from commensal colonizer of the nasopharynx to invasive pathogen. In vitro experiments, and mouse models have shown that S. pneumoniae can be internalized by host cells, which coupled with intracellular vesicle transport through the cells, i.e. transcytosis, is suggested to be the first step of invasive disease. To further dissect the process of S. pneumoniae internalization, we chemically inhibited discrete parts of the cellular uptake system. We show that this invasion of the host cells was facilitated via both clathrin- and caveolae-mediated endocytosis. After internalization we demonstrated that the bulk of the internalized S. pneumoniae was killed in the lysosome. Interestingly, inhibition of the lysosome altered transcytosis dynamics as it resulted in an increase in the transport of the internalized bacteria out of the cells via the basal side. These results show that uptake of S. pneumoniae into host cells occurs via multiple pathways, as opposed to the often proposed view of invasion being dependent on specific, and singular receptor-mediated endocytosis. This indicates that the endothelium not only has a critical role as a physical barrier against S. pneumoniae in the blood stream, but also in degrading S. pneumonia cells that have adhered to, and invaded the endothelial cells.
authors.affiliation: Laboratory of Molecular Bacteriology, Department of Medical Microbiology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
authors.forename: Henrik
authors.initials: H
authors.lastname: Gradstedt
authors.forename: Federico
authors.initials: F
authors.lastname: Iovino
authors.forename: Jetta J E
authors.initials: JJ
authors.lastname: Bijlsma
mesh_terms: D021941:Caveolae / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis / Q000276:immunology; D042783:Endothelial Cells / Q000378:metabolism* / Q000382:microbiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008247:Lysosomes / Q000378:metabolism* / Q000382:microbiology*; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000502:physiology*; D060149:Tetraspanin 30 / Q000378:metabolism
chemical_list: D002966:Clathrin; D060149:Tetraspanin 30