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

Journal Article · · BMC Microbiology
 [1];  [2];  [2];  [2];  [2]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); DOE/OSTI
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
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Background: The 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. Results: We 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. Conclusions: We 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.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC); USDOE Laboratory Directed Research and Development (LDRD) Program; National Institutes of Health (NIH)
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1626481
Journal Information:
BMC Microbiology, Journal Name: BMC Microbiology Journal Issue: 1 Vol. 13; ISSN 1471-2180
Publisher:
BioMed CentralCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (4)

Organoid-derived C-Kit+/SSEA4− human retinal progenitor cells promote a protective retinal microenvironment during transplantation in rodents journal March 2019
Functional and Structural Analysis of a Highly-Expressed Yersinia pestis Small RNA following Infection of Cultured Macrophages journal December 2016
PKC-η-MARCKS Signaling Promotes Intracellular Survival of Unopsonized Burkholderia thailandensis journal June 2017
c-Kit modifies the inflammatory status of smooth muscle cells journal June 2017

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Host response
Host-pathogen interactions
Microbiology
RNA interference
Signal transcription
Virulence
Yersinia infection