NHR-49 Transcription Factor Regulates Immunometabolic Response and Survival of Caenorhabditis elegans during Enterococcus faecalis Infection

Dasgupta, Madhumanti; Shashikanth, Meghana; Gupta, Akash; Sandhu, Anjali; De, Atreyee; Javed, Salil; Singh, Varsha

doi:10.1128/iai.00130-20

Cited by 46 publications

(75 citation statements)

References 52 publications

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“…nhr-49(RNAi), but not nhr-45(RNAi) abolished compound rescue, suggesting that NHR-49/HNF4, like MDT-15/MED15, is required for LK56 activity(Fig 7D). , MDT-15/MED15 and NHR-49/HNF4 have been independently linked with innate immune defense in C. elegans[57][58][59], but this is the first time that they have been linked to the same process. An interesting possibility is that fatty acid metabolism, a function commonly associated with both genes[60,61], underlies LK56 rescue.…”

mentioning

confidence: 90%

Novel Immune Modulators EnhanceCaenorhabditis elegansResistance to Multiple Pathogens

Hummell

Revtovich

Kirienko

2020

Preprint

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Traditionally, treatments for bacterial infection have focused on killing the microbe or preventing its growth. As antimicrobial resistance becomes more ubiquitous, attention has begun to shift toward disrupting the host-pathogen interaction by improving the host defense. Using a high-throughput, fragment-based screen to identify compounds that alleviate Pseudomonas aeruginosa-mediated killing of Caenorhabditis elegans, we identified over 20 compounds that stimulated host defense gene expression. Five of these molecules were selected for further characterization. Four compounds showed little toxicity against mammalian cells or worms, consistent with their identification in a phenotypic, high-content screen. Each of the compounds activated several host defense pathways, but the pathways were generally dispensable for compound-mediated rescue in Liquid Killing, suggesting redundancy or that the activation of one or more unknown pathways may be driving compound effects. A genetic mechanism was identified for LK56, which required the Mediator subunit MDT-15/MED15 and NHR-49/HNF4 for its function. Interestingly, LK32, LK34, LK38, and LK56 also rescue C. elegans from P. aeruginosa in an agar-based assay, which uses different virulence factors and defense mechanisms. Rescue in an agar-based assay for LK38 entirely depended upon the PMK-1/p38 MAPK pathway. Three compounds, LK32, LK34, and LK56 also conferred resistance to Enterococcus faecalis, and the two lattermost, LK34 and LK56, also reduced pathogenesis from Staphylococcus aureus. This study supports a growing role for MDT-15 and NHR-49 in immune response and identifies 5 molecules that with significant potential for use as tools in the investigation of innate immunity.

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mentioning

confidence: 90%

Novel Immune Modulators EnhanceCaenorhabditis elegansResistance to Multiple Pathogens

Hummell

Revtovich

Kirienko

2020

Preprint

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“…Interestingly, MDT-15/MED15 and NHR-49/HNF4 have been independently linked with innate immune defense in C. elegans ( 58 – 60 ), but this is the first time that they have been linked to the same process. An interesting possibility is that fatty acid metabolism, a function commonly associated with both genes ( 61 , 62 ), underlies LK56 rescue.…”

Section: Resultsmentioning

confidence: 97%

Novel Immune Modulators Enhance Caenorhabditis elegans Resistance to Multiple Pathogens

Hummell

Revtovich

Kirienko

2021

mSphere

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Traditionally, treatments for bacterial infection have focused on killing the microbe or preventing its growth. As antimicrobial resistance becomes more ubiquitous, the feasibility of this approach is beginning to wane and attention has begun to shift toward disrupting the host-pathogen interaction by improving the host defense. Using a high-throughput, fragment-based screen to identify compounds that alleviate Pseudomonas aeruginosa-mediated killing of Caenorhabditis elegans, we identified over 20 compounds that stimulated host defense gene expression. Five of these molecules were selected for further characterization. Four of five compounds showed little toxicity against mammalian cells or worms, consistent with their identification in a phenotypic, high-content screen. Each of the compounds activated several host defense pathways, but the pathways were generally dispensable for compound-mediated rescue in liquid killing, suggesting redundancy or that the activation of unknown pathway(s) may be driving compound effects. A genetic mechanism was identified for LK56, which required the Mediator subunit MDT-15/MED15 and NHR-49/HNF4 for its function. Interestingly, LK32, LK34, LK38, and LK56 also rescued C. elegans from P. aeruginosa in an agar-based assay, which uses different virulence factors and defense mechanisms. Rescue in an agar-based assay for LK38 entirely depended upon the PMK-1/p38 MAPK pathway. Three compounds—LK32, LK34, and LK56—also conferred resistance to Enterococcus faecalis, and the two lattermost, LK34 and LK56, also reduced pathogenesis from Staphylococcus aureus. This study supports a growing role for MDT-15 and NHR-49 in immune response and identifies five molecules that have significant potential for use as tools in the investigation of innate immunity. IMPORTANCE Trends moving in opposite directions (increasing antimicrobial resistance and declining novel antimicrobial development) have precipitated a looming crisis: the nearly complete inability to safely and effectively treat bacterial infections. To avert this, new approaches are needed. One idea is to stimulate host defense pathways to improve the clearance of bacterial infection. Here, we describe five small molecules that promote resistance to infectious bacteria by activating C. elegans’ innate immune pathways. Several are effective against both Gram-positive and Gram-negative pathogens. One of the compounds was mapped to the action of MDT-15/MED15 and NHR-49/HNF4, a pair of transcriptional regulators more generally associated with fatty acid metabolism, potentially highlighting a new link between these biological functions. These studies pave the way for future characterization of the anti-infective activity of the molecules in higher organisms and highlight the compounds’ potential utility for further investigation of immune modulation as a novel therapeutic approach.

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“…Remarkably, STR-2 GPCR also regulates longevity, through its control of lipid metabolism in the intestine [ 31 ]. Since stored fats can boost immune responses [ 32 ], it remains to be investigated if STR-2 can regulate survival of worms on B . nematocida and other Bacillus species.…”

Section: Neuronal Gpcrs As Regulators Of Innate Immunitymentioning

confidence: 99%

G protein-coupled receptors: The choreographers of innate immunity in Caenorhabditis elegans

Venkatesh

Singh

2021

PLoS Pathog

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Caenorhabditis elegans is a free-living, bacterivorous nematode that frequently encounters pathogens while foraging for food in decomposing vegetation. Like other invertebrates, C. elegans entirely relies on its innate immune system to combat invading pathogens. A basal flight or fight response of animals is also observed in worms against infection. The former is an aversion response of C. elegans against select pathogens, and the latter is an inducible innate response comprising of pathogen-specific effectors including lysozymes, lectins, antimicrobial peptides (AMPs), and cytoprotective molecules. Although pathogen recognition in worms is poorly understood, various signaling pathways and immune effectors facilitating defense response are well studied, making this nematode an excellent model to study host-microbe interactions. In higher vertebrates such as mice and humans, sensing of infection through pathogen-associated molecular patterns (PAMPs) or host damage-associated molecular patterns (DAMPs) is primarily mediated by the toll-like receptors (TLRs), nod-like receptors (NLRs), RIG-I like receptors (RLRs), C-type lectin domain (CTLD) proteins, and AIM-like receptors (ALRs) [1]. Humans have 10 TLRs that sense PAMPs and DAMPs. However, TOL-1, the only TLR homolog in C. elegans, does not seem to be essential during infections with most pathogens, except during Salmonella enterica [2] and Serratia marcescens [3] infections. The C. elegans RIG-I like receptor DRH-1 detects products of viral replication and activates an intracellular pathogen response [4]. CLEC-39 and CLEC-49, two CTLD proteins in C. elegans, are essential for immune responses against S. marcescens and are known to bind live bacteria [5]. Despite all these findings, the molecular mechanisms involved in pattern recognition by C. elegans during a majority of infections remain elusive. In this review, we examine the roles of G protein-coupled receptors (GPCRs) as noncanonical pattern recognition receptors (PRRs) and also discuss how GPCR signaling in C. elegans regulates various immune processes.GPCRs form the largest superfamily of cell surface receptors in eukaryotes; C. elegans encodes approximately 1,300 genes encoding putative GPCRs [6]. They are involved in a variety of physiological processes [7] and also for detecting various environmental cues, including bacterial secondary metabolites [8]. In recent years, several studies on infection in C. elegans have revealed the importance of GPCRs and their signaling in host defense. In this review, we examine the role of GPCRs in innate immunity via the modulation of "flight" or "fight" responses of C. elegans. Neuronal GPCRs as regulators of innate immunityThe nervous system is the primary site of sensory perception and signal integration in animals, making it ideal for systemic regulation of immune responses. The search for PRRs and

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NHR-49 Transcription Factor Regulates Immunometabolic Response and Survival of Caenorhabditis elegans during Enterococcus faecalis Infection

Cited by 46 publications

References 52 publications

Novel Immune Modulators EnhanceCaenorhabditis elegansResistance to Multiple Pathogens

Novel Immune Modulators EnhanceCaenorhabditis elegansResistance to Multiple Pathogens

Novel Immune Modulators Enhance Caenorhabditis elegans Resistance to Multiple Pathogens

G protein-coupled receptors: The choreographers of innate immunity in Caenorhabditis elegans

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