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Mycobacterium tuberculosis m4C DNA methyltransferase Rv3204 promotes mycobacteria survival under oxidative stress

ABSTRACT: ROS can damage cellular components and is a key player in many cellular signaling. Tuberculosis remains a major global public health concern largely due to the ability of its causative agent-Mycobacterium tuberculosis (Mtb) to subvert ROS toxicity. DNA methylation deficiency was previously shown to attenuate the Mtb virulence. But the role of DNA methyltransferase in Mycobacteria survival and the link with ROS are unknown. Mycobacterial protein Rv3204 is a DNA methyltransferase specific for N4-methylcytosine instead of N6-methyladenine (m6A) or 5-methylocytosine (m5C). The survival rate of m4C methyltransferase deletion mutants was lowered, accompanied by higher accumulation of ROS and failure of upregulating the transcription of gene engaged in ROS clearance upon rifampin(Rif) exposure.

ORGANISM(S): Mycolicibacterium smegmatis MC2 155

PROVIDER: GSE139646 | GEO | 2019/11/01

REPOSITORIES: GEO

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Project description:Background: Tuberculosis (TB) remains a major public health problem, especially in developing countries, with 1.5 million deaths annually worldwide. Antibiotics are commonly used in the treatment of bacterial infections. As with most drugs, antibiotic treatment can also alter host metabolism, leading to adverse side-effects. Antibiotics can also interfere with the immune system, indirectly through the disturbance of the body’s microbiota or directly by modulating the functions of immune cells. It is therefore important to understand how antibiotic treatment modulates immune cell functions. Here we aim to evaluate the impact of first-line anti-TB drugs on the response of human macrophages infected with Mycobacterium tuberculosis (MTB). Results: Human macrophages were stimulated with heat-killed Mycobacterium tuberculosis (hk-MTB) and treated with isoniazid (INH), rifampicin (RIF), ethambutol, pyrazinamide (PZA) or amikacin (AMK). After 24h of treatment, RNA was collected and we characterized the genome-wide gene expression profiles of drug-treated cells by RNAseq. 556, 752 and 7 genes were differentially expressed in hk-MTB-stimulated macrophages upon RIF, PZA and EMB treatment respectively, whereas in uninfected macrophages, 448 and 11 genes were differentially expressed upon RIF and PZA treatment respectively. No genes were differentially expressed upon INH and AMK treatment. We classified all modulated genes by performing gene-set enrichment analysis. The gene set regulated by PZA in infected macrophages was significantly enriched for genes involved in Integral to lumenal side of endoplasmic reticulum membrane, Cytokine-mediated signaling pathway or Interferon-gamma-mediated signaling pathway. In hk-MTB-stimulated macrophages treated by RIF, we found an enrichment in Endoplasmic reticulum unfolded protein response, NADP binding or Lipid metabolic process. Conclusions: Our results highlight the importance to understand how antibiotic treatment modulates macrophage (Mφ) functions, and more generally, how it impacts the host immune response.

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Mycobacterium tuberculosis m4C DNA methyltransferase Rv3204 promotes mycobacteria survival under oxidative stress

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