03345nas a2200313   4500008004100000022001400041245018000055210007000235260000900305300000800314490000700322520226900329100002002598700001602618700002402634700001602658700002202674700001902696700001902715700001802734700001902752700002802771700001802799700001902817700001702836700002802853700002102881856012902902       2026                        eng d  a2041-488900aβ-catenin-driven innate and metabolic reprograming in macrophages fuel T-cell-dependent inflammation in Toxoplasma gondii infection: implications for therapeutic intervention0 aβcatenindriven innate and metabolic reprograming in macrophages   cJUN   a5680 v173 a<p>
	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 beta-catenin signaling mediates immune recognition of T. gondii. Notably, this parasite hijacks the PI3K-AKT-beta-catenin pathway in macrophages to promote its replication. While beta-catenin ablation, either genetically or pharmacologically (XAV939), disavows this process, thereby inhibiting replication. Phospho-beta-catenin-TCF4 drives IRF4 transcription, followed by phosphorylation of IRF4, which regulates CYBB transcription. Augmented CYBB enhances mitochondrial-ROS and triggers mitophagy via PINK1/PARKIN, whereas ablation of beta-catenin preserves mitochondrial fitness, thereby impeding parasite 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-1 beta inflammasome cascade. This cascade leads to gasdermin-D-mediated pyroptosis, a process that critically depends on the phosphorylation of beta-catenin. T. gondii's ASP5 protease plays an essential role in the phosphorylation of beta-catenin-mediated inflammasome activation. Metabolically, beta-catenin-dependent enhanced ROS stabilized HIF-1 alpha, which stimulates the HKII-LDH-A axis, promoting the Warburg effect, histone acetylation and pro-inflammatory M1-macrophage polarization (IL-12/IL-6/IL-23/TNF-alpha). beta-catenin ablation shifts metabolism to oxidative-phosphorylation, fostering M2-phenotype (IL-2/IL-10/TGF-beta) that abrogates parasites survival. beta-catenin also strengthens MHC-TCR avidity, driving Th1/Tc1, Th9/Tc9, and Th17/Tc17 paradigm, whereas beta-catenin inhibition promotes anti-inflammatory Th2/Tc2/Threg/Tcreg differentiation. Additionally, macrophage intrinsic beta-catenin dictates metabolic divergence in both CD4(+) and CD8(+)T-cells. Notably, beta-catenin-deletion in macrophages protects mice (beta-cat Delta M Phi) against infection, highlighting that XAV939 has therapeutic potential against toxoplasmosis.</p>
1 aKumari, Geetika1 aKumar, Amit1 aMuduli, Rasmiranjan1 aDas, Mayami1 aBhowmik, Prithwik1 aSingha, Biplab1 aNamdeo, Ankita1 aDcosta, Criss1 aWadhwa, Neerja1 aMaras, Jaswinder, Singh1 aKundu, Rakesh1 aGupta, Nishith1 aAnand, Ruchi1 aShanmugam, Dhanasekaran1 aMajumdar, Tanmay  uhttps://library.ncl.res.in/content/%CE%B2-catenin-driven-innate-and-metabolic-reprograming-macrophages-fuel-t-cell-dependent