@article {161133, title = {Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis.}, journal = {Nat Commun}, volume = {16}, year = {2025}, month = {2025 Oct 23}, pages = {9370}, abstract = {

Effective clearance of Mycobacterium tuberculosis (Mtb) requires targeting drug-tolerant populations within host macrophages. Here, we show that macrophage metabolic states govern redox heterogeneity and drug response in intracellular Mtb. Using a redox-sensitive fluorescent reporter (Mrx1-roGFP2), flow cytometry, and transcriptomics, we found that macrophages with high oxidative phosphorylation (OXPHOS) and low glycolysis harbor reductive, drug-tolerant Mtb, whereas glycolytically active macrophages generate mitochondrial ROS via reverse electron transport, imposing oxidative stress on Mtb and enhancing drug efficacy. Computational and genetic analyses identified NRF2 as a key regulator linking host metabolism to bacterial redox state and drug tolerance. Pharmacological reprogramming of macrophages with the FDA-approved drug meclizine (MEC) shifted metabolism towards glycolysis, suppressed redox heterogeneity, and reduced Mtb drug tolerance in macrophages and mice. MEC exhibited no adverse interactions with frontline anti-TB drugs. These findings demonstrate the therapeutic potential of host metabolic reprogramming to overcome Mtb drug tolerance.

}, keywords = {Animals, Antitubercular Agents, Drug Tolerance, Energy Metabolism, Female, Glycolysis, Humans, Macrophages, Mice, Mice, Inbred C57BL, Mitochondria, Mycobacterium tuberculosis, NF-E2-Related Factor 2, Oxidation-Reduction, Oxidative Phosphorylation, Oxidative Stress, Reactive Oxygen Species, Tuberculosis}, issn = {2041-1723}, doi = {10.1038/s41467-025-64407-w}, author = {Yadav, Vikas and Sahoo, Sarthak and Malhotra, Nitish and Mishra, Richa and Sreedharan, Sreesa and Rajmani, Raju S and Shanmugam, Siva and Shandil, Radha K and Narayanan, Shridhar and Thacker, Vivek V and Laxman, Sunil and Jolly, Mohit Kumar and Seshasayee, Aswin Sai Narain and Singh, Amit} } @article {157492, title = {M. tuberculosis surface sulfoglycolipid SL-1 activates the mechanosensitive channel TRPV4 to enhance lysosomal biogenesis and exocytosis in macrophages}, journal = {Mol Biol Cell}, volume = {36}, year = {2025}, month = {2025 Jun 01}, pages = {ar76}, abstract = {

Intracellular pathogens manipulate host cellular pathways to ensure their survival. (Mtb) disrupts phagosomal trafficking to prevent fusion with lysosomes. Beyond this localized effect, Mtb globally remodels the host lysosomal system, predominantly through its virulence-associated surface lipid, sulfolipid-1 (SL-1). SL-1 enhances lysosomal biogenesis via the mTORC1-TFEB axis; however, the upstream mediators remain unknown. Here, we show that SL-1 induces calcium influx into macrophages and identify the mechanosensitive calcium channel transient receptor potential vanilloid subtype 4 (TRPV4) as a crucial upstream mediator of SL-1-induced lysosomal remodeling. TRPV4 influences multiple aspects of lysosomal function, including biogenesis, acidification, enzymatic activity, phagosome maturation, and lysosomal exocytosis. These effects are recapitulated during Mtb infection, underscoring the relevance of SL-1- and TRPV4-dependent lysosomal remodeling in an infection context. TRPV4 expression is upregulated during Mtb infection and partially localizes to both lysosomes and the Mtb-containing vacuole. Remarkably, TRPV4 activation, independent of SL-1, is sufficient to enhance lysosomal biogenesis, identifying TRPV4 as a key regulator of lysosomal homeostasis. Together, these findings uncover a novel mechanism of lysosomal remodeling driven by a pathogen lipid virulence factor and reveal a previously unrecognized role for TRPV4 in modulating lysosomal homeostasis in macrophages.

}, keywords = {Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Calcium, Exocytosis, Glycolipids, Humans, Lysosomes, Macrophages, Mice, Mice, Inbred C57BL, Mycobacterium tuberculosis, Phagosomes, TRPV Cation Channels}, issn = {1939-4586}, doi = {10.1091/mbc.E24-12-0560}, url = {https://www.molbiolcell.org/doi/10.1091/mbc.E24-12-0560?url_ver=Z39.88-2003\&rfr_id=ori:rid:crossref.org\&rfr_dat=cr_pub\%20\%200pubmed}, author = {Umar, Ibrahim and Gulzar, Shah-E-Jahan and Sundaramurthy, Varadharajan} } @article {149383, title = {CDS2 expression regulates de novo phosphatidic acid synthesis.}, journal = {Biochem J}, volume = {481}, year = {2024}, month = {2024 Oct 16}, pages = {1449-1473}, abstract = {

CDS enzymes (CDS1 and 2 in mammals) convert phosphatidic acid (PA) to CDP-DG, an essential intermediate in the de novo synthesis of PI. Genetic deletion of CDS2 in primary mouse macrophages resulted in only modest changes in the steady-state levels of major phospholipid species, including PI, but substantial increases in several species of PA, CDP-DG, DG and TG. Stable isotope labelling experiments employing both 13C6- and 13C6D7-glucose revealed loss of CDS2 resulted in a minimal reduction in the rate of de novo PI synthesis but a substantial increase in the rate of de novo PA synthesis from G3P, derived from DHAP via glycolysis. This increased synthesis of PA provides a potential explanation for normal basal PI synthesis in the face of reduced CDS capacity (via increased provision of substrate to CDS1) and increased synthesis of DG and TG (via increased provision of substrate to LIPINs). However, under conditions of sustained GPCR-stimulation of PLC, CDS2-deficient macrophages were unable to maintain enhanced rates of PI synthesis via the {\textquoteright}PI cycle{\textquoteright}, leading to a substantial loss of PI. CDS2-deficient macrophages also exhibited significant defects in calcium homeostasis which were unrelated to the activation of PLC and thus probably an indirect effect of increased basal PA. These experiments reveal that an important homeostatic response in mammalian cells to a reduction in CDS capacity is increased de novo synthesis of PA, likely related to maintaining normal levels of PI, and provides a new interpretation of previous work describing pleiotropic effects of CDS2 deletion on lipid metabolism/signalling.

}, keywords = {Animals, Calcium, Diacylglycerol Cholinephosphotransferase, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphatidic Acids}, issn = {1470-8728}, doi = {10.1042/BCJ20240456}, author = {Collins, Daniel M and Janardan, Vishnu and Barneda, David and Anderson, Karen E and Niewczas, Izabella and Taylor, Diane and Qiu, Danye and Jessen, Henning J and Lopez-Clavijo, Andrea F and Walker, Simon and Raghu, Padinjat and Clark, Jonathan and Stephens, Len R and Hawkins, Phillip T} } @article {149370, title = {Neuroepithelial bodies and terminal bronchioles are niches for distinctive club cells that repair the airways following acute notch inhibition.}, journal = {Cell Rep}, volume = {43}, year = {2024}, month = {2024 Sep 24}, pages = {114654}, abstract = {

Lower airway club cells (CCs) serve the dual roles of a secretory cell and a stem cell. Here, we probe how the\ CC fate is regulated. We find that, in response to acute perturbation of Notch signaling, CCs adopt distinct fates. Although the vast majority transdifferentiate into multiciliated cells, a "variant" subpopulation (v-CCs), juxtaposed to neuroepithelial bodies (NEBs; 5\%-10\%) and located at bronchioalveolar duct junctions (\>80\%), does not. Instead, v-CCs transition into lineage-ambiguous states but can revert to a CC fate upon restoration of Notch signaling and repopulate the airways with CCs and multiciliated cells. The v-CC response to Notch inhibition is dependent on localized activation of β-catenin in v-CCs. We propose that the CC fate is stabilized by canonical Notch signaling, that airways are susceptible to perturbations to this pathway, and that NEBs/terminal bronchioles comprise niches that modulate CC plasticity via β-catenin activation to facilitate airway repair post Notch inhibition.

}, keywords = {Animals, beta Catenin, Bronchioles, Mice, Mice, Inbred C57BL, Neuroepithelial Bodies, Receptors, Notch, Signal Transduction}, issn = {2211-1247}, doi = {10.1016/j.celrep.2024.114654}, author = {Lingamallu, Sai Manoz and Deshpande, Aditya and Joy, Neenu and Ganeshan, Kirthana and Ray, Neelanjana and Ladher, Rajesh Kumar and Taketo, Makoto Mark and Lafkas, Daniel and Guha, Arjun} } @article {909, title = {The dynamic impact of repeated stress on the hippocampal spatial map.}, journal = {Hippocampus}, volume = {25}, year = {2015}, month = {2015 Jan}, pages = {38-50}, abstract = {

Stress alters the function of many physiological processes throughout the body, including in the brain. A neural circuit particularly vulnerable to the effects of stress is the hippocampus, a key component of the episodic and spatial memory system in both humans and rodents. Earlier studies have provided snapshots of morphological, molecular, physiological and behavioral changes in the hippocampus following either acute or repeated stress. However, the cumulative impact of repeated stress on in vivo hippocampal physiology remains unexplored. Here we report the stress-induced modulation of the spatially receptive fields of the hippocampal CA1 {\textquoteright}place cells{\textquoteright} as mice explore familiar and novel tracks after 5 and 10 days of immobilization stress. We find that similar to what has been observed following acute stress, five days of repeated stress results in decreased excitability of CA1 pyramidal cells. Following ten days of chronic stress, however, this decreased hippocampal excitability is no longer evident, suggesting adaptation may have occurred. In addition to these changes in neuronal excitability, we find deficient context discrimination, wherein both short-term and chronic stress impair the ability of the hippocampus to unambiguously distinguish novel and familiar environments. These results suggest that a loss of network flexibility may underlie some of the behavioral deficits accompanying chronic stress.

}, keywords = {Animals, Behavior, Animal, CA1 Region, Hippocampal, Discrimination (Psychology), Generalization (Psychology), Male, Mice, Mice, Inbred C57BL, Spatial Memory, Stress, Psychological, Time Factors}, issn = {1098-1063}, doi = {10.1002/hipo.22348}, author = {Tomar, Anupratap and Polygalov, Denis and Chattarji, Sumantra and McHugh, Thomas J} }