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Proceedings of the National Academy of Sciences of the United States of America
Nov 12, 2024;121 (46): e2405719121.

Microbial metabolism disrupts cytokine activity to impact host immune response.

Eleanor K P Marshall, Catarina Nunes, Sophie Burbaud, Crystal M Vincent, Natalie O Munroe, Carolina J Simoes da Silva, Ashima Wadhawan, William H Pearson, Jasper Sangen, Lucas Boeck, R Andres Floto, Marc S Dionne
Author Information
  1. Eleanor K P Marshall: Centre for Bacterial Resistance Biology, Imperial College London, London SW7 2AZ, United Kingdom. ORCID
  2. Catarina Nunes: Centre for Bacterial Resistance Biology, Imperial College London, London SW7 2AZ, United Kingdom.
  3. Sophie Burbaud: Department of Medicine, Molecular Immunity Unit, University of Cambridge, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
  4. Crystal M Vincent: Centre for Bacterial Resistance Biology, Imperial College London, London SW7 2AZ, United Kingdom. ORCID
  5. Natalie O Munroe: Centre for Bacterial Resistance Biology, Imperial College London, London SW7 2AZ, United Kingdom. ORCID
  6. Carolina J Simoes da Silva: Centre for Bacterial Resistance Biology, Imperial College London, London SW7 2AZ, United Kingdom.
  7. Ashima Wadhawan: Centre for Bacterial Resistance Biology, Imperial College London, London SW7 2AZ, United Kingdom.
  8. William H Pearson: Centre for Bacterial Resistance Biology, Imperial College London, London SW7 2AZ, United Kingdom.
  9. Jasper Sangen: Department of Medicine, Molecular Immunity Unit, University of Cambridge, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
  10. Lucas Boeck: Department of Biomedicine, University of Basel, Basel 4031, Switzerland.
  11. R Andres Floto: Department of Medicine, Molecular Immunity Unit, University of Cambridge, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
  12. Marc S Dionne: Centre for Bacterial Resistance Biology, Imperial College London, London SW7 2AZ, United Kingdom. ORCID
PMID: 39514319 DOI: 10.1073/pnas.2405719121

Abstract

Host-pathogen interactions are shaped by the metabolic status of both the host and pathogen. The host must regulate metabolism to fuel the immune response, while the pathogen must extract metabolic resources from the host to enable its own survival. In this study, we focus on the metabolic interactions of with . We identify MAB_1132c as an asparagine transporter required for pathogenicity in . We show that this requirement is specifically associated with damage to the host: flies infected with MAB_1132c knockout bacteria, or with wild-type bacteria grown in asparagine-restricted conditions, are longer lived without showing a significant change in bacterial load. This is associated with a reduction in the host innate immune response, demonstrated by the decreased transcription of antimicrobial peptides as well as a significant reduction in the ability of the infection to disrupt systemic insulin signaling. Much of the increase in host survival during infection with asparagine-limited can be attributed to alterations in unpaired cytokine signaling. This demonstrates that asparagine transport in prior to infection is not required for replicative fitness in vivo but does significantly influence the interaction with the host immune responses.

Keywords

Drosophila melanogaster Mycobacterium abscessus infection innate immunity metabolism

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Grants

  1. 2367572/UKRI | Medical Research Council (MRC)
  2. MR/P028225/1/Medical Research Council
  3. RPG-2022-337/Leverhulme Trust
  4. 107032AIA/Wellcome Trust (WT)
  5. MR/R00997X/1/UKRI | Medical Research Council (MRC)
  6. 207467/Z/17/Z/Wellcome Trust (WT)
  7. /Wellcome Trust
  8. 226602/Z/22/Z/Wellcome Trust (WT)
  9. BB/W001004/1/UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)

MeSH Term

Animals
Drosophila melanogaster
Host-Pathogen Interactions
Cytokines
Mycobacterium abscessus
Immunity, Innate
Asparagine
Mycobacterium Infections, Nontuberculous
Signal Transduction
Amino Acid Transport Systems
Bacterial Proteins

Chemicals

Cytokines
Asparagine
Amino Acid Transport Systems
Bacterial Proteins
Journal Article

Word Cloud

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