Possible explaination of the specific Pathogen / MPB theory - Epigenetic Silencing of Host Cell Defense Genes Enhances Intracellular Survival of Pathogens

Epigenetic Silencing of Host Cell Defense Genes Enhances Intracellular Survival of the Rickettsial Pathogen Anaplasma phagocytophilum

Article
Metrics
Related Content
Comments: 0

To add a note, highlight some text. Hide notes
Make a general comment

Jump to

Abstract
Author Summary
Introduction
Results
Discussion
Materials and Methods
Supporting Information
Acknowledgments
Author Contributions
References

Jose C. Garcia-Garcia1, Nicole C. Barat1, Sarah J. Trembley2, J. Stephen Dumler1*

1 Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 2 Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
Abstract Top

Intracellular bacteria have evolved mechanisms that promote survival within hostile host environments, often resulting in functional dysregulation and disease. Using the Anaplasma phagocytophilum–infected granulocyte model, we establish a link between host chromatin modifications, defense gene transcription and intracellular bacterial infection. Infection of THP-1 cells with A. phagocytophilum led to silencing of host defense gene expression. Histone deacetylase 1 (HDAC1) expression, activity and binding to the defense gene promoters significantly increased during infection, which resulted in decreased histone H3 acetylation in infected cells. HDAC1 overexpression enhanced infection, whereas pharmacologic and siRNA HDAC1 inhibition significantly decreased bacterial load. HDAC2 does not seem to be involved, since HDAC2 silencing by siRNA had no effect on A. phagocytophilum intracellular propagation. These data indicate that HDAC up-regulation and epigenetic silencing of host cell defense genes is required for A. phagocytophilum infection. Bacterial epigenetic regulation of host cell gene transcription could be a general mechanism that enhances intracellular pathogen survival while altering cell function and promoting disease.

HDAC inhibitors block innate immunity

Konrad A. Bode and
Alexander H. Dalpke

+ Author Affiliations

UNIVERSITY OF HEIDELBERG

In this issue of Blood, Roger and colleagues present data on the magnitude of influence that broad-spectrum HDAC inhibitors exert on TLR-driven immune responses, thus demonstrating that HDAC inhibitors are immunosuppressive drugs.

Histone deacetylase (HDAC) inhibitors have become promising candidates for the treatment of different types of cancer. “At least 80 clinical trials are under way, testing more than eleven different HDAC inhibitory agents,”1p1 for their antitumor effect in hematologic and solid malignancies. The HDAC inhibitor vorinostat is now an approved add-on therapy for cutaneous T-cell lymphoma.2 HDAC inhibitors induce growth arrest, differentiation, and programmed cell death, and inhibit invasion and angiogenesis. However, over the years, evidence has accumulated showing that HDAC inhibitors also have immunomodulatory activity even in nonapoptotic concentrations. Although HDAC inhibitors increase acetylation of histones, a condition associated with increased transcriptional accessibility, multiple reports have shown that HDAC inhibitors possess suppressive effects on immune response gene induction. Individual cytokines that are induced by microbial components triggering Toll-like receptors (TLRs) were reported to be inhibited by HDAC inhibitors.3–5 Yet, the extent of those inhibitory effects and possible functional consequences during infections were largely unknown.

Addition of broad-spectrum HDAC inhibitors to macrophages stimulated through TLRs results in a dominant inhibition of gene expres​sion(up to 60% of TLR-induced genes) encompassing suppression of all major functions of macrophages. Consequently, in vivo susceptibility to infections is increased when the HDAC inhibitor valproate is administered to mice, whereas overreactivity of innate immunity as observed in septic shock is decreased.

[The effects of a histone deacetylase (HDAC) inhibitor on endotoxin-induced endothelial cell injury].
[Article in Chinese]
He HM, Li A, Zhang SW, Duan ML.
Source

Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
Abstract
OBJECTIVE:

To examine the effects of HDAC inhibitor trichostatin A (TSA) on lipopolysaccharide (LPS) induced genes expression in cultured endothelial cells in order to understand the mechanisms involved in the protection of endothelial cells against vascular endothelium injury during endotoxemia.
METHODS:

Cultured EAhy926 cells (a cell line with the features of vascular endothelial cells) were treated with LPS at 100 ng/ml [the dose was chosen for minimum impact on cell survival as determined using Methyl thiazolyl tetrazolium (MTT) assay], or LPS and TSA (100 μg/ml). The expressions of toll-like receptor 4 (TLR4) and HDAC2 were measured by Western blotting 3, 6, 9, 12 and 24 hours after the beginning of the treatment.
RESULTS:

The expressions of TLR4 (as measured by densitometry) was found significantly higher (P< 0.01) in LPS treated cells (1.01±0.14, 1.25±0.16, 1.20±0.19) 9, 12 and 24 hours after the beginning of the treatment as compared to untreated cells (0.34±0.05); The expression of HDAC2 was also found significantly higher (P< 0.01) after LPS treatment for 12 and 24 hours (1.14±0.10, 1.20±0.04) in comparison with untreated control (0.17±0.02). In LPS+TSA treated cells, TLR4 expres​sion(0.37±0.07) was significantly lower (P< 0.05) after 12 hours of treatment in comparison with its LPS treated counterpart (1.25±0.16), while the level of TLR4 expression stayed unchanged 24 hours after the beginning of the treatment, as compared to the result at 12 hours (0.37±0.10 vs. 1.20±0.19, P> 0.05). No visible HDAC2 expression was detected in the cells treated with LPS+TSA.
CONCLUSION:

LPS stimulated the increase of TLR4 and HDAC2 expression in the vascular endothelial cells studied while TSA suppress the LPS induced TLR4 and HDAC2 expression in these cells.

Yanks wrote:Systemic LPS administration resulted in rapid brain TNFα increase that remained elevated for 10 months,

the only pathogen i'd be willing to admit may be involved is an unknown virus.