Biology subjects

Wani, K. A.

Publications and source records attributed to Wani, K. A..

9 recordsLinked to original sources

bioRxiv2026

Monounsaturated fatty acid depletion is a metabolic pattern of pathogenesis surveilled to activate p38 MAPK innate immunity

Pathogen infection profoundly remodels host metabolism. Whether hosts sense specific pathogen-induced metabolic changes to identify microbial infection is not known. Here, we find that depletion the monounsaturated fatty acid oleate is a metabolic pattern of pathogenesis, specifically surveilled by the nematode C. elegans to identify active infection with a bacterial pathogen. We previously demonstrated that the enzymatic TIR (Toll/interleukin-1 receptor/resistance)-domain containing protein, TIR-1/SARM1, the key upstream activator of p38 MAPK PMK-1 immunity, is a guard protein in an effector-triggered immune response, positioned specifically on the surface of lysosome-related organelles to sense the toxic effects of bacterial infection. Here, we show that acute loss of oleate in intestinal cells during bacterial infection causes lysosome-related organelles to collapse, which induces the aggregation and activation of TIR-1/SARM1. Further, we find that oleate deficiency is a host vulnerability that concomitantly activates the c-Jun N-terminal kinase (JNK) KGB-1 nutrient sensing pathway, an adaptive response that promotes expression of TIR-1/SARM1 on lysosome-related organelles and is required for survival during infection. These data establish a mechanistic connection between fatty acid nutrition and innate immune regulation, and reveal that specific changes in host metabolism are surveilled to identify pathogen attack.

immunology↗

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↗

bioRxiv2026

kri-1/KRIT1 restrains skn-1/NRF2 activation to promote innate immune and lipid homeostasis

Animals must differentially allocate essential metabolic resources in response to changing environmental conditions to ensure reproductive success. For example, adult C. elegans coordinate innate immune defenses during infection and also allocate fat stores to the germline, each of which are required for evolutionary fitness. The genetic mechanisms that integrate resource allocation and host defenses in this context, however, are not fully understood. From a forward genetic screen for novel regulators of innate immune gene transcription, we identified kri-1, the nematode homolog of human Krev interaction trapped protein KRIT1. Mutations in human KRIT1 underlie cerebral cavernous malformations, a disease marked by defects in vascular integrity. Similarly, C. elegans kri-1/KRIT1 is required for the integrity of the intestinal epithelial cell barrier. We find also that kri-1/KRIT1 is required for host tolerance to bacterial infection, fecundity, and normal development. In this context, kri-1/KRIT1 restrains the activity of the cytoprotective transcription factor skn-1/NRF2 to control immune gene transcription and intestinal lipid mobilization during aging, a process necessary for healthy reproduction, but functions independently of skn-1/NRF2 to promote epithelial integrity and pathogen tolerance. These data reveal a broad role for a strongly conserved regulator in essential physiological processes that are required for reproductive fidelity and evolutionary success.

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↗

bioRxiv2025

Transcriptional responses to prolonged oxidative stress require cholinergic activation of G-protein-coupled receptor signaling

Organisms have evolved protective strategies that are geared toward limiting cellular damage and enhancing organismal survival in the face of environmental stresses, but how these protective mechanisms are coordinated remains unclear. Here, we define a requirement for neural activity in mobilizing the antioxidant defenses of the nematode Caenorhabditis elegans both during chronic oxidative stress and prior to its onset. We show that acetylcholine-deficient mutants are particularly vulnerable to chronic oxidative stress. We find that extended oxidative stress mobilizes a broad transcriptional response which is strongly dependent on both cholinergic signaling and activation of the muscarinic G-protein acetylcholine coupled receptor (mAChR) GAR-3. Gene enrichment analysis revealed a lack of upregulation of proteasomal proteolysis machinery in both cholinergic-deficient and gar-3 mAChR mutants, suggesting that muscarinic activation is critical for stress-responsive upregulation of protein degradation pathways. Further, we find that GAR-3 overexpression in cholinergic motor neurons prolongs survival during chronic oxidative stress. Our studies demonstrate neuronal modulation of antioxidant defenses through cholinergic activation of G protein-coupled receptor signaling pathways, defining new potential links between cholinergic signaling, oxidative damage, and neurodegenerative disease.

neuroscience↗

bioRxiv2023

Pathogen effector-triggered aggregation of TIR-1/SARM1 on lysosome-related organelles activates intestinal immunity

TIR-domain proteins with enzymatic activity are essential for immunity in plants, animals, and bacteria. However, it is not known how these proteins function in pathogen sensing in animals. We discovered that a TIR-domain protein (TIR-1/SARM1) is strategically expressed on the membranes of a lysosomal sub-compartment, which enables intestinal epithelial cells in the nematode C. elegans to survey for pathogen effector-triggered host damage. We showed that a redox active virulence effector secreted by the bacterial pathogen Pseudomonas aeruginosa alkalinized and condensed a specific subset of lysosomes by inducing intracellular oxidative stress. Concentration of TIR-1/SARM1 on the surface of these organelles triggered its multimerization, which engages its intrinsic NADase activity, to activate the p38 innate immune pathway and protect the host against microbial intoxication. Thus, lysosomal TIR-1/SARM1 is a sensor for oxidative stress induced by pathogenic bacteria to activate metazoan intestinal immunity.

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

Transcriptional suppression of sphingolipid catabolism controls pathogen resistance in C. elegans

Sphingolipids are required for diverse biological functions and are degraded by specific catabolic enzymes. However, the mechanisms that regulate sphingolipid catabolism are not known. Here we characterize a transcriptional axis that regulates sphingolipid breakdown to control resistance against bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematode C. elegans, we identified the nuclear hormone receptor nhr-66, a ligand-gated transcription factor homologous to human hepatocyte nuclear factor 4. Tandem chromatin immunoprecipitation-sequencing and RNA sequencing experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism genes. Transcriptional de-repression of two sphingolipid catabolic enzymes in nhr-66 loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogen Pseudomonas aeruginosa. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipids, a process that is necessary for pathogen resistance.

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↗