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GeneChip analyses of global transcriptional responses of murine macrophages to the lethal toxin of Bacillus anthracis.

ABSTRACT: We performed GeneChip analyses on RNA from Bacillus anthracis lethal toxin (LeTx)-treated RAW 264.7 murine macrophages to investigate global effects of anthrax toxin on host cell gene expression. Stringent analysis of data revealed that the expression of several mitogen-activated protein kinase kinase-regulatory genes was affected within 1.5 h post-exposure to LeTx. By 3.0 h, the expression of 103 genes was altered, including those involved in intracellular signaling, energy production, and protein metabolism.

SUBMITTER: Comer JE

PROVIDER: S-EPMC1064962 | biostudies-literature | 2005 Mar

REPOSITORIES: biostudies-literature

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GeneChip analyses of global transcriptional responses of murine macrophages to the lethal toxin of Bacillus anthracis.

Comer Jason E JE Galindo Cristi L CL Chopra Ashok K AK Peterson Johnny W JW

Infection and immunity 20050301 3

We performed GeneChip analyses on RNA from Bacillus anthracis lethal toxin (LeTx)-treated RAW 264.7 murine macrophages to investigate global effects of anthrax toxin on host cell gene expression. Stringent analysis of data revealed that the expression of several mitogen-activated protein kinase kinase-regulatory genes was affected within 1.5 h post-exposure to LeTx. By 3.0 h, the expression of 103 genes was altered, including those involved in intracellular signaling, energy production, and prot ...[more]

PMID: 15731093

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Project description:BackgroundAnthrax lethal toxin (LT), produced by the Gram-positive bacterium Bacillus anthracis, is a highly effective zinc dependent metalloprotease that cleaves the N-terminus of mitogen-activated protein kinase kinases (MAPKK or MEKs) and is known to play a role in impairing the host immune system during an inhalation anthrax infection. Here, we present the transcriptional responses of LT treated human monocytes in order to further elucidate the mechanisms of LT inhibition on the host immune system.ResultsWestern Blot analysis demonstrated cleavage of endogenous MEK1 and MEK3 when human monocytes were treated with 500 ng/mL LT for four hours, proving their susceptibility to anthrax lethal toxin. Furthermore, staining with annexin V and propidium iodide revealed that LT treatment did not induce human peripheral monocyte apoptosis or necrosis. Using Affymetrix Human Genome U133 Plus 2.0 Arrays, we identified over 820 probe sets differentially regulated after LT treatment at the p <0.001 significance level, interrupting the normal transduction of over 60 known pathways. As expected, the MAPKK signaling pathway was most drastically affected by LT, but numerous genes outside the well-recognized pathways were also influenced by LT including the IL-18 signaling pathway, Toll-like receptor pathway and the IFN alpha signaling pathway. Multiple genes involved in actin regulation, signal transduction, transcriptional regulation and cytokine signaling were identified after treatment with anthrax LT.ConclusionWe conclude LT directly targets human peripheral monocytes and causes multiple aberrant gene responses that would be expected to be associated with defects in human monocyte's normal signaling transduction pathways and function. This study provides further insights into the mechanisms associated with the host immune system collapse during an anthrax infection, and suggests that anthrax LT may have additional downstream targets outside the well-known MAPK pathway.

Dataset Information

GeneChip analyses of global transcriptional responses of murine macrophages to the lethal toxin of Bacillus anthracis.

Publications

GeneChip analyses of global transcriptional responses of murine macrophages to the lethal toxin of Bacillus anthracis.

Similar Datasets

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