The <i>Caenorhabditis elegans</i> p38 MAPK Gene plays a key role in protection from mycobacteria

Galbadage, Thushara; Shepherd, Tonya F.; Cirillo, Suat L. G.; Gumienny, Tina L.; Cirillo, Jeffrey D.

doi:10.1002/mbo3.341

Cited by 20 publications

(16 citation statements)

References 60 publications

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“…Although previous studies have shown that TOL-1 is important for early development and pathogen recognition in C. elegans , the downstream pathways activated by TOL-1 during early development remain unclear ( 53 , 57 ). Recently, Brandt and colleagues revealed that TOL-1 contributes to the development and function of BAG neurons required for the pathogen-avoidance behavior in C. elegans via TOL-1-to-p38 MAPK pathway ( 51 , 58 ). In addition, C. elegans with a TOL-1 mutation is more susceptible to certain bacterial infections than the wild type, suggesting that TOL-1 also likely participates in microbial defense ( 53 , 56 , 59 , 60 ).…”

Section: Tlrs In Invertebratesmentioning

confidence: 99%

Toll-Like Receptors, Associated Biological Roles, and Signaling Networks in Non-Mammals

et al. 2018

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The innate immune system is the first line of defense against pathogens, which is initiated by the recognition of pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs). Among all the PRRs identified, the toll-like receptors (TLRs) are the most ancient class, with the most extensive spectrum of pathogen recognition. Since the first discovery of Toll in Drosophila melanogaster, numerous TLRs have been identified across a wide range of invertebrate and vertebrate species. It seems that TLRs, the signaling pathways that they initiate, or related adaptor proteins are essentially conserved in a wide variety of organisms, from Porifera to mammals. Molecular structure analysis indicates that most TLR homologs share similar domain patterns and that some vital participants of TLR signaling co-evolved with TLRs themselves. However, functional specification and emergence of new signaling pathways, as well as adaptors, did occur during evolution. In addition, ambiguities and gaps in knowledge still exist regarding the TLR network, especially in lower organisms. Hence, a systematic review from the comparative angle regarding this tremendous signaling system and the scenario of evolutionary pattern across Animalia is needed. In the current review, we present overview and possible evolutionary patterns of TLRs in non-mammals, hoping that this will provide clues for further investigations in this field.

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Section: Tlrs In Invertebratesmentioning

confidence: 99%

Toll-Like Receptors, Associated Biological Roles, and Signaling Networks in Non-Mammals

et al. 2018

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“…For the C. elegans co-infection liquid assay, methodology with few modifications was used (Brenner 1974;Hae-Eun et al 2017). Alternatively, for infection, specific numbers of CFU of M. marinium treated with 2,2-BP bacteria from an overnight culture were directly inoculated into the liquid medium for feeding or to infect the nematodes for 7 days plates were incubated at 25 °C, animals were scored as live or dead on a daily basis and images were taken on the 7th day of infection at 10× magnification equipped with Coslab camera (Galbadage et al 2016).…”

Section: Maintenance and Survival Of Caenorhabditis Elegansmentioning

confidence: 99%

“…To evaluate the consequences of iron deficiency in MTB, the colonization of C. elegans, an established infection model for mycobacteria (Galbadage et al 2016), was tested. Antimycobacterial effects of iron restriction were validated in C. elegans nematode model infected with M. marinum.…”

Section: Iron Restriction Inhibited the Virulence Of M Marinum In C Elegansmentioning

confidence: 99%

Understanding lipidomic basis of iron limitation induced chemosensitization of drug-resistant Mycobacterium tuberculosis

et al. 2019

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Under limited micronutrients condition, Mycobacterium tuberculosis (MTB) has to struggle for acquisition of the limited micronutrients available in the host. One such crucial micronutrient that MTB requires for the growth and sustenance is iron. The present study aimed to sequester the iron supply of MTB to control drug resistance in MTB. We found that iron restriction renders hypersensitivity to multidrug-resistant MTB strains against first-line anti-TB drugs. To decipher the effect of iron restriction on possible mechanisms of chemosensitization and altered cellular circuitry governing drug resistance and virulence of MTB, we explored MTB cellular architecture. We could identify non-intact cell envelope, tampered MTB morphology and diminished mycolic acid under iron restricted MDR-MTB cells. Deeper exploration unraveled altered lipidome profile observed through conventional TLC and advanced mass spectrometry-based LC-ESI-MS techniques. Lipidome analysis not only depicted profound alterations of various lipid classes which are crucial for pathogenecity but also exposed leads such as indispensability of iron to sustain metabolic, genotoxic and oxidative stresses. Furthermore, iron deprivation led to inhibited biofilm formation and capacity of MTB to adhere buccal epithelial cells. Lastly, we demonstrated enhanced survival of Mycobacterium-infected Caenorhabditis elegans model under iron limitation. The present study offers evidence and proposes alteration of lipidome profile and affected virulence traits upon iron chelation. Taken together, iron deprivation could be a potential strategy to rescue MDR and enhance the effectiveness of existing anti-TB drugs. Keywords Myocbacterium • Iron • Lipids • Membrane • Lipidomics • Glyoxylate cycle • Biofilm Abbreviations MTB Mycobacterium tuberculosis MDR Multidrug resistance ADC Albumin dextrose catalase OADC Oleic albumin dextrose catalase 2,4 DNP 2,4 dinitrophenol CFW Calcoflour white CV Crystal violet Electronic supplementary material The online version of this article (

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“…None of the known canonical DNAsensing pathways identified in higher eukaryotes are conserved in C. elegans. While the C. elegans genome does encode one TLR (TOL-1) (Pujol et al 2001), it appears to have a limited role in immunity (Tenor and Aballay 2008;Galbadage et al 2016;Rangan et al 2016;Battisti et al 2017); furthermore, the immune functions of TOL-1 may operate mainly via a developmental function (Brandt and Ringstad 2015). The absence of these systems suggests that C. elegans may possess alternative and novel pathways to fulfill this important defense function.…”

Section: Discussionmentioning

confidence: 99%

Restoration of Proteostasis in the Endoplasmic Reticulum Reverses an Inflammation-Like Response to Cytoplasmic DNA inCaenorhabditis elegans

et al. 2019

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Caenorhabditis elegans possesses a rudimentary innate immune response that serves as a model for various aspects of the human innate immune response. To date, a nematode response to pathogenic cytoplasmic DNA has not been identified... Innate immune responses protect organisms against various insults, but may lead to tissue damage when aberrantly activated. In higher organisms, cytoplasmic DNA can trigger inflammatory responses that can lead to tissue degeneration. Simpler metazoan models could shed new mechanistic light on how inflammatory responses to cytoplasmic DNA lead to pathologies. Here, we show that in a DNase II-defective Caenorhabditis elegans strain, persistent cytoplasmic DNA leads to systemic tissue degeneration and loss of tissue functionality due to impaired proteostasis. These pathological outcomes can be therapeutically alleviated by restoring protein homeostasis, either via ectopic induction of the ER unfolded protein response or N-acetylglucosamine treatment. Our results establish C. elegans as an ancestral metazoan model for studying the outcomes of inflammation-like conditions caused by persistent cytoplasmic DNA and provide insight into potential therapies for human conditions involving chronic inflammation.

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The Caenorhabditis elegans p38 MAPK Gene plays a key role in protection from mycobacteria

Cited by 20 publications

References 60 publications

Toll-Like Receptors, Associated Biological Roles, and Signaling Networks in Non-Mammals

Toll-Like Receptors, Associated Biological Roles, and Signaling Networks in Non-Mammals

Understanding lipidomic basis of iron limitation induced chemosensitization of drug-resistant Mycobacterium tuberculosis

Restoration of Proteostasis in the Endoplasmic Reticulum Reverses an Inflammation-Like Response to Cytoplasmic DNA inCaenorhabditis elegans

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