c-KIT signaling is targeted by pathogenic Yersiniato suppress the host immune response

BMC Microbiology

Research Article

Sofiya N Micheva-Viteva¹  Elizabeth Hong-Geller¹  Yulin Shou¹  Kristy L Nowak-Lovato¹  Kirk D Rector² 

[1] Bioscience Division, Los Alamos National Laboratory, 87544, Los Alamos, NM, USA;Chemistry Division, Los Alamos National Laboratory, 87544, Los Alamos, NM, USA;

关键词: RNA interference;    Yersinia;    Host response;    Signal transcription;    Virulence;    Host-pathogen interactions;   

DOI  :  10.1186/1471-2180-13-249

 received in 2013-06-27, accepted in 2013-10-31,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundThe pathogenic Yersinia species exhibit a primarily extracellular lifestyle through manipulation of host signaling pathways that regulate pro-inflammatory gene expression and cytokine release. To identify host genes that are targeted by Yersinia during the infection process, we performed an RNA interference (RNAi) screen based on recovery of host NF-κB-mediated gene activation in response to TNF-α stimulation upon Y. enterocolitica infection.ResultsWe screened shRNAs against 782 genes in the human kinome and 26 heat shock genes, and identified 19 genes that exhibited ≥40% relative increase in NF-κB reporter gene activity. The identified genes function in multiple cellular processes including MAP and ERK signaling pathways, ion channel activity, and regulation of cell growth. Pre-treatment with small molecule inhibitors specific for the screen hits c-KIT and CKII recovered NF-κB gene activation and/or pro-inflammatory TNF-α cytokine release in multiple cell types, in response to either Y. enterocolitica or Y. pestis infection.ConclusionsWe demonstrate that pathogenic Yersinia exploits c-KIT signaling in a T3SS-dependent manner to downregulate expression of transcription factors EGR1 and RelA/p65, and pro-inflammatory cytokines. This study is the first major functional genomics RNAi screen to elucidate virulence mechanisms of a pathogen that is primarily dependent on extracellular-directed immunomodulation of host signaling pathways for suppression of host immunity.

【 授权许可】

Unknown   
© Micheva-Viteva et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.