Uropathogenic Escherichia coli cause resistance to apoptotic cell death of infected cells by epigenetically suppressing BIM expression

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ZhangZhengguo_2015_12_21.pdf (3.08 MB)

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2015

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DOI:
http://dx.doi.org/10.22029/jlupub-14247

Abstract

Urinary tract infections caused by uropathogenic Escherichia coli (UPEC) pathovars belong to the most frequent infections in humans. In men, pathogens can also spread to the genital tract via the continuous ductal system, eliciting bacterial prostatitis and/or epididymo-orchitis. Upon infection, activation of host cell death pathways is an intrinsic mechanism to eliminate the invading pathogens, conversely pathogens have evolved multiple strategies to manipulate host cell death pathways to propagate, replicate, and evade the host innate immune response. In light of the established observation that UPEC can manipulate intracellular signaling pathways to subvert innate immune responses, we sought to uncover if this pathogen is also able to interfere with the host cell death pathways. Here, it has been shown that the UPEC virulence factor alpha-hemolysin abrogates activation of the host cell pro-survival AKT signaling pathway depending on extracellular calcium. Inactivation of the AKT signaling pathway is further characterized by activation of the AKT-dependent FOXO family signaling pathway. Activation of FOXO1 and FOXO3 transcription factors were documented by their dephosphorylation and nuclear accumulation in testicular Sertoli cells. Although dephosphorylated FOXO was localized in the nuclei of Sertoli cells and showed increased DNA-binding activity following UPEC infection, no change in the expression levels of FOXO target genes such as BIM were observed. UPEC can suppress BIM expression induced by LY249002, a potent inhibitor of PI3Ks, which results in attenuation of caspase 3 activation and blockage of apoptosis. Mechanistically, UPEC-mediated AKT/ACLY inhibition could induce global deacetylation of histone 3 and histone 4, leading to an epigenetic suppression of expression of the FOXO target gene BIM by histone modifications in the Bim promoter region. In addition, no alteration was documented in the DNA methylation status. Taken together, these results suggest that UPEC can epigenetically silence BIM expression, a molecular switch that prevents apoptosis.

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