Pertussis Toxin Exploits Specific Host Cell Signaling Pathways for Promoting Invasion and Translocation of Escherichia coli K1 RS218 in Human Brain-derived Microvascular Endothelial Cells.

Abstract

Pertussis toxin (PTx), an AB5 toxin and major virulence factor of the whooping cough-causing pathogen Bordetella pertussis, has been shown to affect the blood-brain barrier. Dysfunction of the blood-brain barrier may facilitate penetration of bacterial pathogens into the brain, such as Escherichia coli K1 (RS218). In this study, we investigated the influence of PTx on blood-brain barrier permissiveness to E. coli infection using human brain-derived endothelial HBMEC and TY10 cells as in vitro models. Our results indicate that PTx acts at several key points of host cell intracellular signaling pathways, which are also affected by E. coli K1 RS218 infection. Application of PTx increased the expression of the pathogen binding receptor gp96. Further, we found an activation of STAT3 and of the small GTPase Rac1, which have been described as being essential for bacterial invasion involving host cell actin cytoskeleton rearrangements at the bacterial entry site. In addition, we showed that PTx induces a remarkable relocation of VE-cadherin and β-catenin from intercellular junctions. The observed changes in host cell signaling molecules were accompanied by differences in intracellular calcium levels, which might act as a second messenger system for PTx. In summary, PTx not only facilitates invasion of E. coli K1 RS218 by activating essential signaling cascades; it also affects intercellular barriers to increase paracellular translocation.

• Authors: Sascha Karassek, Laura Starost, Johanna Solbach, Lilo Greune, Yasuteru Sano, Takashi Kanda, KwangSik Kim, M Alexander Schmidt
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 41 Pg. 24835-43 (Oct 09 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26324705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antigens, CD
• Cadherins
• Membrane Glycoproteins
• RNA, Messenger
• STAT3 Transcription Factor
• beta Catenin
• cadherin 5
• endoplasmin
• Pertussis Toxin
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• rac1 GTP-Binding Protein

Topics

• Antigens, CD (metabolism)
• Bacterial Translocation (drug effects)
• Brain (cytology)
• Cadherins (metabolism)
• Cell Membrane (drug effects, metabolism)
• Endothelial Cells (cytology, drug effects, metabolism, microbiology)
• Escherichia coli (drug effects, physiology)
• Humans
• Membrane Glycoproteins (genetics)
• Microvessels (cytology)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Pertussis Toxin (pharmacology)
• Protein Transport (drug effects)
• RNA, Messenger (genetics, metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Up-Regulation (drug effects)
• beta Catenin (metabolism)
• rac1 GTP-Binding Protein (metabolism)