The purine nucleoside phosphorylase pnp-1 regulates epithelial cell resistance to infection in C. elegans

Intestinal epithelial cells are subject to attack by a diverse array of microbes, including intracellular as well as extracellular pathogens. While defense in epithelial cells can be triggered by pattern recognition receptor-mediated detection of microbe-associated molecular patterns, there is much...

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Published inPLoS pathogens Vol. 17; no. 4; p. e1009350
Main Authors Tecle, Eillen, Chhan, Crystal B., Franklin, Latisha, Underwood, Ryan S., Hanna-Rose, Wendy, Troemel, Emily R.
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 01.04.2021
Public Library of Science (PLoS)
Subjects
Analysis
Animals
Bacteria
Bacterial diseases
Bacterial infections
Bacterial Infections - prevention & control
Biology and Life Sciences
Caenorhabditis elegans
Caenorhabditis elegans - metabolism
Cell Count - methods
Disease resistance
Drug resistance in microorganisms
Epithelial cells
Epithelial Cells - metabolism
Epithelium
Experiments
Gene expression
Genes
Genomes
HIV
Host-bacteria relationships
Human immunodeficiency virus
Immunological tolerance
Infections
Kinases
Medicine and Health Sciences
Metabolites
Mutants
Mutation
Nucleosides
Nucleotides
Pathogens
Phenotypes
Phosphorylase
Physical Sciences
Physiological aspects
Pseudomonas aeruginosa
Purine Nucleosides - metabolism
Purine-Nucleoside Phosphorylase - deficiency
Purine-Nucleoside Phosphorylase - genetics
Purines
Receptors, Pattern Recognition - metabolism
Research and Analysis Methods
Vertebrates
Viruses
United States
Online AccessGet full text
ISSN1553-7374
1553-7366
1553-7374
DOI10.1371/journal.ppat.1009350

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Abstract Intestinal epithelial cells are subject to attack by a diverse array of microbes, including intracellular as well as extracellular pathogens. While defense in epithelial cells can be triggered by pattern recognition receptor-mediated detection of microbe-associated molecular patterns, there is much to be learned about how they sense infection via perturbations of host physiology, which often occur during infection. A recently described host defense response in the nematode C . elegans called the Intracellular Pathogen Response (IPR) can be triggered by infection with diverse natural intracellular pathogens, as well as by perturbations to protein homeostasis. From a forward genetic screen, we identified the C . elegans ortholog of purine nucleoside phosphorylase pnp-1 as a negative regulator of IPR gene expression, as well as a negative regulator of genes induced by extracellular pathogens. Accordingly, pnp-1 mutants have resistance to both intracellular and extracellular pathogens. Metabolomics analysis indicates that C . elegans pnp-1 likely has enzymatic activity similar to its human ortholog, serving to convert purine nucleosides into free bases. Classic genetic studies have shown how mutations in human purine nucleoside phosphorylase cause immunodeficiency due to T-cell dysfunction. Here we show that C . elegans pnp-1 acts in intestinal epithelial cells to regulate defense. Altogether, these results indicate that perturbations in purine metabolism are likely monitored as a cue to promote defense against epithelial infection in the nematode C . elegans .
AbstractList Intestinal epithelial cells are subject to attack by a diverse array of microbes, including intracellular as well as extracellular pathogens. While defense in epithelial cells can be triggered by pattern recognition receptor-mediated detection of microbe-associated molecular patterns, there is much to be learned about how they sense infection via perturbations of host physiology, which often occur during infection. A recently described host defense response in the nematode C. elegans called the Intracellular Pathogen Response (IPR) can be triggered by infection with diverse natural intracellular pathogens, as well as by perturbations to protein homeostasis. From a forward genetic screen, we identified the C. elegans ortholog of purine nucleoside phosphorylase pnp-1 as a negative regulator of IPR gene expression, as well as a negative regulator of genes induced by extracellular pathogens. Accordingly, pnp-1 mutants have resistance to both intracellular and extracellular pathogens. Metabolomics analysis indicates that C. elegans pnp-1 likely has enzymatic activity similar to its human ortholog, serving to convert purine nucleosides into free bases. Classic genetic studies have shown how mutations in human purine nucleoside phosphorylase cause immunodeficiency due to T-cell dysfunction. Here we show that C. elegans pnp-1 acts in intestinal epithelial cells to regulate defense. Altogether, these results indicate that perturbations in purine metabolism are likely monitored as a cue to promote defense against epithelial infection in the nematode C. elegans.
Intestinal epithelial cells are subject to attack by a diverse array of microbes, including intracellular as well as extracellular pathogens. While defense in epithelial cells can be triggered by pattern recognition receptor-mediated detection of microbe-associated molecular patterns, there is much to be learned about how they sense infection via perturbations of host physiology, which often occur during infection. A recently described host defense response in the nematode C. elegans called the Intracellular Pathogen Response (IPR) can be triggered by infection with diverse natural intracellular pathogens, as well as by perturbations to protein homeostasis. From a forward genetic screen, we identified the C. elegans ortholog of purine nucleoside phosphorylase pnp-1 as a negative regulator of IPR gene expression, as well as a negative regulator of genes induced by extracellular pathogens. Accordingly, pnp-1 mutants have resistance to both intracellular and extracellular pathogens. Metabolomics analysis indicates that C. elegans pnp-1 likely has enzymatic activity similar to its human ortholog, serving to convert purine nucleosides into free bases. Classic genetic studies have shown how mutations in human purine nucleoside phosphorylase cause immunodeficiency due to T-cell dysfunction. Here we show that C. elegans pnp-1 acts in intestinal epithelial cells to regulate defense. Altogether, these results indicate that perturbations in purine metabolism are likely monitored as a cue to promote defense against epithelial infection in the nematode C. elegans.Intestinal epithelial cells are subject to attack by a diverse array of microbes, including intracellular as well as extracellular pathogens. While defense in epithelial cells can be triggered by pattern recognition receptor-mediated detection of microbe-associated molecular patterns, there is much to be learned about how they sense infection via perturbations of host physiology, which often occur during infection. A recently described host defense response in the nematode C. elegans called the Intracellular Pathogen Response (IPR) can be triggered by infection with diverse natural intracellular pathogens, as well as by perturbations to protein homeostasis. From a forward genetic screen, we identified the C. elegans ortholog of purine nucleoside phosphorylase pnp-1 as a negative regulator of IPR gene expression, as well as a negative regulator of genes induced by extracellular pathogens. Accordingly, pnp-1 mutants have resistance to both intracellular and extracellular pathogens. Metabolomics analysis indicates that C. elegans pnp-1 likely has enzymatic activity similar to its human ortholog, serving to convert purine nucleosides into free bases. Classic genetic studies have shown how mutations in human purine nucleoside phosphorylase cause immunodeficiency due to T-cell dysfunction. Here we show that C. elegans pnp-1 acts in intestinal epithelial cells to regulate defense. Altogether, these results indicate that perturbations in purine metabolism are likely monitored as a cue to promote defense against epithelial infection in the nematode C. elegans.
Intestinal epithelial cells are subject to attack by a diverse array of microbes, including intracellular as well as extracellular pathogens. While defense in epithelial cells can be triggered by pattern recognition receptor-mediated detection of microbe-associated molecular patterns, there is much to be learned about how they sense infection via perturbations of host physiology, which often occur during infection. A recently described host defense response in the nematode C . elegans called the Intracellular Pathogen Response (IPR) can be triggered by infection with diverse natural intracellular pathogens, as well as by perturbations to protein homeostasis. From a forward genetic screen, we identified the C . elegans ortholog of purine nucleoside phosphorylase pnp-1 as a negative regulator of IPR gene expression, as well as a negative regulator of genes induced by extracellular pathogens. Accordingly, pnp-1 mutants have resistance to both intracellular and extracellular pathogens. Metabolomics analysis indicates that C . elegans pnp-1 likely has enzymatic activity similar to its human ortholog, serving to convert purine nucleosides into free bases. Classic genetic studies have shown how mutations in human purine nucleoside phosphorylase cause immunodeficiency due to T-cell dysfunction. Here we show that C . elegans pnp-1 acts in intestinal epithelial cells to regulate defense. Altogether, these results indicate that perturbations in purine metabolism are likely monitored as a cue to promote defense against epithelial infection in the nematode C . elegans .
Intestinal epithelial cells are subject to attack by a diverse array of microbes, including intracellular as well as extracellular pathogens. While defense in epithelial cells can be triggered by pattern recognition receptor-mediated detection of microbe-associated molecular patterns, there is much to be learned about how they sense infection via perturbations of host physiology, which often occur during infection. A recently described host defense response in the nematode C . elegans called the Intracellular Pathogen Response (IPR) can be triggered by infection with diverse natural intracellular pathogens, as well as by perturbations to protein homeostasis. From a forward genetic screen, we identified the C . elegans ortholog of purine nucleoside phosphorylase pnp-1 as a negative regulator of IPR gene expression, as well as a negative regulator of genes induced by extracellular pathogens. Accordingly, pnp-1 mutants have resistance to both intracellular and extracellular pathogens. Metabolomics analysis indicates that C . elegans pnp-1 likely has enzymatic activity similar to its human ortholog, serving to convert purine nucleosides into free bases. Classic genetic studies have shown how mutations in human purine nucleoside phosphorylase cause immunodeficiency due to T-cell dysfunction. Here we show that C . elegans pnp-1 acts in intestinal epithelial cells to regulate defense. Altogether, these results indicate that perturbations in purine metabolism are likely monitored as a cue to promote defense against epithelial infection in the nematode C . elegans . All life requires purine nucleotides. However, obligate intracellular pathogens are incapable of generating their own purine nucleotides and thus have evolved strategies to steal these nucleotides from host cells in order to support their growth and replication. Using the small roundworm C . elegans , we show that infection with natural obligate intracellular pathogens is impaired by loss of pnp-1 , the C . elegans ortholog of the vertebrate purine nucleoside phosphorylase (PNP), which is an enzyme involved in salvaging purines. Loss of pnp-1 leads to altered levels of purine nucleotide precursors and increased expression of Intracellular Pathogen Response genes, which are induced by viral and fungal intracellular pathogens of C . elegans . In addition, we find that loss of pnp-1 increases resistance to extracellular pathogen infection and increases expression of genes involved in extracellular pathogen defense. Interestingly, studies from 1975 found that mutations in human PNP impair T-cell immunity, whereas our findings here indicate C . elegans pnp-1 regulates intestinal epithelial immunity. Overall, our work indicates that host purine homeostasis regulates resistance to both intracellular and extracellular pathogen infection.
Forward genetic studies identified pals-22 and pals-25 as antagonistic paralogs that regulate the IPR and associated phenotypes [15,17]. pals-22 and pals-25 belong to the pals gene family in C. elegans, which contains at least 39 pals genes named for the loosely conserved ALS2CR12 protein signature located in the single ALS2CR12 gene found in each of the human and mouse genomes [15,18,19]. The biochemical functions of ALS2CR12 and C. elegans pals genes are unknown, but pals-22 and pals-25 appear to dramatically rewire C. elegans physiology. pals-22 mutants have constitutive expression of IPR genes in the absence of infection, and have improved tolerance of proteotoxic stress, as well as increased resistance against N. parisii and the Orsay virus, but decreased resistance against the bacterial extracellular pathogen Pseudomonas aeruginosa [15,17]. Surprisingly, unlike pals-22, pnp-1 also negatively regulates the expression of genes that are induced by bacterial infection and by other immune regulators. [...]pnp-1 mutants display resistance to the extracellular bacterial pathogen P. aeruginosa. [...]we find that loss of pals-25 does not suppress IPR gene expression in pnp-1 mutants (S2B Fig) as it does in pals-22 mutants [17]. [...]our data indicates that pnp-1 likely acts in parallel to the more potent pals-22/pals-25 pathway to regulate IPR gene expression. pnp-1 mutants have altered levels of purine metabolites Vertebrate PNP functions in the purine salvage pathway where purine nucleotides sequentially are degraded to nucleosides and purine bases.
Forward genetic studies identified pals-22 and pals-25 as antagonistic paralogs that regulate the IPR and associated phenotypes [15,17]. pals-22 and pals-25 belong to the pals gene family in C. elegans, which contains at least 39 pals genes named for the loosely conserved ALS2CR12 protein signature located in the single ALS2CR12 gene found in each of the human and mouse genomes [15,18,19]. The biochemical functions of ALS2CR12 and C. elegans pals genes are unknown, but pals-22 and pals-25 appear to dramatically rewire C. elegans physiology. pals-22 mutants have constitutive expression of IPR genes in the absence of infection, and have improved tolerance of proteotoxic stress, as well as increased resistance against N. parisii and the Orsay virus, but decreased resistance against the bacterial extracellular pathogen Pseudomonas aeruginosa [15,17]. Surprisingly, unlike pals-22, pnp-1 also negatively regulates the expression of genes that are induced by bacterial infection and by other immune regulators. [...]pnp-1 mutants display resistance to the extracellular bacterial pathogen P. aeruginosa. [...]we find that loss of pals-25 does not suppress IPR gene expression in pnp-1 mutants (S2B Fig) as it does in pals-22 mutants [17]. [...]our data indicates that pnp-1 likely acts in parallel to the more potent pals-22/pals-25 pathway to regulate IPR gene expression. pnp-1 mutants have altered levels of purine metabolites Vertebrate PNP functions in the purine salvage pathway where purine nucleotides sequentially are degraded to nucleosides and purine bases.
Audience Academic
Author Tecle, Eillen
Hanna-Rose, Wendy
Franklin, Latisha
Chhan, Crystal B.
Underwood, Ryan S.
Troemel, Emily R.
AuthorAffiliation 1 Division of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
University of Massachusetts Medical School, UNITED STATES
2 Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America
AuthorAffiliation_xml – name: 1 Division of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
– name: University of Massachusetts Medical School, UNITED STATES
– name: 2 Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America
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  surname: Tecle
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  orcidid: 0000-0002-1394-783X
  surname: Chhan
  fullname: Chhan, Crystal B.
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  surname: Franklin
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/33878133$$D View this record in MEDLINE/PubMed
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2021 Tecle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
2021 Tecle et al 2021 Tecle et al
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  doi: 10.1186/1471-2164-6-118
– volume: 207
  start-page: 529
  issue: 2
  year: 2017
  ident: ppat.1009350.ref018
  article-title: Silencing of Repetitive DNA Is Controlled by a Member of an Unusual Caenorhabditis elegans Gene Family
  publication-title: Genetics
  doi: 10.1534/genetics.117.300134
– volume: 28
  start-page: 640
  issue: 4
  year: 2018
  ident: ppat.1009350.ref031
  article-title: Natural Infection of C. elegans by an Oomycete Reveals a New Pathogen-Specific Immune Response
  publication-title: Curr Biol
  doi: 10.1016/j.cub.2018.01.029
– reference: 35797340 - PLoS Pathog. 2022 Jul 7;18(7):e1010699. doi: 10.1371/journal.ppat.1010699
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Snippet Intestinal epithelial cells are subject to attack by a diverse array of microbes, including intracellular as well as extracellular pathogens. While defense in...
Forward genetic studies identified pals-22 and pals-25 as antagonistic paralogs that regulate the IPR and associated phenotypes [15,17]. pals-22 and pals-25...
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SubjectTerms Analysis
Animals
Bacteria
Bacterial diseases
Bacterial infections
Bacterial Infections - prevention & control
Biology and Life Sciences
Caenorhabditis elegans
Caenorhabditis elegans - metabolism
Cell Count - methods
Disease resistance
Drug resistance in microorganisms
Epithelial cells
Epithelial Cells - metabolism
Epithelium
Experiments
Gene expression
Genes
Genomes
HIV
Host-bacteria relationships
Human immunodeficiency virus
Immunological tolerance
Infections
Kinases
Medicine and Health Sciences
Metabolites
Mutants
Mutation
Nucleosides
Nucleotides
Pathogens
Phenotypes
Phosphorylase
Physical Sciences
Physiological aspects
Pseudomonas aeruginosa
Purine Nucleosides - metabolism
Purine-Nucleoside Phosphorylase - deficiency
Purine-Nucleoside Phosphorylase - genetics
Purines
Receptors, Pattern Recognition - metabolism
Research and Analysis Methods
Vertebrates
Viruses
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Title The purine nucleoside phosphorylase pnp-1 regulates epithelial cell resistance to infection in C. elegans
URI https://www.ncbi.nlm.nih.gov/pubmed/33878133
https://www.proquest.com/docview/2528218544
https://www.proquest.com/docview/2516221893
https://pubmed.ncbi.nlm.nih.gov/PMC8087013
https://doaj.org/article/17592f3d8aad46cda21920bfd4ac4dd9
http://dx.doi.org/10.1371/journal.ppat.1009350
Volume 17
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