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Serotonin deficiency from constitutive SKN-1 activation drives pathogen apathy.

Tripti Nair | Brandy A Weathers | Nicole L Stuhr | James D Nhan | Sean P Curran
Nature communications | 2024

When an organism encounters a pathogen, the host innate immune system activates to defend against pathogen colonization and toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy-like behavior towards PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave and continue to feed on the pathogen even when a non-pathogenic and healthspan-promoting food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display the typical pathogen-induced intestinal distension and eventual demise. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling that is required from both neurons and non-neuronal tissues. Serotonin depletion from SKN-1 activation limits pathogen defenses capacity, drives the pathogen-associated apathy behaviors and induces a synthetic sensitivity to selective serotonin reuptake inhibitors. Taken together, our work reveals interesting insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival.

Pubmed ID: 39285192

Associated grants

  • Agency: NIA NIH HHS, United States
    Id: T32 AG000037
  • Agency: NIH HHS, United States
    Id: P40 OD010440
  • Agency: U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging),
    Id: AG052374
  • Agency: NIA NIH HHS, United States
    Id: T32 AG052374
  • Agency: NIA NIH HHS, United States
    Id: R01 AG058610
  • Agency: U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging),
    Id: AG077873
  • Agency: NIA NIH HHS, United States
    Id: P30 AG068345
  • Agency: U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging),
    Id: AG000037
  • Agency: NIA NIH HHS, United States
    Id: F31 AG077873

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NCBI Epigenomics (tool)

RRID:SCR_006151

THIS RESOURCE IS NO LONGER IN SERVICE, documented on January 19, 2022.

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DESeq2 (tool)

RRID:SCR_015687

Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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LC74 (tool)

RRID:WB-STRAIN:WBStrain00024114

Caenorhabditis elegans with name pah-1(ok687) II. from WB.

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N2_(ancestral) (tool)

RRID:WB-STRAIN:WBStrain00000003

Caenorhabditis elegans with name C. elegans wild type (ancestral). from WB.

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DA465 (organism)

RRID:WB-STRAIN:WBStrain00005463

Caenorhabditis elegans with name eat-2(ad465) II. from WB.

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MT7988 (organism)

RRID:WB-STRAIN:WBStrain00027310

Caenorhabditis elegans with name bas-1(ad446) III. from WB.

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Caenorhabditis Genetics Center (biomaterial supply resource)

RRID:SCR_007341

Center that acquires, maintains, and distributes genetic stocks and information about stocks of the small free-living nematode Caenorhabditis elegans for use by investigators initiating or continuing research on this genetic model organism. A searchable strain database, general information about C. elegans, and links to key Web sites of use to scientists, including WormBase, WormAtlas, and WormBook are available.

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Caenorhabditis Genetics Center (biomaterial supply resource)

RRID:SCR_007341

Center that acquires, maintains, and distributes genetic stocks and information about stocks of the small free-living nematode Caenorhabditis elegans for use by investigators initiating or continuing research on this genetic model organism. A searchable strain database, general information about C. elegans, and links to key Web sites of use to scientists, including WormBase, WormAtlas, and WormBook are available.

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N2 (organism)

RRID:WB-STRAIN:WBStrain00000001

Caenorhabditis elegans with name Caenorhabditis elegans wild isolate. from WB.

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MT15434 (organism)

RRID:WB-STRAIN:WBStrain00027519

Caenorhabditis elegans with name tph-1(mg280)/II from WB.

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Caenorhabditis Genetics Center (biomaterial supply resource)

RRID:SCR_007341

Center that acquires, maintains, and distributes genetic stocks and information about stocks of the small free-living nematode Caenorhabditis elegans for use by investigators initiating or continuing research on this genetic model organism. A searchable strain database, general information about C. elegans, and links to key Web sites of use to scientists, including WormBase, WormAtlas, and WormBook are available.

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VC1772 (organism)

RRID:WB-STRAIN:WBStrain00036863

Caenorhabditis elegans with name skn-1(ok2315) IV/nT1 [qIs51] (IV;V). from WB.

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CB1370 (organism)

RRID:WB-STRAIN:WBStrain00004309

Caenorhabditis elegans with name daf-2(e1370) from WB.

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