Endothelial cells are S. pneumoniae death-traps
medwireNews: Researchers have shed light on the mechanisms by which Streptococcus pneumoniae invades endothelial host cells, with surprising results.
They show that S. pneumoniae, rather than having just one route of entry, can in fact enter endothelial cells through two different pathways - clathrin-mediated and caveolae-mediated endocytosis. However, once there, almost all of the bacteria are directed to and killed in the lysosomes.
The team from the University of Groningen in the Netherlands say that their findings highlight the critical role of the endothelium as a physical barrier against S. pneumoniae in the blood stream, and the "often overlooked ability of the endothelial cells to efficiently kill internalized S. pneumoniae."
Using human brain microvascular endothelial cells, the researchers found that all three clathrin-mediated endocytosis inhibitors significantly inhibited S. pneumoniae invasion; amantadine by an average of 43%, sucrose by an average of 63%, and chlorpromazine by 94%. However, they also observed similar reductions when they tested two caveolae-mediated endocytosis inhibitors, PMA and nystatin, which reduced invasion by 59% and 47%, respectively.
"Combined these results clearly demonstrated that S. pneumoniae utilizes both clathrin- and caveolae-mediated endocytosis to gain entry into the endothelial host cell," the authors comment.
The team also shows that the majority of S. pneumoniae is killed in the lysosomes, with 90% gone within 3 hours, something that was prevented by the addition of lysosomal acidification or maturation inhibitors.
And, lysosomal inhibition also led to a change in translocation patterns in the cell, with a 10-fold increase in bacterial translocation to the basolateral side - the portal to the bloodstream.
"This strongly suggests that a fully functional lysosome system is of paramount importance for the killing of internalized S. pneumoniae. Conversely, if the lysosome is impaired, translocation and further dissemination is greatly increased," the authors, led by Jetta Bijlsma, write in PLoS One.
They say the findings should help the currently limited understanding of how the bacterium transforms from a harmless colonizer of the nasopharynx to an invasive disease-causing pathogen.
They note evidence that caveolae-mediated uptake may lead to evasion of the lysosome, which could result in increased virulence of bacteria that enter endothelial cells by this route.
And, whereas it was previously thought that S. pneumoniae entered endothelial cells through a single receptor-dependent form of endocytosis, the authors say their findings suggest that internalization is "more dependent on the underlying functions and uptake mechanisms, than on specific receptors."
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By Kirsty Oswald, medwireNews Reporter