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      pIgR and PECAM-1 bind to pneumococcal adhesins RrgA and PspC mediating bacterial brain invasion

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          Pneumococci are major causes of bacterial meningitis. Iovino et al. show that pneumococci invade the brain and pass the blood–brain barrier by interacting with the endothelial receptors pIgR and PECAM-1 recognizing the pneumococcal adhesin RrgA and PspC on the bacterial surface.


          Streptococcus pneumoniae is the main cause of bacterial meningitis, a life-threating disease with a high case fatality rate despite treatment with antibiotics. Pneumococci cause meningitis by invading the blood and penetrating the blood–brain barrier (BBB). Using stimulated emission depletion (STED) super-resolution microscopy of brain biopsies from patients who died of pneumococcal meningitis, we observe that pneumococci colocalize with the two BBB endothelial receptors: polymeric immunoglobulin receptor (pIgR) and platelet endothelial cell adhesion molecule (PECAM-1). We show that the major adhesin of the pneumococcal pilus-1, RrgA, binds both receptors, whereas the choline binding protein PspC binds, but to a lower extent, only pIgR. Using a bacteremia-derived meningitis model and mutant mice, as well as antibodies against the two receptors, we prevent pneumococcal entry into the brain and meningitis development. By adding antibodies to antibiotic (ceftriaxone)-treated mice, we further reduce the bacterial burden in the brain. Our data suggest that inhibition of pIgR and PECAM-1 has the potential to prevent pneumococcal meningitis.

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          Most cited references 27

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          For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the analysis of scientific images. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.
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              Pneumococcal trafficking across the blood-brain barrier. Molecular analysis of a novel bidirectional pathway.

              Although Streptococcus pneumoniae is a major cause of meningitis in humans, the mechanisms underlying its traversal from the circulation across the blood-brain barrier (BBB) into the subarachnoid space are poorly understood. One mechanism might involve transcytosis through microvascular endothelial cells. In this study we investigated the ability of pneumococci to invade and transmigrate through monolayers of rat and human brain microvascular endothelial cells (BMEC). Significant variability was found in the invasive capacity of clinical isolates. Phase variation to the transparent phenotype increased invasion as much as 6-fold and loss of capsule approximately 200-fold. Invasion of transparent pneumococci required choline in the pneumococcal cell wall, and invasion was partially inhibited by antagonists of the platelet-activating factor (PAF) receptor on the BMEC. Pneumococci that gained access to an intracellular vesicle from the apical side of the monolayer subsequently were subject to three fates. Most opaque variants were killed. In contrast, the transparent phase variants were able to transcytose to the basal surface of rat and human BMEC in a manner dependent on the PAF receptor and the presence of pneumococcal choline-binding protein A. The remaining transparent bacteria entering the cell underwent a previously unrecognized recycling to the apical surface. Transcytosis eventually becomes a dominating process accounting for up to 80% of intracellular bacteria. Our data suggest that interaction of pneumococci with the PAF receptor results in sorting so as to transcytose bacteria across the cell while non-PAF receptor entry shunts bacteria for exit and reentry on the apical surface in a novel recycling pathway.

                Author and article information

                J Exp Med
                J. Exp. Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                05 June 2017
                05 June 2017
                : 214
                : 6
                : 1619-1630
                [1 ]Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
                [2 ]Department of Clinical Microbiology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
                [3 ]Department of Neurology, Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, 1012 WX Amsterdam, Netherlands
                [4 ]Lee Kong Chian School of Medicine (LKC), Nanyang Technological University, Singapore 639798, Singapore
                [5 ]Singapore Centre on Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, Singapore 639798, Singapore
                [6 ]Department of Applied Physics, KTH Royal Institute of Technology, SE-114 28 Stockholm, Sweden
                Author notes
                Correspondence to Birgitta Henriques-Normark: birgitta.henriques@ 123456ki.se
                © 2017 Iovino et al.

                This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

                Funded by: Knut and Alice Wallenberg Foundation, DOI http://dx.doi.org/10.13039/501100004063;
                Funded by: Swedish Research Council, DOI http://dx.doi.org/10.13039/501100004359;
                Funded by: Swedish Foundation for Strategic Research, DOI http://dx.doi.org/10.13039/501100001729;
                Funded by: Stockholm County Council, DOI http://dx.doi.org/10.13039/501100004348;
                Award ID: ALF grant
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