Probiotic-mediated p38 MAPK immune signaling prolongs the survival of Caenorhabditis elegans exposed to pathogenic bacteria

AbstractThe host-microbiota cross-talk represents an important factor contributing to innate immune response and host resistance during infection. It has been shown that probiotic lactobacilli exhibit the ability to modulate innate immunity and enhance pathogen elimination. Here we showed that heat-inactivated probiotic strain Lactobacillus curvatus BGMK2-41 stimulates immune response and resistance of the Caenorhabditis elegans against Staphylococcus aureus and Pseudomonas aeruginosa. By employing qRT-PCR and western blot analysis we showed that heat-inactivated BGMK2-41 activated PMK-1/p38 MAPK immunity pathway which prolongs the survival of C. elegans exposed to pathogenic bacteria in nematode killing assays. The C. elegans pmk-1 mutant was used to demonstrate a mechanistic basis for the antimicrobial potential of BGMK2-41, showing that BGMK2-41 upregulated PMK-1/p38 MAPK dependent transcription of C-type lectins, lysozymes and tight junction protein CLC-1. Overall, this study suggests that PMK-1/p38 MAPK‐dependent immune regulation by BGMK2-41 is essential for probiotic-mediated C. elegans protection against gram-positive and gram-negative bacteria and could be further explored for development of probiotics with the potential to increase resistance of the host towards pathogens.

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Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1422858112 ◽

2015 ◽

Vol 112 (18) ◽

pp. E2366-E2375 ◽

Cited By ~ 51

Author(s):

Zhiji Ren ◽

Victor R. Ambros

Keyword(s):

Immune Response ◽

Caenorhabditis Elegans ◽

P38 Mapk ◽

Innate Immune Response ◽

Regulatory Networks ◽

Mapk Pathway ◽

Regulation Of Gene Expression ◽

Innate Immune ◽

Developmental Timing ◽

C Elegans

Animals maintain their developmental robustness against natural stresses through numerous regulatory mechanisms, including the posttranscriptional regulation of gene expression by microRNAs (miRNAs). Caenorhabditis elegans miRNAs of the let-7 family (let-7-Fam) function semiredundantly to confer robust stage specificity of cell fates in the hypodermal seam cell lineages. Here, we show reciprocal regulatory interactions between let-7-Fam miRNAs and the innate immune response pathway in C. elegans. Upon infection of C. elegans larvae with the opportunistic human pathogen Pseudomonas aeruginosa, the developmental timing defects of certain let-7-Fam miRNA mutants are enhanced. This enhancement is mediated by the p38 MAPK innate immune pathway acting in opposition to let-7-Fam miRNA activity, possibly via the downstream Activating Transcription Factor-7 (ATF-7). Furthermore, let-7-Fam miRNAs appear to exert negative regulation on the worm’s resistance to P. aeruginosa infection. Our results show that the inhibition of pathogen resistance by let-7 involves downstream heterochronic genes and the p38 MAPK pathway. These findings suggest that let-7-Fam miRNAs are integrated into innate immunity gene regulatory networks, such that this family of miRNAs modulates immune responses while also ensuring robust timing of developmental events under pathogen stress.

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Sonic Stimulation and Low Power Microwave Radiation Can Modulate Bacterial Virulence Towards Caenorhabditis elegans

Anti-Infective Agents ◽

10.2174/2211352516666181102150049 ◽

2019 ◽

Vol 17 (2) ◽

pp. 150-162

Author(s):

Priya Patel ◽

Hiteshi Patel ◽

Dhara Vekariya ◽

Chinmayi Joshi ◽

Pooja Patel ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Microwave Radiation ◽

Pathogenic Bacteria ◽

Bacterial Virulence ◽

Therapeutic Approaches ◽

Microwave Exposure ◽

C Elegans ◽

Sonic Treatment ◽

Global Threat ◽

Sound Treatment

<P>Background: In view of the global threat of antimicrobial resistance, novel alternative approaches to deal with infectious bacteria are warranted, in addition to the conventional invasive therapeutic approaches. Objective: This study aimed at investigating whether exposure to sonic stimulation or microwave radiation can affect virulence of pathogenic bacteria toward the model nematode host Caenorhabditis elegans. Methods: Caenorhabditis elegans worms infected with different pathogenic bacteria were subjected to sonic treatment to investigate whether such sound treatment can exert any therapeutic effect on the infected worms. Virulence of microwave exposed bacteria was also assessed using this nematode host. Results: Sound corresponding to 400 Hz, and the divine sound ‘Om’ conferred protective effect on C. elegans in face of bacterial infection, particularly that caused by Serratia marcescens or Staphylococcus aureus. The observed effect seemed to occur due to influence of sound on bacteria, and not on the worm. Additionally, effect of microwave exposure on bacterial virulence was also investigated, wherein microwave exposure could reduce virulence of S. aureus towards C. elegans. Conclusion: Sonic stimulation/ microwave exposure was demonstrated to be capable of modulating bacterial virulence.</P>

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Lipopolysaccharide exposure induces oxidative damage in Caenorhabditis elegans: protective effects of carnosine

BMC Pharmacology and Toxicology ◽

10.1186/s40360-020-00455-w ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Jing Ma ◽

Xiaoyuan Xu ◽

Ranran Wang ◽

Haijing Yan ◽

Huijuan Yao ◽

...

Keyword(s):

Oxidative Stress ◽

Caenorhabditis Elegans ◽

Signaling Pathway ◽

P38 Mapk ◽

Mapk Signaling ◽

Protective Effects ◽

Related Gene ◽

Rt Pcr ◽

C Elegans ◽

Apoptosis Related Gene

Abstract Background The present study was designed to investigate the protective effects and mechanisms of carnosine on lipopolysaccharide (LPS)-induced injury in Caenorhabditis elegans. Methods C. elegans individuals were stimulated for 24 h with LPS (100 μg/mL), with or without carnosine (0.1, 1, 10 mM). The survival rates and behaviors were determined. The activities of superoxide dismutase (SOD), glutathione reductase (GR), and catalase (CAT) and levels of malondialdehyde (MDA) and glutathione (GSH) were determined using the respective kits. Reverse transcription polymerase chain reaction (RT-PCR) was performed to validate the differential expression of sod-1, sod-2, sod-3, daf-16, ced-3, ced-9, sek-1, and pmk-1. Western blotting was used to determine the levels of SEK1, p38 mitogen-activated protein kinase (MAPK), cleaved caspase3, and Bcl-2. C. elegans sek-1 (km2) mutants and pmk-1 (km25) mutants were used to elucidate the role of the p38 MAPK signaling pathway. Results Carnosine improved the survival of LPS-treated C. elegans and rescued behavioral phenotypes. It also restrained oxidative stress by decreasing MDA levels and increasing SOD, GR, CAT, and GSH levels. RT-PCR results showed that carnosine treatment of wild-type C. elegans up-regulated the mRNA expression of the antioxidant-related genes sod-1, sod-2, sod-3, and daf-16. The expression of the anti-apoptosis-related gene ced-9 and apoptosis-related gene ced-3 was reversed by carnosine. In addition, carnosine treatment significantly decreased cleaved caspase3 levels and increased Bcl-2 levels in LPS-treated C. elegans. Apoptosis in the loss-of-function strains of the p38 MAPK signaling pathway was suppressed under LPS stress; however, the apoptotic effects of LPS were blocked in the sek-1 and pmk-1 mutants. The expression levels of sek-1 and pmk-1 mRNAs were up-regulated by LPS and reversed by carnosine. Finally, the expression of p-p38MAPK and SEK1 was significantly increased by LPS, which was reversed by carnosine. Conclusion Carnosine treatment protected against LPS injury by decreasing oxidative stress and inhibiting apoptosis through the p38 MAPK pathway.

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Loss of DNase II function in the gonad is associated with a higher expression of antimicrobial genes in Caenorhabditis elegans

Biochemical Journal ◽

10.1042/bj20150563 ◽

2015 ◽

Vol 470 (1) ◽

pp. 145-154 ◽

Cited By ~ 8

Author(s):

Hsiang Yu ◽

Huey-Jen Lai ◽

Tai-Wei Lin ◽

Chang-Shi Chen ◽

Szecheng J. Lo

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Caenorhabditis Elegans ◽

Innate Immune Response ◽

Innate Immune ◽

Dnase Ii ◽

C Elegans ◽

Elevated Expression

This study uncovered NUC-1 and CRN-7 function in germline apoptosis. Mutations of nuc-1 and crn-7 led to elevated expression of five innate-immunity-related genes and demonstrated that DNase II activity is associated with an innate immune response in C. elegans.

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Intergenerational Pathogen-Induced Diapause in Caenorhabditis elegans Is Modulated by mir-243

mBio ◽

10.1128/mbio.01950-20 ◽

2020 ◽

Vol 11 (5) ◽

Author(s):

Carolaing Gabaldón ◽

Marcela Legüe ◽

M. Fernanda Palominos ◽

Lidia Verdugo ◽

Florence Gutzwiller ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Noncoding Rna ◽

Pathogenic Bacteria ◽

Developmental Change ◽

Differential Expression Analysis ◽

Phenotypic Analysis ◽

Content Type ◽

C Elegans ◽

Two Generations ◽

Dauer Formation

ABSTRACT The interaction and communication between bacteria and their hosts modulate many aspects of animal physiology and behavior. Dauer entry as a response to chronic exposure to pathogenic bacteria in Caenorhabditis elegans is an example of a dramatic survival response. This response is dependent on the RNA interference (RNAi) machinery, suggesting the involvement of small RNAs (sRNAs) as effectors. Interestingly, dauer formation occurs after two generations of interaction with two unrelated moderately pathogenic bacteria. Therefore, we sought to discover the identity of C. elegans RNAs involved in pathogen-induced diapause. Using transcriptomics and differential expression analysis of coding and long and small noncoding RNAs, we found that mir-243-3p (the mature form of mir-243) is the only transcript continuously upregulated in animals exposed to both Pseudomonas aeruginosa and Salmonella enterica for two generations. Phenotypic analysis of mutants showed that mir-243 is required for dauer formation under pathogenesis but not under starvation. Moreover, DAF-16, a master regulator of defensive responses in the animal and required for dauer formation was found to be necessary for mir-243 expression. This work highlights the role of a small noncoding RNA in the intergenerational defensive response against pathogenic bacteria and interkingdom communication. IMPORTANCE Persistent infection of the bacterivore nematode C. elegans with bacteria such as P. aeruginosa and S. enterica makes the worm diapause or hibernate. By doing this, the worm closes its mouth, avoiding infection. This response takes two generations to be implemented. In this work, we looked for genes expressed upon infection that could mediate the worm diapause triggered by pathogens. We identify mir-243-3p as the only transcript commonly upregulated when animals feed on P. aeruginosa and S. enterica for two consecutive generations. Moreover, we demonstrate that mir-243-3p is required for pathogen-induced dauer formation, a new function that has not been previously described for this microRNA (miRNA). We also find that the transcriptional activators DAF-16, PQM-1, and CRH-2 are necessary for the expression of mir-243 under pathogenesis. Here we establish a relationship between a small RNA and a developmental change that ensures the survival of a percentage of the progeny.

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Cranberry Extract Standardized for Proanthocyanidins Promotes the Immune Response of Caenorhabditis elegans to Vibrio cholerae through the p38 MAPK Pathway and HSF-1

PLoS ONE ◽

10.1371/journal.pone.0103290 ◽

2014 ◽

Vol 9 (7) ◽

pp. e103290 ◽

Cited By ~ 21

Author(s):

Jessica Dinh ◽

Joseph T. Angeloni ◽

Daniel B. Pederson ◽

Xiaoxia Wang ◽

Min Cao ◽

...

Keyword(s):

Immune Response ◽

Caenorhabditis Elegans ◽

Vibrio Cholerae ◽

P38 Mapk ◽

Mapk Pathway ◽

P38 Mapk Pathway

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A Stenotrophomonas maltophilia Strain Evades a Major Caenorhabditis elegans Defense Pathway

Infection and Immunity ◽

10.1128/iai.00711-15 ◽

2015 ◽

Vol 84 (2) ◽

pp. 524-536 ◽

Cited By ~ 5

Author(s):

Corin V. White ◽

Brian J. Darby ◽

Robert J. Breeden ◽

Michael A. Herman

Keyword(s):

Caenorhabditis Elegans ◽

Stenotrophomonas Maltophilia ◽

Pathogenic Bacteria ◽

Pathogen Resistance ◽

Nosocomial Pathogen ◽

Content Type ◽

C Elegans ◽

Novel Host ◽

Bacterial Accumulation ◽

Intestinal Distension

Stenotrophomonas maltophiliais a ubiquitous bacterium and an emerging nosocomial pathogen. This bacterium is resistant to many antibiotics, associated with a number of infections, and a significant health risk, especially for immunocompromised patients. Given thatCaenorhabditis elegansshares many conserved genetic pathways and pathway components with higher organisms, the study of its interaction with bacterial pathogens has biomedical implications.S. maltophiliahas been isolated in association with nematodes from grassland soils, and it is likely thatC. elegansencounters this bacterium in nature. We found that a localS. maltophiliaisolate, JCMS, is more virulent than the otherS. maltophiliaisolates (R551-3 and K279a) tested. JCMS virulence correlates with intestinal distension and bacterial accumulation and requires the bacteria to be alive. Many of the conserved innate immune pathways that serve to protectC. elegansfrom various pathogenic bacteria also play a role in combatingS. maltophiliaJCMS. However,S. maltophiliaJCMS is virulent to normally pathogen-resistant DAF-2/16 insulin-like signaling pathway mutants. Furthermore, several insulin-like signaling effector genes were not significantly differentially expressed betweenS. maltophiliaJCMS and avirulent bacteria (Escherichia coliOP50). Taken together, these findings suggest thatS. maltophiliaJCMS evades the pathogen resistance conferred by the loss of DAF-2/16 pathway components. In summary, we have discovered a novel host-pathogen interaction betweenC. elegansandS. maltophiliaand established a new animal model with which to study the mode of action of this emerging nosocomial pathogen.

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Analysis of the Caenorhabditis elegans innate immune response to Coxiella burnetii

Innate Immunity ◽

10.1177/1753425916679255 ◽

2016 ◽

Vol 23 (2) ◽

pp. 111-127 ◽

Cited By ~ 16

Author(s):

James M Battisti ◽

Lance A Watson ◽

Myo T Naung ◽

Adam M Drobish ◽

Ekaterina Voronina ◽

...

Keyword(s):

Immune Response ◽

Caenorhabditis Elegans ◽

Innate Immune Response ◽

Coxiella Burnetii ◽

Molecular Mechanisms ◽

Q Fever ◽

Innate Immune ◽

Human Pathogens ◽

C Elegans ◽

Intestinal Distension

The nematode Caenorhabditis elegans is well established as a system for characterization and discovery of molecular mechanisms mediating microbe-specific inducible innate immune responses to human pathogens. Coxiella burnetii is an obligate intracellular bacterium that causes a flu-like syndrome in humans (Q fever), as well as abortions in domesticated livestock, worldwide. Initially, when wild type C. elegans (N2 strain) was exposed to mCherry-expressing C. burnetii (CCB) a number of overt pathological manifestations resulted, including intestinal distension, deformed anal region and a decreased lifespan. However, nematodes fed autoclave-killed CCB did not exhibit these symptoms. Although vertebrates detect C. burnetii via TLRs, pathologies in tol-1(–) mutant nematodes were indistinguishable from N2, and indicate nematodes do not employ this orthologue for detection of C. burnetii. sek-1(–) MAP kinase mutant nematodes succumbed to infection faster, suggesting that this signaling pathway plays a role in immune activation, as previously shown for orthologues in vertebrates during a C. burnetii infection. C. elegans daf-2(–) mutants are hyper-immune and exhibited significantly reduced pathological consequences during challenge. Collectively, these results demonstrate the utility of C. elegans for studying the innate immune response against C. burnetii and could lead to discovery of novel methods for prevention and treatment of disease in humans and livestock.

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Transgenerational Diapause as an Avoidance Strategy against Bacterial Pathogens in Caenorhabditis elegans

mBio ◽

10.1128/mbio.01234-17 ◽

2017 ◽

Vol 8 (5) ◽

Cited By ~ 25

Author(s):

M. Fernanda Palominos ◽

Lidia Verdugo ◽

Carolaing Gabaldon ◽

Bernardo Pollak ◽

Javiera Ortíz-Severín ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Behavioral Change ◽

Pathogenic Bacteria ◽

Behavioral Changes ◽

Survival Strategies ◽

Information Encoding ◽

C Elegans ◽

Two Generations ◽

And Behavior ◽

Dauer Larvae

ABSTRACT The dynamic response of organisms exposed to environmental pathogens determines their survival or demise, and the outcome of this interaction depends on the host’s susceptibility and pathogen-dependent virulence factors. The transmission of acquired information about the nature of a pathogen to progeny may ensure effective defensive strategies for the progeny’s survival in adverse environments. Environmental RNA interference (RNAi) is a systemic and heritable mechanism and has recently been linked to antibacterial and antifungal defenses in both plants and animals. Here, we report that the second generation of Caenorhabditis elegans living on pathogenic bacteria can avoid bacterial infection by entering diapause in an RNAi pathway-dependent mechanism. Furthermore, we demonstrate that the information encoding this survival strategy is transgenerationally transmitted to the progeny via the maternal germ line. IMPORTANCE Bacteria vastly influence physiology and behavior, and yet, the specific mechanisms by which they cause behavioral changes in hosts are not known. We use C. elegans as a host and the bacteria they eat to understand how microbes trigger a behavioral change that helps animals to survive. We found that animals faced with an infection for two generations could enter a hibernationlike state, arresting development by forming dauer larvae. Dauers have closed mouths and effectively avoid infection. Animals accumulate information that is transgenerationally transmitted to the next generations to form dauers. This work gives insight on how bacteria communicate in noncanonical ways with their hosts, resulting in long-lasting effects providing survival strategies to the community. IMPORTANCE Bacteria vastly influence physiology and behavior, and yet, the specific mechanisms by which they cause behavioral changes in hosts are not known. We use C. elegans as a host and the bacteria they eat to understand how microbes trigger a behavioral change that helps animals to survive. We found that animals faced with an infection for two generations could enter a hibernationlike state, arresting development by forming dauer larvae. Dauers have closed mouths and effectively avoid infection. Animals accumulate information that is transgenerationally transmitted to the next generations to form dauers. This work gives insight on how bacteria communicate in noncanonical ways with their hosts, resulting in long-lasting effects providing survival strategies to the community.

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