Pertussis Toxin Exploits Host Cell Signaling Pathways Induced by Meningitis-Causing E. coli K1-RS218 and Enhances Adherence of Monocytic THP-1 Cells to Human Cerebral Endothelial Cells

Abstract

Pertussis toxin (PTx), the major virulence factor of the whooping cough-causing bacterial pathogen Bordetella pertussis, permeabilizes the blood–brain barrier (BBB) in vitro and in vivo. Breaking barriers might promote translocation of meningitis-causing bacteria across the BBB, thereby facilitating infection. PTx activates several host cell signaling pathways exploited by the neonatal meningitis-causing Escherichia coli K1-RS218 for invasion and translocation across the BBB. Here, we investigated whether PTx and E. coli K1-RS218 exert similar effects on MAPK p38, NF-κB activation and transcription of downstream targets in human cerebral endothelial TY10 cells using qRT-PCR, Western blotting, and ELISA in combination with specific inhibitors. PTx and E. coli K1-RS218 activate MAPK p38, but only E. coli K1-RS218 activates the NF-κB pathway. mRNA and protein levels of p38 and NF-κB downstream targets including IL-6, IL-8, CxCL-1, CxCL-2 and ICAM-1 were increased. The p38 specific inhibitor SB203590 blocked PTx-enhanced activity, whereas E. coli K1-RS218’s effects were inhibited by the NF-κB inhibitor Bay 11-7082. Further, we found that PTx enhances the adherence of human monocytic THP-1 cells to human cerebral endothelial TY10 cells, thereby contributing to enhanced translocation. These modulations of host cell signaling pathways by PTx and meningitis-causing E. coli support their contributions to pathogen and monocytic THP-1 cells translocation across the BBB.

Characterizing the innate and adaptive responses of immunized mice toBordetella pertussisinfection usingin vivoimaging and transcriptomic analysis

“…3d). PT has been shown to induce production of Cxcl2 in TY10 cerebral endothelial cells which further suggests a causal relationship between non-neutralized PT and Cxcl2 production 41 .…”

Helicobacter pylori Neutrophil-Activating Protein Directly Interacts with and Activates Toll-like Receptor 2 to Induce the Secretion of Interleukin-8 from Neutrophils and ATRA-Induced Differentiated HL-60 Cells

“…Unexpectedly, pretreatment of PTX by itself stimulated neutrophils to secrete IL-8 ( Figure 7 D). It is possible that PTX induces the secretion of IL-8 from neutrophils as it does from endothelial cells [ 32 ]. Nevertheless, the inhibitory effect of PTX on the HP-NAP-induced secretion of IL-8 by neutrophils was still significant ( Figure 7 D).…”

“…The ADP-ribosylation that is mediated by the A-protomer of PTX further inhibits the activation of Gi/o proteins by preventing them from coupling to their cognate GPCR [ 42 ]. A previous study showed that PTX by itself was able to induce the secretion of IL-8 in endothelial cells through the activation of p38-MAPK [ 32 ]. The IL-8 secretion induced by PTX could be due to its effect on the ADP-ribosylation of Gi/o-proteins or its cellular actions that are independent of ADP-ribosylation.…”