Immunometabolism in Caenorhabditis elegans

Anderson, Sarah M.; Pukkila-Worley, Read

doi:10.1371/journal.ppat.1008897

Cited by 25 publications

(19 citation statements)

References 29 publications

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“…The p38 PMK-1 pathway controls the expression of innate immune effector genes. Inputs from chemosensory neurons, bacterial density, tissue damage and nucleotide metabolism also regulate the tonic level of p38 PMK-1 pathway activity (16,(48)(49)(50)(51)(52). These data suggest that p38 PMK-1 phosphorylation is adjusted in different environments to anticipate dangerous threats during periods of vulnerability.…”

Section: Discussionmentioning

confidence: 93%

“…In this model, the p38 PMK-1 pathway functions as a rheostat that receives inputs from signals associated with potentially dangerous environmental conditions to prime host immune effector genes. Indeed, inputs from chemosensory neurons, bacterial density, tissue damage and nucleotide metabolism also regulate the tonic level of p38 PMK-1 pathway activity [3,[53][54][55][56][57], suggesting that p38 PMK-1 phosphorylation is adjusted to anticipate dangerous threats during periods of vulnerability. Thus, upon encountering a pathogen, immune defenses can be further augmented by other mechanisms that detect pathogen specifically.…”

Section: Discussionmentioning

confidence: 99%

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A TIR-1/SARM1 phase transition underlies p38 immune pathway activation in theC. elegansintestine

Peterson

Icso²,

Salisbury

et al. 2021

Preprint

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Intracellular signaling regulators can be concentrated into membrane-free, higher-ordered protein assemblies to initiate protective responses during stress — a process known as phase transition. Here, we show that a phase transition of the C. elegans Toll/interleukin-1 receptor domain protein (TIR-1), a homolog of the mammalian sterile alpha and TIR motif-containing 1 (SARM1), primes host immune defenses when dietary sterols are limited to handle subsequent bacterial infection. TIR-1/SARM1 is an upstream component of the p38 PMK-1 pathway in intestinal cells, an innate immune defense and stress response pathway in metazoans. Under conditions of low cholesterol availability, multimerization and precipitation of TIR-1/SARM1 potentiates the intrinsic NAD+ glycohydrolase activity of this protein complex, increases p38 PMK-1 phosphorylation, and promotes pathogen clearance from the intestine. Dietary cholesterol is required for C. elegans to survive infection with pathogenic bacteria and to support development, fecundity, and lifespan. Thus, activation of the p38 PMK-1 pathway in sterol-deficient animals is an adaptive response that allows a metazoan host to anticipate environmental threats under conditions of essential metabolite scarcity.SIGNIFICANCE STATEMENTThe nematode C. elegans must consume dietary sterols to support growth and reproduction. However, access to dietary sterols in its natural habitat is not guaranteed and thus, nematodes have evolved mechanisms to promote survival in sterol-poor environments. Here, we demonstrate that activation of the p38 PMK-1 innate immune pathway in response to low sterol availability promotes clearance of a bacterial pathogen from the intestine. Pre-emptive activation of innate immune defenses occurs through a phase transition of TIR-1/SARM1, an upstream component of the p38 PMK-1 pathway, which activates its intrinsic NAD+ glycohydrolase activity. Thus, nematodes anticipate threats from infectious pathogens during a time when the animal is relatively susceptible to infection.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

A TIR-1/SARM1 phase transition underlies p38 immune pathway activation in theC. elegansintestine

Peterson

Icso²,

Salisbury

et al. 2021

Preprint

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“…Lipid metabolism has been shown to be required for proper innate immune system activation and pathogen defense. 44 These genes could play similar roles in both isolates and thus, while they may reflect a divergence in specific gene activation, they could represent a similarity in how N2 and CB4856 animals utilize lipid metabolism enzymes to facilitate the innate immune response.…”

Section: Isolates Exhibit Distinct Transcriptomic Responses To Infectionmentioning

confidence: 99%

Wild-type Caenorhabditis elegans Isolates Exhibit Distinct Gene Expression Profiles in Response to Microbial Infection

Lansdon

Carlson

Ackley

2021

Preprint

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The soil-dwelling nematode Caenorhabditis elegans serves as a model system to study innate immunity against microbial pathogens. C. elegans have been collected from around the world, where they, presumably, adapted to regional microbial ecologies. Here we use survival assays and RNA-sequencing to better understand how two isolates from disparate climates respond to pathogenic bacteria. We found that, relative to N2 (originally isolated in Bristol, UK), CB4856 (isolated in Hawaii), was more susceptible to the Gram-positive pathogen, Staphylococcus epidermidis, but equally susceptible to Staphylococcus aureus as well as two Gram-negative pathogens, Providencia rettgeri and Pseudomonas aeruginosa. We performed transcriptome analysis of infected worms and found gene-expression profiles were considerably different in an isolate-specific and pathogen-specific manner. We performed GO term analysis to categorize differential gene expression in response to S. epidermidis. In N2, genes that encoded detoxification enzymes and extracellular matrix proteins were significantly enriched, while in CB4856, genes that encoded detoxification enzymes, C-type lectins, and lipid metabolism proteins were enriched, suggesting they have different responses to these bacterial pathogens, despite being the same species. Overall, discerning gene expression signatures in an isolate by pathogen manner can help us to understand the different possibilities for the evolution of immune responses within organisms.

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“…Over the past few decades, this model has also been recognized as a valuable tool in revealing fundamental principles in innate immunity and host-pathogen interactions ( 16 ). Most recently, C. elegans was also established as an important model for unraveling key concepts in immunometabolism ( 17 ). Most of the success in the use of C. elegans in research relies on the fact that this species is a valuable representative of metazoans, including humans.…”

Section: Introductionmentioning

confidence: 99%

“…For example, 83% of the worm proteome contains human homologs ( 18 , 19 ). Importantly, various molecular pathways involved in immunometabolic responses in mammals are conserved in C. elegans ( Figure 1 ) ( 17 , 20 , 21 ). Moreover, the key role of mitochondria as a signaling hub for innate immune responses also seems to be conserved between vertebrates and C. elegans ( 22 , 23 ).…”

Section: Introductionmentioning

confidence: 99%

Rotenone Modulates Caenorhabditis elegans Immunometabolism and Pathogen Susceptibility

et al. 2022

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Mitochondria are central players in host immunometabolism as they function not only as metabolic hubs but also as signaling platforms regulating innate immunity. Environmental exposures to mitochondrial toxicants occur widely and are increasingly frequent. Exposures to these mitotoxicants may pose a serious threat to organismal health and the onset of diseases by disrupting immunometabolic pathways. In this study, we investigated whether the Complex I inhibitor rotenone could alter C. elegans immunometabolism and disease susceptibility. C. elegans embryos were exposed to rotenone (0.5 µM) or DMSO (0.125%) until they reached the L4 larval stage. Inhibition of mitochondrial respiration by rotenone and disruption of mitochondrial metabolism were evidenced by rotenone-induced detrimental effects on mitochondrial efficiency and nematode growth and development. Next, through transcriptomic analysis, we investigated if this specific but mild mitochondrial stress that we detected would lead to the modulation of immunometabolic pathways. We found 179 differentially expressed genes (DEG), which were mostly involved in detoxification, energy metabolism, and pathogen defense. Interestingly, among the down-regulated DEG, most of the known genes were involved in immune defense, and most of these were identified as commonly upregulated during P. aeruginosa infection. Furthermore, rotenone increased susceptibility to the pathogen Pseudomonas aeruginosa (PA14). However, it increased resistance to Salmonella enterica (SL1344). To shed light on potential mechanisms related to these divergent effects on pathogen resistance, we assessed the activation of the mitochondrial unfolded protein response (UPRmt), a well-known immunometabolic pathway in C. elegans which links mitochondria and immunity and provides resistance to pathogen infection. The UPRmt pathway was activated in rotenone-treated nematodes further exposed for 24 h to the pathogenic bacteria P. aeruginosa and S. enterica or the common bacterial food source Escherichia coli (OP50). However, P. aeruginosa alone suppressed UPRmt activation and rotenone treatment rescued its activation only to the level of DMSO-exposed nematodes fed with E. coli. Module-weighted annotation bioinformatics analysis was also consistent with UPRmt activation in rotenone-exposed nematodes consistent with the UPR being involved in the increased resistance to S. enterica. Together, our results demonstrate that the mitotoxicant rotenone can disrupt C. elegans immunometabolism in ways likely protective against some pathogen species but sensitizing against others.

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Immunometabolism in Caenorhabditis elegans

Cited by 25 publications

References 29 publications

A TIR-1/SARM1 phase transition underlies p38 immune pathway activation in theC. elegansintestine

A TIR-1/SARM1 phase transition underlies p38 immune pathway activation in theC. elegansintestine

Wild-type Caenorhabditis elegans Isolates Exhibit Distinct Gene Expression Profiles in Response to Microbial Infection

Rotenone Modulates Caenorhabditis elegans Immunometabolism and Pathogen Susceptibility

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