{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T01:07:28Z","timestamp":1789002448976,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,7]]},"group-title":"Cell Biology","reference-count":85,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["R35GM129294"],"award-info":[{"award-number":["R35GM129294"]}]},{"name":"NIH","award":["3R21CA280500-01A1S1"],"award-info":[{"award-number":["3R21CA280500-01A1S1"]}]},{"name":"NIH","award":["AI055449-17"],"award-info":[{"award-number":["AI055449-17"]}]},{"name":"NSF","award":["2244041"],"award-info":[{"award-number":["2244041"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Innate immunity is the first line of defense against invading pathogens and is essential for maintaining host survival. While the majority of innate immunity studies have focused on pathogen recognition and antimicrobial responses, increasing evidence suggests that lipid metabolism plays a fundamental role in shaping immune function. Understanding how these metabolic pathways contribute to immunity is crucial in the context of bacterial infections caused by opportunistic pathogens such as\n                  <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                  . Host defense against\n                  <jats:italic>P. aeruginosa<\/jats:italic>\n                  requires the coordination of innate immune and metabolic responses; however, the mechanisms linking lipid metabolism to pathogen resistance remain poorly understood. Research into the relationship between lipid homeostasis and innate immunity may reveal factors governing host-pathogen interactions and identify novel strategies to enhance resistance to infection.\n                <\/jats:p>\n                <jats:p>\n                  Here, we demonstrate that\n                  <jats:italic>P. aeruginosa<\/jats:italic>\n                  liquid-based pathogenesis (LK-\n                  <jats:italic>Pa<\/jats:italic>\n                  ) triggers a shift in host metabolism which differs from the one observed in response to agar-based pathogenesis. Our bioinformatic analyses revealed a highly similar metabolic profile (enrichment of lipid metabolism) in worms exposed to LK-\n                  <jats:italic>Pa<\/jats:italic>\n                  or the iron chelator phenanthroline, suggesting a shared host response to iron deprivation. We further characterized the host genetic factors driving this metabolic shift and established their importance for host defense against LK-\n                  <jats:italic>Pa<\/jats:italic>\n                  as well as liquid-based pathogenesis by Gram-positive pathogens\n                  <jats:italic>Enterococcus faecalis<\/jats:italic>\n                  and\n                  <jats:italic>Staphylococcus aureus<\/jats:italic>\n                  . Notably, our results indicate that LK-\n                  <jats:italic>Pa<\/jats:italic>\n                  triggers host lipid droplet depletion, an upstream component that leads to increased \u03b2-oxidation. Finally, we demonstrate that LK-\n                  <jats:italic>Pa<\/jats:italic>\n                  triggers repression of MXL-3 which results in HLH-30-dependent metabolic rewiring.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Author Summary<\/jats:title>\n                  <jats:p>\n                    Pathogenesis alters host metabolism in ways that can either enhance survival or promote disease. Understanding how pathogenesis triggers host metabolic rewiring may reveal novel strategies to combat antimicrobial-resistant infections. Using\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    , we studied how the opportunistic pathogen\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    reshapes host metabolism during liquid-based infection.\n                  <\/jats:p>\n                  <jats:p>\n                    Our results reveal that liquid-based pathogenesis induces extensive activation of host lipid metabolism, a distinct transcriptional response from the one triggered during agar-based pathogenesis. This lipid signature closely resembles the host response to iron deprivation, suggesting that in the case of\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    , bacterial siderophore production is a major driver of host metabolic rewiring. We identified seventeen lipid genes crucial for survival during\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    exposure in liquid; most of them were also needed for defense against the Gram-positive pathogens\n                    <jats:italic>E. faecalis<\/jats:italic>\n                    and\n                    <jats:italic>S. aureus<\/jats:italic>\n                    . Notably, most of these genes function independently of activating known organellar surveillance pathways.\n                  <\/jats:p>\n                  <jats:p>\n                    Instead, we show that\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    liquid-based pathogenesis triggers host lipid droplet depletion and induces a metabolic shift towards \u03b2-oxidation. This process is driven by inhibition of the nutrient-responsive transcription factor MXL-3 and subsequent activation of the lysosomal transcription factor HLH-30, which drives expression of \u03b2-oxidation genes. Altogether, our findings identify an MXL-3 -HLH-30 regulatory axis that couples pathogen-induced metabolic stress to lipid mobilization and reveal metabolic rewiring as a host defense mechanism during bacterial infection.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.03.749215","type":"posted-content","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T21:15:12Z","timestamp":1788815712000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>P. aeruginosa<\/i>\n                  liquid-based pathogenesis triggers HLH-30-dependent metabolic rewiring in\n                  <i>C. elegans<\/i>"],"prefix":"10.64898","author":[{"given":"Lois A.","family":"Armendariz","sequence":"first","affiliation":[{"name":"Department of BioSciences, 6100 Main St, MS140, Rice University, Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elissa","family":"Tjahjono","sequence":"additional","affiliation":[{"name":"Department of BioSciences, 6100 Main St, MS140, Rice University, Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvette","family":"Acevedo","sequence":"additional","affiliation":[{"name":"Department of BioSciences, 6100 Main St, MS140, Rice University, Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda","family":"Vaca","sequence":"additional","affiliation":[{"name":"Department of BioSciences, 6100 Main St, MS140, Rice University, Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Lowder","sequence":"additional","affiliation":[{"name":"Department of BioSciences, 6100 Main St, MS140, Rice University, Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of BioSciences, 6100 Main St, MS140, Rice University, Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of BioSciences, 6100 Main St, MS140, Rice University, Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey V.","family":"Revtovich","sequence":"additional","affiliation":[{"name":"Department of BioSciences, 6100 Main St, MS140, Rice University, Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainsley","family":"High","sequence":"additional","affiliation":[{"name":"Department of BioSciences, 6100 Main St, MS140, Rice University, Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan","family":"Park","sequence":"additional","affiliation":[{"name":"Department of BioSciences, 6100 Main St, MS140, Rice University, Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1537-4967","authenticated-orcid":false,"given":"Natalia V.","family":"Kirienko","sequence":"additional","affiliation":[{"name":"Department of BioSciences, 6100 Main St, MS140, Rice University, Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026090917351023000_2026.09.03.749215v1.1","doi-asserted-by":"publisher","DOI":"10.4137\/PMC.S14459"},{"key":"2026090917351023000_2026.09.03.749215v1.2","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.100784"},{"key":"2026090917351023000_2026.09.03.749215v1.3","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S530557"},{"key":"2026090917351023000_2026.09.03.749215v1.4","doi-asserted-by":"publisher","DOI":"10.3205\/dgkh000290"},{"key":"2026090917351023000_2026.09.03.749215v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e20561"},{"key":"2026090917351023000_2026.09.03.749215v1.6","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2024.1374466"},{"key":"2026090917351023000_2026.09.03.749215v1.7","doi-asserted-by":"publisher","DOI":"10.1186\/s12941-024-00728-w"},{"key":"2026090917351023000_2026.09.03.749215v1.8","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics12030557"},{"key":"2026090917351023000_2026.09.03.749215v1.9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008897"},{"key":"2026090917351023000_2026.09.03.749215v1.10","doi-asserted-by":"publisher","DOI":"10.1101\/2025.05.26.656193"},{"key":"2026090917351023000_2026.09.03.749215v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.08.027"},{"key":"2026090917351023000_2026.09.03.749215v1.12","doi-asserted-by":"publisher","DOI":"10.3390\/cells10040880"},{"key":"2026090917351023000_2026.09.03.749215v1.13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004143"},{"key":"2026090917351023000_2026.09.03.749215v1.14","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.62775"},{"key":"2026090917351023000_2026.09.03.749215v1.15","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13413"},{"key":"2026090917351023000_2026.09.03.749215v1.16","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00130-20"},{"key":"2026090917351023000_2026.09.03.749215v1.17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000415"},{"key":"2026090917351023000_2026.09.03.749215v1.18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007893"},{"key":"2026090917351023000_2026.09.03.749215v1.19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1318262111"},{"key":"2026090917351023000_2026.09.03.749215v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2837"},{"key":"2026090917351023000_2026.09.03.749215v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2012.10.041"},{"key":"2026090917351023000_2026.09.03.749215v1.22","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R021006"},{"key":"2026090917351023000_2026.09.03.749215v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-023-01189-1"},{"key":"2026090917351023000_2026.09.03.749215v1.24","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R067520"},{"key":"2026090917351023000_2026.09.03.749215v1.25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006876"},{"key":"2026090917351023000_2026.09.03.749215v1.26","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.119.302919"},{"key":"2026090917351023000_2026.09.03.749215v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.211"},{"key":"2026090917351023000_2026.09.03.749215v1.28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn923"},{"key":"2026090917351023000_2026.09.03.749215v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36181-0"},{"key":"2026090917351023000_2026.09.03.749215v1.30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1424954112"},{"key":"2026090917351023000_2026.09.03.749215v1.31","doi-asserted-by":"publisher","DOI":"10.1002\/gene.10243"},{"key":"2026090917351023000_2026.09.03.749215v1.32","doi-asserted-by":"publisher","DOI":"10.1080\/19491034.2016.1238999"},{"key":"2026090917351023000_2026.09.03.749215v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.02.050"},{"key":"2026090917351023000_2026.09.03.749215v1.34","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.17670"},{"key":"2026090917351023000_2026.09.03.749215v1.35","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30090"},{"key":"2026090917351023000_2026.09.03.749215v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.12.064"},{"key":"2026090917351023000_2026.09.03.749215v1.37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008011"},{"key":"2026090917351023000_2026.09.03.749215v1.38","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1113"},{"key":"2026090917351023000_2026.09.03.749215v1.39","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2018.1449508"},{"key":"2026090917351023000_2026.09.03.749215v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/nature13818"},{"key":"2026090917351023000_2026.09.03.749215v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2009.387"},{"key":"2026090917351023000_2026.09.03.749215v1.42","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-020-00812-5"},{"key":"2026090917351023000_2026.09.03.749215v1.43","doi-asserted-by":"publisher","DOI":"10.1534\/g3.112.003830"},{"key":"2026090917351023000_2026.09.03.749215v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(03)00102-3"},{"key":"2026090917351023000_2026.09.03.749215v1.45","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01275"},{"key":"2026090917351023000_2026.09.03.749215v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/415092a"},{"key":"2026090917351023000_2026.09.03.749215v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-022-01614-0"},{"key":"2026090917351023000_2026.09.03.749215v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-97148-z"},{"key":"2026090917351023000_2026.09.03.749215v1.49","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1573107"},{"key":"2026090917351023000_2026.09.03.749215v1.50","doi-asserted-by":"publisher","DOI":"10.1126\/science.1087782"},{"key":"2026090917351023000_2026.09.03.749215v1.51","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2023.2204004"},{"key":"2026090917351023000_2026.09.03.749215v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-0497-0"},{"key":"2026090917351023000_2026.09.03.749215v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2741"},{"key":"2026090917351023000_2026.09.03.749215v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3267"},{"key":"2026090917351023000_2026.09.03.749215v1.55","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2718"},{"key":"2026090917351023000_2026.09.03.749215v1.56","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M111.016345"},{"key":"2026090917351023000_2026.09.03.749215v1.57","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-023-01136-6"},{"key":"2026090917351023000_2026.09.03.749215v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.05.002"},{"key":"2026090917351023000_2026.09.03.749215v1.59","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000848"},{"key":"2026090917351023000_2026.09.03.749215v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth933"},{"key":"2026090917351023000_2026.09.03.749215v1.61","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1094145"},{"key":"2026090917351023000_2026.09.03.749215v1.62","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2026.2662638"},{"key":"2026090917351023000_2026.09.03.749215v1.63","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.70937"},{"key":"2026090917351023000_2026.09.03.749215v1.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.micres.2023.127421"},{"key":"2026090917351023000_2026.09.03.749215v1.65","doi-asserted-by":"publisher","DOI":"10.1895\/wormbook.1.101.1"},{"key":"2026090917351023000_2026.09.03.749215v1.66","doi-asserted-by":"publisher","DOI":"10.1051\/medsci\/20031967725"},{"key":"2026090917351023000_2026.09.03.749215v1.67","doi-asserted-by":"publisher","DOI":"10.1242\/dev.116.3.755"},{"key":"2026090917351023000_2026.09.03.749215v1.68","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01502-13"},{"key":"2026090917351023000_2026.09.03.749215v1.69","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2005.04.062"},{"key":"2026090917351023000_2026.09.03.749215v1.70","doi-asserted-by":"publisher","DOI":"10.1038\/nature01278"},{"key":"2026090917351023000_2026.09.03.749215v1.71","doi-asserted-by":"publisher","DOI":"10.1101\/gr.2505604"},{"key":"2026090917351023000_2026.09.03.749215v1.72","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.2.715"},{"key":"2026090917351023000_2026.09.03.749215v1.73","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.000758"},{"key":"2026090917351023000_2026.09.03.749215v1.74","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.7b00135"},{"key":"2026090917351023000_2026.09.03.749215v1.75","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.191378698"},{"key":"2026090917351023000_2026.09.03.749215v1.76","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2013.03.003"},{"key":"2026090917351023000_2026.09.03.749215v1.77","doi-asserted-by":"publisher","DOI":"10.3791\/58068"},{"key":"2026090917351023000_2026.09.03.749215v1.78","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-021-04344-9"},{"key":"2026090917351023000_2026.09.03.749215v1.79","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-0473-0_50"},{"key":"2026090917351023000_2026.09.03.749215v1.80","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80958-7"},{"key":"2026090917351023000_2026.09.03.749215v1.81","doi-asserted-by":"publisher","DOI":"10.1021\/cb2002973"},{"key":"2026090917351023000_2026.09.03.749215v1.82","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01376-13"},{"key":"2026090917351023000_2026.09.03.749215v1.83","doi-asserted-by":"crossref","unstructured":"Revtovich, A.V. , Tjahjono, E. , Singh, K.V. , Hanson, B.M. , Murray, B.E. , and Kirienko, N.V . (2021). Development and Characterization of High-Throughput Caenorhabditis elegans \u2013 Enterococcus faecium Infection Model. Front. Cell. Infect. Microbiol. 11.","DOI":"10.3389\/fcimb.2021.667327"},{"key":"2026090917351023000_2026.09.03.749215v1.84","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00950-20"},{"key":"2026090917351023000_2026.09.03.749215v1.85","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.2774"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.03.749215","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:35:19Z","timestamp":1789000519000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.03.749215"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,7]]},"references-count":85,"URL":"https:\/\/doi.org\/10.64898\/2026.09.03.749215","relation":{},"subject":[],"published":{"date-parts":[[2026,9,7]]},"subtype":"preprint"}}