NHR-49/PPAR-α and HLH-30/TFEB cooperate for C. elegans host defense via a flavin-containing monooxygenase

  1. Khursheed A Wani
  2. Debanjan Goswamy
  3. Stefan Taubert
  4. Ramesh Ratnappan
  5. Arjumand Ghazi
  6. Javier E Irazoqui  Is a corresponding author
  1. University of Massachusetts Medical School, United States
  2. University of British Columbia, Canada
  3. University of Pittsburgh School of Medicine, United States

Abstract

The model organism Caenorhabditis elegans mounts transcriptional defense responses against intestinal bacterial infections that elicit overlapping starvation and infection responses, the regulation of which is not well understood. Direct comparison of C. elegans that were starved or infected with Staphylococcus aureus revealed a large infection-specific transcriptional signature, which was almost completely abrogated by deletion of transcription factor hlh-30/TFEB, except for six genes including a flavin-containing monooxygenase (FMO) gene, fmo-2/FMO5. Deletion of fmo-2/FMO5 severely compromised infection survival, thus identifying the first FMO with innate immunity functions in animals. Moreover, fmo-2/FMO5 induction required the nuclear hormone receptor, NHR-49/PPAR-α, which controlled host defense cell non-autonomously. These findings reveal an infection-specific host response to S. aureus, identify HLH-30/TFEB as its main regulator, reveal FMOs as important innate immunity effectors in animals, and identify the mechanism of FMO regulation through NHR-49/PPAR-α during S. aureus infection, with implications for host defense and inflammation in higher organisms.

Data availability

RNA-seq reads are deposited in SRA (NCBI/NIH)

The following data sets were generated

Article and author information

Author details

  1. Khursheed A Wani

    Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Debanjan Goswamy

    Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Stefan Taubert

    Medical Genetics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2432-7257
  4. Ramesh Ratnappan

    Departments of Pediatrics, Developmental Biology and Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7055-9043
  5. Arjumand Ghazi

    Departments of Pediatrics, Developmental Biology and Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5859-4206
  6. Javier E Irazoqui

    Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    Javier.Irazoqui@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6553-1329

Funding

National Institute of General Medical Sciences (GM101056)

  • Javier E Irazoqui

National Institutes of Aging (R01AG051659)

  • Arjumand Ghazi

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

Reviewing Editor

  1. Scott F Leiser, University of Michigan, United States

Version history

  1. Received: September 4, 2020
  2. Accepted: April 29, 2021
  3. Accepted Manuscript published: May 12, 2021 (version 1)
  4. Accepted Manuscript updated: May 17, 2021 (version 2)
  5. Version of Record published: May 21, 2021 (version 3)

Copyright

© 2021, Wani 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.

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  1. Khursheed A Wani
  2. Debanjan Goswamy
  3. Stefan Taubert
  4. Ramesh Ratnappan
  5. Arjumand Ghazi
  6. Javier E Irazoqui
(2021)
NHR-49/PPAR-α and HLH-30/TFEB cooperate for C. elegans host defense via a flavin-containing monooxygenase
eLife 10:e62775.
https://doi.org/10.7554/eLife.62775

Share this article

https://doi.org/10.7554/eLife.62775

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