β-catenin driven innate and metabolic reprograming in macrophages fuel T-cells dependent inflammation in Toxoplasma gondii infection: implications for therapeutic intervention

β-catenin driven innate and metabolic reprograming in macrophages fuel T-cells dependent inflammation in Toxoplasma gondii infection: implications for therapeutic intervention | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article β-catenin driven innate and metabolic reprograming in macrophages fuel T-cells dependent inflammation in Toxoplasma gondii infection: implications for therapeutic intervention TANMAY MAJUMDAR, Geetika Kumari, Amit Kumar, Rasmiranjan Muduli, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8453530/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Toxoplasma gondii activates innate immunity via TLR11/12 in mice, but the lack of functional human counterparts leaves a gap in understanding parasite sensing in humans. Here, we bridge this gap by uncovering a host-intrinsic sensing mechanism, wherein β-catenin signaling mediates immune recognition of T. gondii. Notably, this parasite hijacks the PI3K-AKT-β-catenin pathway in macrophages to promote its replication. While β-catenin ablation, either genetically or pharmacological (XAV939), disavows this process thereby inhibiting replication. Phospho-β-catenin-TCF4 drives IRF4 transcription, followed by phosphorylation of IRF4 regulates CYBB transcription. Augmented CYBB enhances mitochondrial-ROS and triggering mitophagy via PINK1/PARKIN, whereas ablation of β-catenin preserves mitochondrial-fitness, thereby impeding parasites growth. Enhanced ROS can oxidize host mitochondrial DNA, which then functions as a host-associated molecular pattern (HAMP). This activates the cytosolic pathogen recognition receptor (PRR) AIM2, triggering the AIM2-NLRP3-ASC-caspase-1-IL-1β inflammasome cascade. This cascade leads to gasdermin-D-mediated pyroptosis, a process that critically depends on the phosphorylation of β-catenin. T. gondii’s ASP5 protease plays an essential role in phosphorylation of β-catenin mediated inflammasome activation. Metabolically, β-catenin reliant enhanced ROS stabilized HIF-1α which stimulates HKII-LDH-A axis, promoting Warburg-effect, histone-lactylation, and pro-inflammatory M1-macrophage polarization (IL-12/IL-6/IL-23/TNF-α). β-catenin ablation shifts metabolism to oxidative-phosphorylation, fostering M2-phenotype (IL-2/IL-10/TGF-β) that abrogates parasites survival. β-catenin also strengthens MHC-TCR avidity, driving Th1/Tc1, Th9/Tc9, and Th17/Tc17 paradigm, whereas β-catenin inhibition promotes anti-inflammatory Th2/Tc2/Threg/Tcreg differentiation. Additionally, macrophage intrinsic β-catenin dictates metabolic divergence in both CD4⁺ and CD8⁺T-cells. Notably, β-catenin-deletion in macrophages protects mice (β-catΔMΦ) against infection highlighting that XAV939 has therapeutic-potential against toxoplasmosis. Biological sciences/Immunology/Inflammation/Inflammasome Biological sciences/Immunology/Cell death and immune response Biological sciences/Microbiology Health sciences/Pathogenesis/Inflammation/Acute inflammation Toxoplasma gondii macrophage β-catenin mitophagy inflammasomes metabolism Warburg effect T-cells Therapeutics Full Text Additional Declarations There is no duality of interest Supplementary Files FIGURES4.tif FIGURE S4 VideoS1C.mp4 Video S1C FIGURES7.tif FIGURE S7 VideoS1AB.mp4 Video S1A,B FIGURES8.tif FIGURE S8 FIGURES1.tif FIGURE S1 FIGURES3.tif FIGURE S3 FIGURES2.tif FIGURE S2 DataAnalysis.docx Data Analysis and Source FIGURES6.tif FIGURE S6 FIGURES9.tif FIGURE S9 FIGURES5.tif FIGURE S5 DataSet.zip Raw Data Set Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8453530","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":569628202,"identity":"d9d49cd0-3979-4717-be23-97b2aba8ae96","order_by":0,"name":"TANMAY 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AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Toxoplasma gondii, macrophage, β-catenin, mitophagy, inflammasomes, metabolism, Warburg effect, T-cells, Therapeutics","lastPublishedDoi":"10.21203/rs.3.rs-8453530/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8453530/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Toxoplasma gondii activates innate immunity via TLR11/12 in mice, but the lack of functional human counterparts leaves a gap in understanding parasite sensing in humans. Here, we bridge this gap by uncovering a host-intrinsic sensing mechanism, wherein β-catenin signaling mediates immune recognition of T. gondii. Notably, this parasite hijacks the PI3K-AKT-β-catenin pathway in macrophages to promote its replication. While β-catenin ablation, either genetically or pharmacological (XAV939), disavows this process thereby inhibiting replication. Phospho-β-catenin-TCF4 drives IRF4 transcription, followed by phosphorylation of IRF4 regulates CYBB transcription. Augmented CYBB enhances mitochondrial-ROS and triggering mitophagy via PINK1/PARKIN, whereas ablation of β-catenin preserves mitochondrial-fitness, thereby impeding parasites growth. Enhanced ROS can oxidize host mitochondrial DNA, which then functions as a host-associated molecular pattern (HAMP). This activates the cytosolic pathogen recognition receptor (PRR) AIM2, triggering the AIM2-NLRP3-ASC-caspase-1-IL-1β inflammasome cascade. This cascade leads to gasdermin-D-mediated pyroptosis, a process that critically depends on the phosphorylation of β-catenin. T. gondii’s ASP5 protease plays an essential role in phosphorylation of β-catenin mediated inflammasome activation. Metabolically, β-catenin reliant enhanced ROS stabilized HIF-1α which stimulates HKII-LDH-A axis, promoting Warburg-effect, histone-lactylation, and pro-inflammatory M1-macrophage polarization (IL-12/IL-6/IL-23/TNF-α). β-catenin ablation shifts metabolism to oxidative-phosphorylation, fostering M2-phenotype (IL-2/IL-10/TGF-β) that abrogates parasites survival. β-catenin also strengthens MHC-TCR avidity, driving Th1/Tc1, Th9/Tc9, and Th17/Tc17 paradigm, whereas β-catenin inhibition promotes anti-inflammatory Th2/Tc2/Threg/Tcreg differentiation. Additionally, macrophage intrinsic β-catenin dictates metabolic divergence in both CD4⁺ and CD8⁺T-cells. 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