ArticleThe Journal of experimental medicine2016
Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo.
Article in The Journal of experimental medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 148 papers.
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Who cites it
148 citing papers in PubMed, 215 citations in OpenAlex.
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- A host-directed adjuvant sensitizes intracellular bacterial persisters to antibiotics.Nature microbiology · 2025Article
- Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis.Nature communications · 2025Article
- Systems-level characterization of EGFR kinase inhibitors reveals heterogeneous effects on Mtb-macrophage interactions.bioRxiv : the preprint server for biology · 2025Article
- Incorporation of macrophage immune stresses into an intracellular assay of drug tolerance inAntimicrobial agents and chemotherapy · 2025Article
- Molecular Indicator for Distinguishing Multi-drug-Resistant Tuberculosis from Drug Sensitivity Tuberculosis and Potential Medications for Treatment.Molecular biotechnology · 2025Article
88 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Successful chemotherapy against Mycobacterium tuberculosis (Mtb) must eradicate the bacterium within the context of its host cell. However, our understanding of the impact of this environment on antimycobacterial drug action remains incomplete. Intriguingly, we find that Mtb in myeloid cells isolated from the lungs of experimentally infected mice exhibit tolerance to both isoniazid and rifampin to a degree proportional to the activation status of the host cells. These data are confirmed by in vitro infections of resting versus activated macrophages where cytokine-mediated activation renders Mtb tolerant to four frontline drugs. Transcriptional analysis of intracellular Mtb exposed to drugs identified a set of genes common to all four drugs. The data imply a causal linkage between a loss of fitness caused by drug action and Mtb's sensitivity to host-derived stresses. Interestingly, the environmental context exerts a more dominant impact on Mtb gene expression than the pressure on the drugs' primary targets. Mtb's stress responses to drugs resemble those mobilized after cytokine activation of the host cell. Although host-derived stresses are antimicrobial in nature, they negatively affect drug efficacy. Together, our findings demonstrate that the macrophage environment dominates Mtb's response to drug pressure and suggest novel routes for future drug discovery programs.
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