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

Federico Iovino; Joo-Yeon Engelen-Lee; Matthijs Brouwer; Diederik van de Beek; Arie van der Ende; Merche Valls Seron; Peter Mellroth; Sandra Muschiol; Jan Bergstrand; Jerker Widengren; Birgitta Henriques-Normark

doi:10.1084/jem.20161668

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

J Exp Med. 2017 Jun 5;214(6):1619-1630. doi: 10.1084/jem.20161668. Epub 2017 May 17.

Authors

Federico Iovino^{1

2}, Joo-Yeon Engelen-Lee³, Matthijs Brouwer³, Diederik van de Beek³, Arie van der Ende³, Merche Valls Seron³, Peter Mellroth^{1

2}, Sandra Muschiol^{1

2}, Jan Bergstrand⁴, Jerker Widengren⁴, Birgitta Henriques-Normark^{5

2

6

7}

Affiliations

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 Department of Applied Physics, KTH Royal Institute of Technology, SE-114 28 Stockholm, Sweden.
⁵ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden birgitta.henriques@ki.se.
⁶ Lee Kong Chian School of Medicine (LKC), Nanyang Technological University, Singapore 639798, Singapore.
⁷ Singapore Centre on Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, Singapore 639798, Singapore.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adhesins, Bacterial / metabolism*
Animals
Antibodies, Bacterial / pharmacology
Antibodies, Bacterial / therapeutic use
Bacterial Proteins / metabolism*
Biopsy
Blood-Brain Barrier / drug effects
Blood-Brain Barrier / microbiology
Blood-Brain Barrier / pathology
Brain / drug effects
Brain / microbiology*
Brain / pathology
Endothelial Cells / drug effects
Endothelial Cells / metabolism
Endothelial Cells / microbiology
Fimbriae Proteins / metabolism*
Humans
Meningitis, Bacterial / drug therapy
Meningitis, Bacterial / microbiology
Meningitis, Bacterial / pathology
Mice, Inbred C57BL
Microscopy
Platelet Endothelial Cell Adhesion Molecule-1 / metabolism*
Protein Binding / drug effects
Receptors, Polymeric Immunoglobulin / metabolism*
Streptococcus pneumoniae / isolation & purification
Streptococcus pneumoniae / pathogenicity*
Virulence Factors / metabolism*

Substances

Adhesins, Bacterial
Antibodies, Bacterial
Bacterial Proteins
Platelet Endothelial Cell Adhesion Molecule-1
Receptors, Polymeric Immunoglobulin
RrgA protein, Streptococcus pneumoniae
SpsA protein, Streptococcus pneumoniae
Virulence Factors
Fimbriae Proteins