Neisseria meningitidis elicits a pro-inflammatory response involving IκBζ in a human blood-cerebrospinal fluid barrier model

Journal of Neuroinflammation

Christian Schwerk²  Horst Schroten²  Tobias Tenenbaum²  Hiroshi Ishikawa³  Norbert Gretz⁴  Peter Findeisen¹  Christel Weiss⁵  Carolin Stump-Guthier²  Natascha Quednau²  Ulrike Steinmann²  Li Li⁴  Julia Borkowski² 

[1] Institute for Clinical Chemistry, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany;Department of Pediatrics, Pediatric Infectious Diseases, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany;Department of NDU Life Sciences, Nippon Dental University, School of Life Dentistry, Chiyoda-ku, Tokyo, Japan;Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, 68167, Germany;Institute of Medical Statistics and Biomathematics, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Strasse 13-17, Mannheim, 68167, Germany

关键词: Transcriptomics;    Toll-like receptors;    Neisseria meningitidis;    Microarray;    Host-pathogen interactions;    Choroid plexus;    Cellular immune response;    Blood-cerebrospinal fluid barrier;   

Others  :  1150731
DOI  :  10.1186/s12974-014-0163-x

 received in 2014-02-25, accepted in 2014-08-29,  发布年份 2014

【 摘 要 】

Background

The human-specific, Gram-negative bacterium Neisseria meningitidis (Nm) is a leading cause of bacterial meningitis worldwide. The blood-cerebrospinal fluid barrier (BCSFB), which is constituted by the epithelial cells of the choroid plexus (CP), has been suggested as one of the potential entry sites of Nm into the CSF and can contribute to the inflammatory response during infectious diseases of the brain. Toll-like receptors (TLRs) are involved in mediating signal transduction caused by the pathogens.

Methods

Using a recently established in vitro model of the human BCSFB based on human malignant CP papilloma (HIBCPP) cells we investigated the cellular response of HIBCPP cells challenged with the meningitis-causing Nm strain, MC58, employing transcriptome and RT-PCR analysis, cytokine bead array, and enzyme-linked immunosorbent assay (ELISA). In comparison, we analyzed the answer to the closely related unencapsulated carrier isolate Nm ?14. The presence of TLRs in HIBCPP and their role during signal transduction caused by Nm was studied by RT-PCR and the use of specific agonists and mutant bacteria.

Results

We observed a stronger transcriptional response after infection with strain MC58, in particular with its capsule-deficient mutant MC58siaD^?, which correlated with bacterial invasion levels. Expression evaluation and Gene Set Enrichment Analysis pointed to a NF?B-mediated pro-inflammatory immune response involving up-regulation of the transcription factor I?B?. Infected cells secreted significant levels of pro-inflammatory chemokines and cytokines, including, among others, IL8, CXCL1-3, and the I?B? target gene product IL6. The expression profile of pattern recognition receptors in HIBCPP cells and the response to specific agonists indicates that TLR2/TLR6, rather than TLR4 or TLR2/TLR1, is involved in the cellular reaction following Nm infection.

Conclusions

Our data show that Nm can initiate a pro-inflammatory response in human CP epithelial cells probably involving TLR2/TLR6 signaling and the transcriptional regulator I?B?.

【 授权许可】

   
2014 Borkowski et al.; licensee BioMed Central Ltd.

【 图 表 】

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