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Cited by 63Tuberculosis Research and EpidemiologyMycobacterium research and diagnosisBacterial Genetics and Biotechnology

Path‐seq identifies an essential mycolate remodeling program for mycobacterial host adaptation

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Peterson, Eliza JR, Bailo, Rebeca, Rothchild, Alissa C, Arrieta‐Ortiz, Mario L, Kaur, Amardeep, Pan, Min, Mai, Dat, Abidi, Abrar A +4 more·2019·Molecular Systems Biology
DOI 10.15252/msb.20188584PMC PMC6398593

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Abstract

The success of Mycobacterium tuberculosis (MTB) stems from its ability to remain hidden from the immune system within macrophages. Here, we report a new technology (Path‐seq) to sequence miniscule amounts of MTB transcripts within up to million‐fold excess host RNA. Using Path‐seq and regulatory network analyses, we have discovered a novel transcriptional program for in vivo mycobacterial cell wall remodeling when the pathogen infects alveolar macrophages in mice. We have discovered that MadR transcriptionally modulates two mycolic acid desaturases desA1 / desA2 to initially promote cell wall remodeling upon in vitro macrophage infection and, subsequently, reduces mycolate biosynthesis upon entering dormancy. We demonstrate that disrupting MadR program is lethal to diverse mycobacteria making this evolutionarily conserved regulator a prime antitubercular target for both early and late stages of infection.

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  • FadD32 is highly transcribed in growth and likely downregulated in stasis, so inhibitors of this enzyme are unlikely to be effective in stasis.

    “FadD32 is highly transcribed in growth60 and likely downregulated in stasis59, so inhibitors of this enzyme are unlikely to be effective in stasis.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [60]

    The Results section (page unavailable) identifies fadD32 among mycolic-acid biosynthesis genes upregulated during early infection and says new cell-wall biosynthesis is repressed upon entry into dormancy. The Discussion (page unavailable) also describes reduced mycolate biosynthesis during dormancy. These passages support the proposed trend, but do not establish that fadD32 itself is downregulated in stasis; the statement about inhibitor effectiveness is the citing authors’ inference, not a finding attributed to this source. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • pcaA is transcriptionally upregulated in the active phase, and blocks phagosome-lysosome fusion and stimulation of the pro-inflammatory cytokine tumour necrosis factor in macrophage infections, which implies that cis cyclopropanations are important for early stages of infection.

    “pcaA is transcriptionally upregulated in the active phase60, and blocks phagosome–lysosome fusion96 and stimulation of the pro-​inflammatory cytokine tumour necrosis factor in macrophage infections97, which implies that cis cyclopropanations are impor- tant for early stages of infection.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [60]

  • The transcription of the FAS-I genes fas, accD4 and accD5 seems to correlate with growth.

    “The transcrip- tion of the FAS-​I genes fas, accD4 and accD5 seems to correlate with growth59,60,88.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [60]

    The Results section links repression of desA1 and desA2 to reduced mycobacterial viability, while the Discussion describes their expression under normal growth conditions. Neither passage addresses whether transcription of fas, accD4, or accD5 correlates with growth; searches for those genes and FAS-I expression found no supporting passage. Page numbers were not available in our copy. (LLM, conf=0.70)

    Experimental — accuracy not yet measured

  • During growth, embA and embB levels may be higher than embC levels because embC levels are repressed early in macrophage infections.

    “However, embC levels are repressed early in macrophage infections, so during growth, embA and embB levels may be higher than embC levels60.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [60]

    The Results section on early macrophage infection reports changes in desA1 and desA2 expression, not repression of embC or a comparison with embA and embB (page unavailable). Searches for embC, the three emb genes together, and early embC repression found no passage addressing the cited claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Peterson, E. J., Bailo, R., Rothchild, A. C., Arrieta‐Ortiz, M. L., Kaur, A., Pan, M., Mai, D., Abidi, A. A., Cooper, C., Aderem, A., Bhatt, A., & Baliga, N. S.
Affiliations
  • Institute for Systems Biology (US)
  • University of Birmingham (GB)
  • Seattle Children's Research Institute (US)
  • Lawrence Berkeley National Laboratory (US)
Corresponding author
  • Bhatt, Apoorva
  • Baliga, Nitin S
ORCID
Venue
Molecular Systems Biology
Publisher
Springer Science and Business Media LLC
Published
2019-03-01
Volume
15
Issue
3
Pages
e8584-e8584
ISSN
1744-4292 (ISSN-L)
DOI
10.15252/msb.20188584
PMC
PMC6398593
OpenAlex
W2918529265
Cited by
63
References
8
Citations by year
2026: 1 · 2025: 5 · 2024: 6 · 2023: 9 · 2022: 12 · 2021: 13 · 2020: 7 · 2019: 10
FWCI
8.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Systems Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
Funders
  • National Science Foundation (1518261)
  • RCUK|Biotechnology and Biological Sciences Research Council (BB/N01314X/1)
  • HHS|NIH|National Institute of Allergy and Infectious Diseases (R01AI128215, U19AI10676, U19AI135976)
  • MIBTP PhD Sutdentship
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords
Mycobacterium tuberculosis, alveolar macrophages, bacterial dormancy, host-pathogen interaction, tuberculosis drug targets
MeSH terms
Adaptation, Physiological, Animals, Antigens, Bacterial, Bacterial Proteins, Cell Wall, Macrophages, Mycobacterium tuberculosis, Mycolic Acids, Tuberculosis, Systems Biology, Mice, Gene Regulatory Networks, Host-Pathogen Interactions

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