Anthrax Lethal Toxin Impairs IL-8 Expression in Epithelial Cells through Inhibition of Histone H3 Modification

Abstract

Lethal toxin (LT) is a critical virulence factor of Bacillus anthracis, the etiological agent of anthrax, whose pulmonary form is fatal in the absence of treatment. Inflammatory response is a key process of host defense against invading pathogens. We report here that intranasal instillation of a B. anthracis strain bearing inactive LT stimulates cytokine production and polymorphonuclear (PMN) neutrophils recruitment in lungs. These responses are repressed by a prior instillation of an LT preparation. In contrast, instillation of a B. anthracis strain expressing active LT represses lung inflammation. The inhibitory effects of LT on cytokine production are also observed in vitro using mouse and human pulmonary epithelial cells. These effects are associated with an alteration of ERK and p38-MAPK phosphorylation, but not JNK phosphorylation. We demonstrate that although NF-κB is essential for IL-8 expression, LT downregulates this expression without interfering with NF-κB activation in epithelial cells. Histone modifications are known to induce chromatin remodelling, thereby enhancing NF-κB binding on promoters of a subset of genes involved in immune response. We show that LT selectively prevents histone H3 phosphorylation at Ser 10 and recruitment of the p65 subunit of NF-κB at the IL-8 and KC promoters. Our results suggest that B. anthracis represses the immune response, in part by altering chromatin accessibility of IL-8 promoter to NF-κB in epithelial cells. This epigenetic reprogramming, in addition to previously reported effects of LT, may represent an efficient strategy used by B. anthracis for invading the host.

Cellular Adaptation to Anthrax Lethal Toxin-Induced Mitochondrial Cholesterol Enrichment, Hyperpolarization, and Reactive Oxygen Species Generation through Downregulating MLN64 in Macrophages

“…5). Previously, LeTx was shown to induce epigenetic reprograming through histone modifications, including inhibition of histone H3 phosphorylation at Ser 10 that caused suppression of IL-18 production (45). LeTx also induces expression of the jumonji C family histone 3 lysine-27 (H3K27) demethylase 3, which was correlated with toxin resistance (19).…”

Bacterial Virulence Factors: Secreted for Survival

“…Lethal toxin is reported to cause modifications in the histone epigenetics of IL-8 promoter (Fig. 2a), which causes lesser binding of NF-jB transcription factor, hence causing reduced translational rates of IL-8 [53]. However, the exact molecular pathways through which these modifications take place are yet to be elucidated.…”

Inhibition of Interleukin 1β (IL-1β) Expression by Anthrax Lethal Toxin (LeTx) Is Reversed by Histone Deacetylase 8 (HDAC8) Inhibition in Murine Macrophages

“…PA is a carrier protein that incorporates LF into the cytoplasm; LF is a metalloprotease that cleaves all MAPK kinases (MEK1-7), except MEK5 (11) and MEK7 (12). Inactivation of these MEKs results in almost complete inactivation of MAPKs, including the ERKs and p38 MAPK (p38), but partial or no effects on JNK/SAPKs in macrophages (13,14) and other cell types (12,15). Inhibition of ERKs and p38 by LeTx suppresses expression of various inflammatory cytokines in macrophages (16 -18).…”