1. Genetics and Genomics
  2. Microbiology and Infectious Disease

The mutational signatures of poor treatment outcomes on the drug-susceptible Mycobacterium tuberculosis genome

  1. Yiwang Chen
  2. Qi Jiang
  3. Mijiti Peierdun
  4. Howard E Takiff
  5. Qian Gao  Is a corresponding author
  1. Fudan University, China
  2. Wuhan University, China
  3. Xinjiang Medical University, China
  4. Instituto Venezolano de Investigaciones Cientificas, Venezuela
https://doi.org/10.7554/eLife.84815
Share this article
Cite this article
  1. Yiwang Chen
  2. Qi Jiang
  3. Mijiti Peierdun
  4. Howard E Takiff
  5. Qian Gao
(2023)
The mutational signatures of poor treatment outcomes on the drug-susceptible Mycobacterium tuberculosis genome
eLife 12:e84815.
https://doi.org/10.7554/eLife.84815
  2. Download BibTeX
  3. Download .RIS

Abstract

Drug resistance is a known risk factor for poor tuberculosis (TB) treatment outcomes, but the contribution of other bacterial factors to poor outcomes in drug susceptible TB is less well understood. Here, we generate a population-based dataset of drug-susceptible Mycobacterium tuberculosis (MTB) isolates from China to identify factors associated with poor treatment outcomes. We analyzed whole-genome sequencing (WGS) data of MTB strains from 3196 patients, including 3105 patients with good and 91 patients with poor treatment outcomes, and linked genomes to patient epidemiological data. A genome-wide association study (GWAS) was performed to identify bacterial genomic variants associated with poor outcomes. Risk factors identified by logistic regression analysis were used in clinical models to predict treatment outcomes. GWAS identified fourteen MTB fixed mutations associated with poor treatment outcomes, but only 24.2% (22/91) of strains from patients with poor outcomes carried at least one of these mutations. Isolates from patients with poor outcomes showed a higher ratio of reactive oxygen species (ROS)-associated mutations compared to isolates from patients with good outcomes (26.3% vs 22.9%, t test, P=0.027). Patient age, sex, and duration of diagnostic delay were also independently associated with poor outcomes. Bacterial factors alone had poor power to predict poor outcomes with an AUC of 0.58. The AUC with host factors alone was 0.70, but increased significantly to 0.74 (DeLong's test, P = 0.01) when bacterial factors were also included. In conclusion, although we identified MTB genomic mutations that are significantly associated with poor treatment outcomes in drug-susceptible TB cases, their effects appear to be limited.

Data availability

Files containing sequencing reads were deposited in the National Institutes of Health Sequence Read Archive under BioProject PRJNA869190.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Yiwang Chen

    School of Basic Medical Sciences, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  2. Qi Jiang

    School of Public Health, Wuhan University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Mijiti Peierdun

    Department of Epidemiology and Biostatistics, Xinjiang Medical University, Urumqi, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Howard E Takiff

    Instituto Venezolano de Investigaciones Cientificas, Caracas, Venezuela
    Competing interests
    The authors declare that no competing interests exist.

  5. Qian Gao

    School of Basic Medical Sciences, Fudan University, Shanghai, China
    For correspondence
    qiangao@fudan.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8489-3672

Funding

National Natural Science Foundation of China (81661128043,81871625)

  • Qian Gao

National Natural Science Foundation of China (82230078)

  • Qi Jiang

Shanghai Municipal Science and Technology Major Project (ZD2021CY001)

  • Qian Gao

Fundamental Research Funds for the Central Universities (2042021kf0041)

  • Qi Jiang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Bavesh D Kana, University of the Witwatersrand, South Africa

Version history

  1. Received: November 9, 2022
  2. Preprint posted: November 21, 2022 (view preprint)
  3. Accepted: May 2, 2023
  4. Accepted Manuscript published: May 3, 2023 (version 1)
  5. Version of Record published: May 16, 2023 (version 2)

Copyright

© 2023, Chen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 423
    Page views
  • 98
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Yiwang Chen
  2. Qi Jiang
  3. Mijiti Peierdun
  4. Howard E Takiff
  5. Qian Gao
(2023)
The mutational signatures of poor treatment outcomes on the drug-susceptible Mycobacterium tuberculosis genome
eLife 12:e84815.
https://doi.org/10.7554/eLife.84815

Categories and tags

Further reading

    1. Epidemiology and Global Health
    2. Genetics and Genomics

    Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks

    Arturo Torres Ortiz, Michelle Kendall ... Louis Grandjean
    Research Article

    Accurate inference of who infected whom in an infectious disease outbreak is critical for the delivery of effective infection prevention and control. The increased resolution of pathogen whole-genome sequencing has significantly improved our ability to infer transmission events. Despite this, transmission inference often remains limited by the lack of genomic variation between the source case and infected contacts. Although within-host genetic diversity is common among a wide variety of pathogens, conventional whole-genome sequencing phylogenetic approaches exclusively use consensus sequences, which consider only the most prevalent nucleotide at each position and therefore fail to capture low frequency variation within samples. We hypothesized that including within-sample variation in a phylogenetic model would help to identify who infected whom in instances in which this was previously impossible. Using whole-genome sequences from SARS-CoV-2 multi-institutional outbreaks as an example, we show how within-sample diversity is partially maintained among repeated serial samples from the same host, it can transmitted between those cases with known epidemiological links, and how this improves phylogenetic inference and our understanding of who infected whom. Our technique is applicable to other infectious diseases and has immediate clinical utility in infection prevention and control.

    1. Cancer Biology
    2. Genetics and Genomics

    Complementary CRISPR screen highlights the contrasting role of membrane-bound and soluble ICAM-1 in regulating antigen specific tumor cell killing by cytotoxic T cells

    Ann-Kathrin Herzfeldt, Marta Puig Gamez ... Lee Kim Swee
    Research Article

    Cytotoxic CD8+ T lymphocytes (CTLs) are key players of adaptive anti-tumor immunity based on their ability to specifically recognize and destroy tumor cells. Many cancer immunotherapies rely on unleashing CTL function. However, tumors can evade killing through strategies which are not yet fully elucidated. To provide deeper insight into tumor evasion mechanisms in an antigen-dependent manner, we established a human co-culture system composed of tumor and primary immune cells. Using this system, we systematically investigated intrinsic regulators of tumor resistance by conducting a complementary CRISPR screen approach. By harnessing CRISPR activation (CRISPRa) and CRISPR knockout (KO) technology in parallel, we investigated gene gain-of-function as well as loss-of-function across genes with annotated function in a colon carcinoma cell line. CRISPRa and CRISPR KO screens uncovered 187 and 704 hits respectively, with 60 gene hits overlapping between both. These data confirmed the role of interferon‑γ (IFN-γ), tumor necrosis factor α (TNF-α) and autophagy pathways and uncovered novel genes implicated in tumor resistance to killing. Notably, we discovered that ILKAP encoding the integrin-linked kinase-associated serine/threonine phosphatase 2C, a gene previously unknown to play a role in antigen specific CTL-mediated killing, mediate tumor resistance independently from regulating antigen presentation, IFN-γ or TNF-α responsiveness. Moreover, our work describes the contrasting role of soluble and membrane-bound ICAM-1 in regulating tumor cell killing. The deficiency of membrane-bound ICAM-1 (mICAM-1) or the overexpression of soluble ICAM-1 (sICAM-1) induced resistance to CTL killing, whereas PD-L1 overexpression had no impact. These results highlight the essential role of ICAM-1 at the immunological synapse between tumor and CTL and the antagonist function of sICAM-1.

    1. Genetics and Genomics
    2. Neuroscience

    Methylglyoxal-derived hydroimidazolone, MG-H1, increases food intake by altering tyramine signaling via the GATA transcription factor ELT-3 in Caenorhabditis elegans

    Muniesh Muthaiyan Shanmugam, Jyotiska Chaudhuri ... Pankaj Kapahi
    Research Article

    The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produce flavorful food ubiquitously, from the baking industry to our everyday lives. However, the Maillard reaction also occurs in all cells, from prokaryotes to eukaryotes, forming Advanced Glycation End-products (AGEs). AGEs are a heterogeneous group of compounds resulting from the irreversible reaction between biomolecules and α-dicarbonyls (α-DCs), including methylglyoxal (MGO), an unavoidable byproduct of anaerobic glycolysis and lipid peroxidation. We previously demonstrated that Caenorhabditis elegans mutants lacking the glod-4 glyoxalase enzyme displayed enhanced accumulation of α-DCs, reduced lifespan, increased neuronal damage, and touch hypersensitivity. Here, we demonstrate that glod-4 mutation increased food intake and identify that MGO-derived hydroimidazolone, MG-H1, is a mediator of the observed increase in food intake. RNAseq analysis in glod-4 knockdown worms identified upregulation of several neurotransmitters and feeding genes. Suppressor screening of the overfeeding phenotype identified the tdc-1-tyramine-tyra-2/ser-2 signaling as an essential pathway mediating AGEs (MG-H1) induced feeding in glod-4 mutants. We also identified the elt-3 GATA transcription factor as an essential upstream regulator for increased feeding upon accumulation of AGEs by partially controlling the expression of tdc-1 gene. Further, the lack of either tdc-1 or tyra-2/ser-2 receptors suppresses the reduced lifespan and rescues neuronal damage observed in glod-4 mutants. Thus, in C. elegans, we identified an elt-3 regulated tyramine-dependent pathway mediating the toxic effects of MG-H1 AGE. Understanding this signaling pathway may help understand hedonistic overfeeding behavior observed due to modern AGEs-rich diets.