Biology subjects

Irazoqui, J. E.

Publications and source records attributed to Irazoqui, J. E..

8 recordsLinked to original sources

bioRxiv2026

Cholinergic activation of HLH-30/TFEB promotes C. elegans infection resilience.

Innate host defense depends on transcriptional programs, which support survival through two strategies that can vary independently. Resistance lowers pathogen burden, while resilience limits the damage a given burden causes. In Caenorhabditis elegans infected with Staphylococcus aureus, the highly conserved transcription factor HLH-30/TFEB drives most of the host response, which mediates infection resilience. We previously showed that EGL-30/Gq, PLC-1/PLC{varepsilon}, and DKF-1/PRKD activate HLH-30/TFEB during infection. The same phospholipase C and protein kinase D step activates TFEB in mouse macrophages infected with Salmonella or S. aureus. However, the input that drives the EGL-30/Gq, PLC-1/PLC{varepsilon}, and DKF-1/PRKD module to activate HLH-30/TFEB during infection remained unknown. Here we report that acetylcholine, acting on muscarinic receptors, is one such input. Atropine and scopolamine, two muscarinic antagonists in clinical use, as well as muscarinic receptor gene silencing blunted HLH-30/TFEB activation by infection. Moreover, a mutation of unc-17/SLC18A3 that lowers acetylcholine release from neurons impaired HLH-30/TFEB activation and induction of its target genes, while pathogen burden remained high. In uninfected animals, muscarinic agonist arecoline was sufficient to activate HLH-30/TFEB, in a muscarinic receptor-dependent manner. Nicotine, in contrast, had no effect. The agonist also lengthened survival of infection without lowering pathogen burden, in an HLH-30/TFEB-dependent manner. Silencing egl-30/GNAQ, plc-1/PLCE1, or dkf-1/PRKD1-3 cut activation by the agonist just as it cut activation by infection, showing that both stimuli require the same module. In mammals the link documented so far between acetylcholine and TFEB runs through nicotinic receptors, so whether the muscarinic route is conserved remains open. Thus, we favor a model in which infection drives neurons to release acetylcholine onto the intestinal epithelium, where muscarinic receptors acting through EGL-30/Gq, PLC-1/PLC{varepsilon}, and DKF-1/PRKD activate HLH-30/TFEB and strengthen infection resilience.

immunology↗

bioRxiv2025

LIPL-1 and LIPL-2 are TCER-1-regulated Lysosomal Lipases with Distinct Roles in Immunity and Fertility

Reproduction and immunity are fundamental, energy intensive processes that often compete for resources, leading to trade-offs observed across diverse species. Lipid metabolism plays a crucial role in integrating these processes, particularly during stressful conditions such as pathogenic infections. Yet the molecular mechanisms governing this integration remain poorly understood. TCER-1, the C. elegans homolog of mammalian TCERG1, suppresses immunity and promotes fertility, especially upon maternal infection. Here, we show that TCER-1 regulates two conserved lysosomal lipases, lipl-1 and lipl-2, to balance reproduction, immunity and lifespan. Using transcriptomic, lipidomic, and molecular-genetic analyses, we demonstrate that while both lipl-1 and lipl-2 mediate infection-induced lipid remodeling, lipl-1 enhances immunity and catalyzes the accumulation of ceramide species linked to stress response and longevity, whereas, lipl-2 unexpectedly does not. Both lipases contribute towards fertility outcomes, but lipl-2 is especially critical for maintaining embryonic-eggshell integrity during maternal infection and aging. Strikingly, expression of human lysosomal acid lipase (LAL), the ortholog of lipl genes, rescues the immune defects triggered by lipl-l loss and enhances immune resilience. Together, these findings uncover functionally distinct roles for lipl-1 and lipl-2 in modulating lipid species that shape immune fitness, healthspan and reproductive health, and suggest a potentially conserved mechanism by which lipid metabolism links fertility and immunity.

genetics↗

bioRxiv2025

Staphylococcus aureus-Induced Degeneration of Nociceptive Neurons in Caenorhabditis elegans

BackgroundIn all animals, the nervous system senses microbial signals to influence host defense. Despite emerging as important sensors of infection to regulate immunity and inflammation, the mechanisms by which pain-sensing nociceptor neurons can detect infections are poorly defined. Using C. elegans as a tractable model host that shares many features with mammalian systems, we investigated nociceptor function during bacterial infection. ResultsIn vivo intracellular Ca2+ imaging of nociceptor ASH neurons revealed a drastic reduction in ASH responses to aversive stimuli in Staphylococcus aureus-infected animals compared to noninfected controls. Morphological examination showed that the ASH neurons lost integrity in the sensory processes that extend to the mouth, in a pathogen growth phase-dependent manner. Neighboring neurons did not exhibit this pathogen-induced neurodegeneration (PaIN) phenotype. Genetic analysis suggested that apoptosis, necrosis, ferroptosis, and autophagy are dispensable for the PaIN phenotype. In contrast, loss of the evolutionarily conserved stress-response transcription factor HLH-30/TFEB reduced the penetrance of ASH PaIN by about 50%. Moreover, infected animals showed defective ASH-mediated evasive behaviors, suggesting that the S. aureus- triggered drop in ASH activation and morphological degeneration are physiologically relevant. ConclusionsCollectively, these findings reveal that nociceptor neurons lose functional and morphological integrity during infection with S. aureus, with severe consequences for animal behavior. Because S. aureus is a critical human pathogen, the induction of nociceptor PaIN may have important implications for human health.

neuroscience↗

bioRxiv2024

Cholinergic agonist PNU282987 induces pro-inflammatory gene expression via the MCOLN1-TFEB pathway in murine macrophages.

Transcription factors TFEB and TFE3 are crucial for regulating autophagy, lysosomal biogenesis, and lipid metabolism, and have significant roles in macrophage function and innate immunity. The alpha7 nicotinic acetylcholine receptor (7nAChR), a ligand-gated Ca2+ channel known for its therapeutic potential in neurological and inflammatory disorders, has been implicated in modulating immune responses by modulating macrophage function. Stimulation of 7nAChR with chemical agonists has been claimed to activate TFEB in pancreatic acinar cells and neurons. However, the impact of 7nAChR activation on TFEB and TFE3 in macrophages remained unknown, posing an important question due to the potential implications for inflammation regulation. This study investigates the effects of acute 7nAChR activation on TFEB-mediated responses in murine macrophages using the specific agonist PNU-282987. We demonstrate that 7nAChR stimulation triggers TFEB nuclear translocation and lysosomal expansion. Surprisingly, PNU-282987 induces a broad pro-inflammatory gene signature without concomitant cytokine secretion, suggesting an uncoupling of gene expression from cytokine release. Mechanistically, TFEB activation requires the lysosomal Ca2+ exporter MCOLN1 and the Ca2+-dependent phosphatase PPP3/calcineurin. Additionally, PNU-282987 elevates reactive oxygen species (ROS) levels, and ROS are involved in TFEB activation by PNU-282987. Notably, even with 7nAChR deletion, compensatory ROS-mediated TFEB activation persists, suggesting the involvement of additional nicotinic receptors. Our findings reveal a novel 7nAChR-TFEB signaling axis in macrophages, offer new insights into the cholinergic regulation of immune responses, establish a baseline for comparison with disease states, and identify potential therapeutic targets for modulating inflammation.

immunology↗

bioRxiv2023

Glucose-fed microbiota alters intestinal epithelium and increases susceptibility to bacterial pathogens

Overconsumption of dietary sugar can lead to many negative health effects including the development of Type 2 diabetes, metabolic syndrome, cardiovascular disease, and neurodegenerative disorders. Recently, the human intestinal microbiota strongly associated with our overall health has also been known to be affected by diet. However, mechanistic insight into the importance of the human intestinal microbiota and the effects of chronic sugar ingestion has not been possible largely due to the complexity of the human microbiome which contains hundreds of types of organisms. Here, we use an interspecies C. elegans-E. coli system, where E. coli are subjected to high sugar, then consumed by the bacterivore host C. elegans to become the microbiota. This glucose-fed microbiota results in a significant lifespan reduction accompanied by reduced healthspan including locomotion, stress resistance, and changes in behavior and feeding. Lifespan reduction is also accompanied by two potential major contributors: increased intestinal bacterial density and increased reactive oxygen species. The glucose-fed microbiota accelerated the age-related development of intestinal cell permeability, intestinal distention, and dysregulation of immune effectors. Ultimately, the changes in the intestinal epithelium due to aging with the glucose fed microbiota results in increased susceptibility to multiple bacterial pathogens. Taken together, our data reveal that chronic ingestion of sugar such as a western diet has profound health effects on the host due to changes in the microbiota and may contribute to the current increased incidence of ailments including inflammatory bowel diseases as well as multiple age-related diseases.

physiology↗

bioRxiv2023

Distinct members of the C. elegans CeMbio reference microbiota exert cryptic virulence and infection protection

Microbiotas are complex microbial communities that colonize specific niches in the host and provide essential organismal functions that are important in health and disease. A key aspect is the ability of each distinct community member to promote or impair host health, alone or in the context of the community, in hosts with varied levels of immune competence. Understanding such interactions is limited by the complexity and experimental accessibility of current systems and models. Recently, a reference twelve-member microbiota for the model organism C. elegans, known as CeMbio, was defined to aid the dissection of conserved host-microbiota interactions. Understanding the physiological impact of the CeMbio bacteria on C. elegans is in its infancy. Here, we show the differential ability of each CeMbio bacterial species to activate innate immunity through the conserved PMK-1/p38 MAPK, ACh/WNT, and HLH-30/TFEB pathways. Using immunodeficient animals, we uncovered several examples of bacterial cryptic virulence, or virulence that was masked by the host defense response. The ability to activate the PMK-1/p38 pathway did not correlate with bacterial virulence in wild type or immunodeficient animals. In contrast, ten out of twelve species activated HLH-30/TFEB, and most showed virulence towards hlh-30-deficient animals. In addition, we identified Pseudomonas lurida as a pathogen in wild type animals, and Acinetobacter guillouiae as avirulent despite activating all three pathways. Moreover, short pre-exposure to A. guillouiae promoted host survival of infection with P. lurida, which was dependent on PMK-1/p38 MAPK and HLH-30/TFEB. These results suggest that the microbiota of C. elegans is rife with "opportunistic" pathogens, and that HLH-30/TFEB is a fundamental and key host protective factor. Furthermore, they support the idea that bacteria like A. guillouiae evolved the ability to induce host innate immunity to improve host fitness when confronted with pathogens, providing new insights into how colonization order impacts host health.

immunology↗

bioRxiv2022

Negative regulation of C. elegans innate immunity by orphan nuclear receptor NHR-42

Positive and negative regulators of innate immunity work together to maintain immune homeostasis. We previously discovered that HLH-30/TFEB is a critical transcription factor that positively regulates host defense genes upon S. aureus infection in C. elegans. However, repression of host defense genes and negative regulation of immunity remain poorly understood. In this study, we identified nhr-42 as a negative regulator of host defense genes functioning downstream of HLH-30/TFEB, with major implications in host survival and metabolism after infection. nhr-42 expression is induced in an HLH-30/TFEB dependent manner mostly in the pharynx upon infection. We find that animals lacking nhr-42 have higher expression of host defense genes, which enables enhanced survival after infection. Antimicrobials expressed in the pharynx such as abf-2, function downstream of nhr-42 to confer resistance to infection by mitigating pathogen burden. Furthermore, nhr-42 deficient animals are defective in lipid mobilization, having higher lipid stores compared to wild type animals after infection. nhr-42 therefore enables C. elegans to limit the host defense response and reallocate energy resources through lipid mobilization after infection. To our knowledge, this is the first report of a transcription factor that represses host defense genes in C. elegans.

immunology↗

bioRxiv2020

NHR-49/PPAR-α and HLH-30/TFEB promote C. elegans host defense via a flavin-containing monooxygenase

During bacterial infection, the host is confronted with multiple overlapping signals that are integrated at the organismal level to produce defensive host responses. How multiple infection signals are sensed by the host and how they elicit the transcription of host defense genes is much less understood at the whole-animal level than at the cellular level. The model organism Caenorhabditis elegans is known to mount transcriptional defense responses against intestinal bacterial infections that elicit overlapping starvation and infection responses, but the regulation of such responses is not well understood. Direct comparison of C. elegans that were starved or infected with Staphylococcus aureus revealed a large infection-specific transcriptional signature. This signature was almost completely abrogated by deletion of transcription factor hlh-30/TFEB, except for six genes including a flavin-containing monooxygenase (FMO) gene, fmo-2/FMO5. Deletion of fmo-2/FMO5 severely compromised infection survival, thus identifying the first FMO with innate immunity functions in animals. Moreover, the mechanism of fmo-2/FMO5 induction required the nuclear hormone receptor, NHR-49/PPAR-, which induced fmo-2/FMO5 and host defense cell non-autonomously. These findings for the first time reveal an infection-specific host response to S. aureus, identify HLH-30/TFEB as its main regulator, reveal that FMOs are important innate immunity effectors in animals, and identify the mechanism of FMO regulation through NHR-49/PPAR- in C. elegans, with important implications for innate host defense in higher organisms.

microbiology↗