Biology subjects

Aballay, A.

Publications and source records attributed to Aballay, A..

11 recordsLinked to original sources

bioRxiv2026

Intestinal lipid metabolism controls immune response through NHR-68 and gut-brain signaling in C. elegans

Animals must allocate limited energetic resources across competing defense programs in response to infection. Here, we show that the conserved nuclear hormone receptor NHR-68 integrates fatty acid metabolism with the neural control of molecular and behavioral immunity in Caenorhabditis elegans. Acting in parallel with NHR-10, NHR-68 controls genes involved in polyunsaturated fatty acid (PUFA) metabolism. Loss of NHR-68 disrupts linoleic acid (LA) homeostasis, impairing pathogen avoidance behavior. Supplementation with LA restores avoidance, and fat-3 inhibition, which elevates LA, enhances pathogen avoidance, whereas loss of LA synthesis by fat-2 inhibition diminishes this behavior, indicating that LA promotes behavioral immunity. We further show that NHR-68 acts in the intestine to regulate linoleic acid homeostasis, and that changes in intestinal lipid metabolism influence an AWC-dependent pathogen-avoidance circuit through intestine-to-neuron communication. NHR-68 suppresses activation of the PMK-1/p38 MAPK and DAF-16/FOXO pathways, which mediate molecular immune responses. These findings identify a gut-brain transcriptional circuit that connects intestinal lipid metabolism to neural and immune outputs, revealing a mechanism by which the metabolic state coordinates behavioral and molecular defenses to optimize host protection.

genetics↗

bioRxiv2026

NMDA Receptor Subunit NMR-2 Regulates Pathogen-Induced Immune Responses via the Nervous System in C. elegans

Neural control of innate immunity must balance restraint of basal immune activity with rapid activation upon pathogen encounter. Glutamate, the primary excitatory neurotransmitter in the nervous system, has been implicated in several neurological disorders associated with inflammation, suggesting a potential link to immune regulation. However, how glutamatergic signaling contributes to immune balance remains unknown. Here, we demonstrated that the NMDA-type ionotropic glutamate receptor subunit NMR-2, a component of the NMDA receptor complex, acts in the C. elegans nervous system as a key regulator of pathogen-induced immune responses. Loss of nmr-2 enhanced resistance to Staphylococcus aureus and Pseudomonas aeruginosa, without elevating basal immune gene expression. The pathogen-induced response controlled by NMR-2 required the conserved PMK-1/p38 MAPK, DAF-16/FOXO, and HLH-30/TFEB pathways. We identified the AVD interneuron as the site of action of NMR-2, where it integrates inputs from upstream sensory neurons ASE, ASK, AQR, and PQR. These findings uncover a neural circuit in which glutamatergic signaling distinguishes basal immune gene expression from pathogen-induced immune responses, revealing a mechanism that promotes effective defense without altering baseline immunity.

immunology↗

bioRxiv2024

A functional screen for ubiquitin regulation identifies an E3 ligase secreted by Pseudomonas aeruginosa

Ubiquitin signaling controls many aspects of eukaryotic biology, including targeted protein degradation and immune defense. Remarkably, invading bacterial pathogens have adapted secreted effector proteins that hijack host ubiquitination to gain control over host responses. These ubiquitin-targeted effectors can exhibit, for example, E3 ligase or deubiquitinase activities, often without any sequence or structural homology to eukaryotic ubiquitin regulators. Such convergence in function poses a challenge to the discovery of additional bacterial virulence factors that target ubiquitin. To overcome this, we have developed a workflow to harvest natively secreted bacterial effectors and functionally screen them for ubiquitin regulatory activities. After benchmarking this approach on diverse ligase and deubiquitinase activities from Salmonella Typhimurium, Enteropathogenic Escherichia coli, and Shigella flexneri, we applied it to the identification of a cryptic E3 ligase activity secreted by Pseudomonas aeruginosa. We identified an unreported P. aeruginosa E3 ligase, which we have termed Pseudomonas Ub ligase 1 (PUL-1), that resembles none of the other E3 ligases previously established in or outside of the eukaryotic system. Importantly, in an animal model of P. aeruginosa infection, PUL-1 ligase activity plays an important role in regulating virulence. Thus, our workflow for the functional identification of ubiquitin-targeted effector proteins carries promise for expanding our appreciation of how host ubiquitin regulation contributes to bacterial pathogenesis.

microbiology↗

bioRxiv2023

Inhibition of the UFD-1-NPL-4 complex triggers an inflammation-like response in Caenorhabditis elegans

The UFD-1 (ubiquitin fusion degradation 1)-NPL-4 (nuclear protein localization homolog 4) heterodimer is involved in extracting ubiquitinated proteins from several plasma membrane locations, including the endoplasmic reticulum. This heterodimer complex helps in the degradation of ubiquitinated proteins via the proteasome with the help of the AAA+ ATPase CDC-48. While the ubiquitin-proteasome system is known to have important roles in maintaining innate immune responses, the role of the UFD-1-NPL-4 complex in regulating immunity remains elusive. In this study, we investigate the role of the UFD-1-NPL-4 complex in maintaining Caenorhabditis elegans innate immune responses. Inhibition of the UFD-1-NPL-4 complex activates an aberrant immune response that reduces the survival of the wild-type worms on the pathogenic bacterium Pseudomonas aeruginosa despite diminishing colonization of the gut with the bacterium. This aberrant immune response improves the survival of severely immunocompromised worms on pathogenic bacteria but is detrimental on nonpathogenic bacteria. Transcriptomics studies reveal that the GATA transcription factor ELT-2 mediates the aberrant immune response upon inhibition of the UFD-1-NPL-4 complex. Collectively, our findings show that inhibition of the UFD-1-NPL-4 complex triggers an aberrant immune response that is detrimental to immunocompetent worms under infection conditions but can be advantageous for immunocompromised worms.

immunology↗

bioRxiv2023

Neuronal NPR-15 controls the interplay between molecular and behavioral immune responses through the amphid sensory neuron-intestinal axis in C. elegans

The survival of hosts during infections relies on their ability to mount effective molecular and behavioral immune responses. Despite extensive research on these defense strategies in various species, including the model organism Caenorhabditis elegans, the neural mechanisms underlying their interaction remain poorly understood. Previous studies have highlighted the role of neural G protein-coupled receptors (GPCRs) in regulating both immunity and pathogen avoidance, which is particularly dependent on aerotaxis. To address this knowledge gap, we conducted a screen of mutants in neuropeptide receptor family genes. We found that loss-of-function mutations in npr-15 activated immunity while suppressing pathogen avoidance behavior. Through further analysis, NPR-15 was found to regulate immunity by modulating the activity of key transcription factors, namely GATA/ELT-2 and TFEB/HLH-30. Surprisingly, the lack of pathogen avoidance of npr-15 mutant animals was not influenced by oxygen levels. Moreover, our studies revealed that the amphid sensory neuron ASJ is involved in mediating the immune and behavioral responses orchestrated by NPR-15. Additionally, NPR-15 was found to regulate avoidance behavior via the TRPM gene, GON-2, which may sense the intestinal distension caused by bacterial colonization to elicit pathogen avoidance. Our study contributes to a broader understanding of host defense strategies and mechanisms underlining the interaction between molecular and behavioral immune responses.

immunology↗

bioRxiv2023

Calcineurin inhibition enhances Caenorhabditis elegans lifespan by defecation defects-mediated calorie restriction and nuclear hormone signaling

Calcineurin is a highly conserved calcium/calmodulin-dependent serine/threonine protein phosphatase with diverse functions. Inhibition of calcineurin is known to enhance the lifespan of Caenorhabditis elegans through multiple signaling pathways. Aiming to study the role of calcineurin in regulating innate immunity, we discover that calcineurin is required for the rhythmic defecation motor program (DMP) in C. elegans. Calcineurin inhibition leads to defects in the DMP, resulting in intestinal bloating, rapid colonization of the gut by bacteria, and increased susceptibility to bacterial infection. We demonstrate that intestinal bloating caused by calcineurin inhibition mimics the effects of calorie restriction, resulting in enhanced lifespan. The TFEB ortholog, HLH-30, is required for lifespan extension mediated by calcineurin inhibition. Finally, we show that the nuclear hormone receptor, NHR-8, is upregulated by calcineurin inhibition and is necessary for the increased lifespan. Our studies uncover a role for calcineurin in the C. elegans DMP and provide a new mechanism for calcineurin inhibition-mediated longevity extension.

physiology↗

bioRxiv2022

Dissection of a sensorimotor circuit that regulates aversion to odors and pathogenic bacteria in C. elegans by whole-brain simulation

Altering behavior to reduce pathogen exposure is a key line of defense against pathogen attack for nearly all animals. The use of Caenorhabditis elegans bacterial infection models have allowed for many insights into the molecular mechanisms of behavioral immunity. However, the neural circuitry between chemosensory neurons that sense pathogenic bacterial cues and the motor neurons responsible for avoidance-associated locomotion remains unknown. We found that backward locomotion was a component of learned pathogen avoidance, as animals pre-exposed to Pseudomonas aeruginosa or Enterococcus faecalis showed reflexive aversion to drops of the bacteria, requiring ASI, AWB, and AWC neurons and ASE, AWB, and AWC neurons, respectively. This response also involved intestinal distention and, for E. faecalis, required expression of TRPM channels in the intestine and excretory system. Using whole-brain simulation and functional assays, we uncovered a sensorimotor circuit governing learned reflexive aversion. This behavior is controlled by a four-layer neural circuit composed of olfactory neurons, interneurons, and motor neurons that control backward locomotion crucial for learned reflexive aversion to pathogenic bacteria, learned avoidance, and a repulsive odor. The discovery of a complete sensorimotor circuit for reflexive aversion demonstrates the utility of using the C. elegans connectome and computational modeling in uncovering new neuronal regulators of behavior.

neuroscience↗

bioRxiv2021

Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30

A body of evidence indicates that metazoan immune and aging pathways are largely interconnected, but the mechanisms involved in their homeostatic control remain unclear. In this study, we found that the PITX (paired like homeodomain) transcription factor UNC-30 controls the tradeoff between immunity and longevity from the nervous system in Caenorhabditis elegans. PITX/UNC-30 functional loss enhanced immunity in a GATA/ELT-2- and p38 MAPK/PMK-1-dependent manner and reduced longevity by activating MXD/MDL-1 and the C2H2-type zinc finger transcription factor PQM-1. The immune inhibitory and longevity stimulatory functions of PITX/UNC-30 required the sensory neuron ASG and a neurotransmitter signaling pathway controlled by NPR-1, which is a G protein-coupled receptor related to mammalian neuropeptide Y receptors. Our findings uncovered a suppressive role of GABAergic signaling in the neural control of a biological tradeoff where energy is allocated towards immunity at the expense of longevity.

immunology↗

bioRxiv2020

TRPM channels mediate learned pathogen avoidance following intestinal distention

Upon exposure to harmful microorganisms, hosts engage in protective molecular and behavioral immune responses, both of which are ultimately regulated by the nervous system. Using the nematode Caenorhabditis elegans, we show that ingestion of E. faecalis leads to a fast pathogen avoidance behavior that results in aversive learning. We have identified multiple sensory mechanisms involved in the regulation of avoidance of E. faecalis, including the GPCR NPR-1-dependent oxygen-sensing pathway, an ASE neuron-dependent pathway, and an AWB and AWC neuron-dependent pathway. Colonization of the anterior part of the intestine by E. faecalis leads to AWB and AWC mediated olfactory aversive learning. Finally, two transient receptor potential melastatin (TRPM) channels, GON-2 and GTL-2, mediate this newly described rapid pathogen avoidance. These results suggest a mechanism by which TRPM channels may sense the intestinal distension caused by bacterial colonization to elicit pathogen avoidance and aversive learning by detecting changes in host physiology.

neuroscience↗

bioRxiv2020

Microbial colonization induces histone acetylation critical for inherited gut-germline-neural signaling

The gut-neural axis plays a critical role in the control of several physiological processes, including the communication of signals from the microbiome to the nervous system, which affects learning, memory, and behavior. However, the pathways involved in gut-neural signaling of gut-governed behaviors remain unclear. We found that the intestinal distension caused by the bacterium Pseudomonas aeruginosa induces histone H4 Lys8 acetylation (H4K8ac) in the germline of Caenorhabditis elegans, which is required for both a bacterial aversion behavior and its transmission to the next generation. We show that induction of H4K8ac in the germline is essential for bacterial aversion and that a 14-3-3 chaperone protein family member, PAR-5, is required for H4K8ac. Our findings highlight a role for H4K8ac in the germline not only in the intergenerational transmission of pathogen avoidance but also in the transmission of pathogenic cues that travel through the gut-neural axis to control the aversive behavior.

immunology↗

bioRxiv2019

Host mucin is subverted by Pseudomonas aeruginosa during infection to provide free glycans required for successful colonization

The mucosal barrier, found lining epithelial cells, serves multiple functions in a range of animals. The major structural components of mucus are mucins, which are heavily glycosylated proteins that are either membrane bound or secreted by the epithelial cells. Mucins are key components of the innate immune system, as they are involved in the clearance of pathogens from the airways and intestines, and their expression is typically upregulated upon epithelial cell exposure to a variety of pathogens. In this study, we identified the mucin MUL-1 as an innate immune factor that appears to be utilized by P. aeruginosa to colonize hosts. We found that while the expression of several mucins, including MUL-1, increased upon P. aeruginosa infection of the nematode Caenorhabditis elegans, silencing of or deletion of mul-1 resulted in enhanced survival and reduced bacterial accumulation. P. aeruginosa required host sialidase CTSA-1.1 to use mucin-derived glycans to colonize the host, while sialidase-encoding bacteria required host MUL-1 but not CTSA-1.1 to cause a lethal infection. This role of mucins and free glycans in host-pathogen interaction appears to be conserved from C. elegans to humans, as P. aeruginosa binding to human lung epithelial cells was also enhanced in the presence of free glycans, and free glycans reversed the binding defect of P. aeruginosa to human lung cells lacking the mucin MUC1.\n\nAuthor SummaryThe gastrointestinal, respiratory, reproductive, and urinary tracts, are large surfaces exposed to the exterior environment and thus, these mucosal epithelial tissues serve as primary routes of infection. One of the first lines of defense present at these barriers is mucus, which is a highly viscous material formed by mucin glycoproteins. Mucins serve various functions, but importantly they aid in the clearance of pathogens and debris from epithelial barriers and serve as innate immune effectors. In this study, we describe the ability of Pseudomonas aeruginosa to utilize mucin-derived glycans to colonize the intestine and ultimately cause death in Caenorhabditis elegans. We also show conserved mechanisms of P. aeruginosa virulence traits, by demonstrating that free glycans alter the ability of the bacteria to bind to human lung alveolar epithelial cells. Over the course of host-pathogen evolution, pathogens seem to have evolved to use mucins for their own advantage, and thus one of the biggest questions is which party benefits from pathogen-mucin binding. By gaining a better understanding of pathogen-mucin interactions, we can better protect against pathogen infection.

microbiology↗