cGAS-STING dependent type I IFN reduces Leptospira interrogans renal colonization in mice

PLoS Pathogens · 2026-01-07 · 1 citations

Leptospira interrogans is the major causative agent of leptospirosis. Humans, canines and agricultural animals are susceptible to Leptospira species and can develop fulminant disease. Rodents serve as reservoir hosts in which the bacteria colonize the renal tubules and are excreted in the urine. The host immune response to Leptospira spp. remains poorly defined. We show that L. interrogans induces a robust type I interferon (IFN) response in human and murine macrophages that is dependent on the cytosolic dsDNA sensor Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of IFN Genes (STING) signaling pathway. Further, we show that mice deficient in the IFNα/β receptor subunit 1 (IFNAR1) or STING had higher bacterial burdens and increased renal colonization following infection in vivo suggesting that cGAS-STING-driven type I IFN is required for the host defense against L. interrogans. These findings demonstrate the significance of cGAS-STING- dependent type I IFN signaling in mammalian innate immune responses to L. interrogans.

Mapping metabolic dependences and capacities using ATP as a biomarker

Research Square · 2025-04-23 · 1 citations

Intrinsic errors in mitochondrial translation trigger a decline in cell fitness

bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-15

Abstract Defects in the faithful expression of the human mitochondrial genome underlies disease states, from rare inherited disorders to common pathologies and the aging process itself. The ensuing decrease in the capacity for oxidative phosphorylation alone cannot account for the phenotype complexity associated with disease. Here, we address how aberrations in mitochondrial nascent chain synthesis per se exert a decline in cell fitness using a classic model of mitochondrial induced premature aging. We identify how intrinsic errors during mitochondrial nascent chain synthesis destabilize organelle gene expression, triggering intracellular stress responses that rewire cellular metabolism and cytokine secretion. Further, we show how these mechanisms extend to pathogenic variants associated with inherited human disorders. Together, our findings reveal how aberrations in mitochondrial protein synthesis can sensitize a cell to metabolic challenges associated with disease and pathogen infection independent of oxidative phosphorylation. Teaser/One-Sentence Summary Aberrations in mitochondrial translation elongation trigger activation of intracellular stress responses associated with disease and aging.

Optical metabolic imaging identifies metabolic shifts and mitochondria heterogeneity in POLG mutator macrophages

bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-15 · 1 citations

Abstract The polymerase gamma (POLG) gene mutation is associated with mitochondria and metabolism disorders, resulting in heterogeneous responses to immunological activation and posing challenges for mitochondrial disease therapy. Optical metabolic imaging captures the autofluorescent signal of two coenzymes, NADH and FAD, and offers a label-free approach to detect cellular metabolic phenotypes, track mitochondria morphology, and quantify metabolic heterogeneity. In this study, fluorescence lifetime imaging (FLIM) of NAD(P)H and FAD revealed that POLG mutator macrophages exhibit a decreased NAD(P)H lifetime, and optical redox ratio compared to the wild-type macrophages, indicating an increased dependence on glycolysis. FLIM revealed that both wild-type and POLG mutator macrophages switch to a decreased NAD(P)H τ 1 , and τ m after immune stimulation by Lipopolysaccharides (LPS). Furthermore, a bimodality index of subpopulation analysis identified heterogenous populations of POLG mutator macrophage responses under immune challenge by LPS. Moreover, to quantify the mitochondria variations in POLG mutator macrophages, a customized thresholding image processing pipeline was developed to segment mitochondria regions within each cell from the NADH image, allowing for the feature analysis of mitochondria clusters. Consequently, the wild-type macrophages exhibited a higher percentage of mitochondria-containing pixels and longer lengths of connected mitochondria, as compared with POLG mutated macrophages. Altogether, these results illustrate the potential of optical metabolic imaging for non-invasive detection and quantification of cellular metabolism, metabolic heterogeneity within cell populations, and intra-cellular mitochondria morphology differences in POLG mutator macrophages. Optical metabolic imaging will be valuable for studying POLG-mutation diseases and evaluating efficacy of potential therapies.

The metabolic basis of cancer-related fatigue

Neuroscience & Biobehavioral Reviews · 2025-01-30 · 14 citations

A shared genetic regulator of metabolism and addiction-related behavior in mice and humans

bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-24

Abstract Substance use disorders and other mental health conditions often co-occur with metabolic disorders, suggesting shared biological underpinnings 1 . These heightened behavioral and physiological responses may have evolved to promote survival during resource scarcity but can become maladaptive in modern environments 2 . The genetic mechanisms linking these traits have remained elusive. Here, we show that a variable gene enhancer in mice jointly regulates genes encoding an epigenetic factor ( Eed ) and a mitochondrial enzyme ( Me3 ) thereby influencing propensity to addiction-related behaviors and mitochondrial function. We further identify variation in a corresponding enhancer in humans regulating EED and ME3 associated with substance use, psychiatric and metabolic disorders. These findings reveal a convergent genetic regulatory network linking mitochondrial biology to behavioral and metabolic risk, offering insight into how genetic variation in beneficial regulatory pathways can predispose individuals to substance use disorders and related conditions.

Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease

Nature Communications · 2025-05-20 · 7 citations

Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBP) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive cytokine secretion and activation of pyroptotic cell death pathways contribute to lung inflammation and morbidity after infection with PA. Our work provides a mechanistic framework for understanding innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD. Mitochondrial diseases lead to chronic health impairment, aggravated by infections and other environmental exposures. Here authors show, in a mouse model of polymerase gamma (Polg)-related mitochondrial disease, that Pseudomonas aeruginosa infection prompts innate immune hyperreactivity via interferon-mediated upregulation of caspase11 and guanylate-binding proteins, leading to lung inflammation.

Necrosis drives susceptibility to <i>Mycobacterium tuberculosis</i> in Polg ^D257A mutator mice

Infection and Immunity · 2025-02-19 · 2 citations

ABSTRACT The genetic and molecular determinants that underlie the heterogeneity of Mycobacterium tuberculosis (Mtb) infection outcomes in humans are poorly understood. Multiple lines of evidence demonstrate that mitochondrial dysfunction can exacerbate mycobacterial disease severity, and mutations in some mitochondrial genes confer susceptibility to mycobacterial infection in humans. Here, we report that mutations in mitochondria DNA (mtDNA) polymerase gamma potentiate susceptibility to Mtb infection in mice. Polg D257A mutator mtDNA mice fail to mount a protective innate immune response at an early infection time point, evidenced by high bacterial burdens, reduced M1 macrophages, and excessive neutrophil infiltration in the lungs. Immunohistochemistry reveals signs of enhanced necrosis in the lungs of Mtb-infected Polg D257A mice, and Polg D257A mutator macrophages are hypersusceptible to extrinsic triggers of necroptosis ex vivo . By assigning a role for mtDNA mutations in driving necrosis during Mtb infection, this work further highlights the requirement for mitochondrial homeostasis in mounting balanced immune responses to Mtb.

Tipping the balance: innate and adaptive immunity in mitochondrial disease

Current Opinion in Immunology · 2025-05-26 · 5 citations

Mitochondrial diseases (MtD) provide a unique window into the complex interplay between metabolism and immune function. These rare disorders, caused by defects in oxidative phosphorylation, result in bioenergetic deficiencies that disrupt multiple organ systems. While traditionally studied for their metabolic impact, MtD also profoundly affect the immune system, altering both innate and adaptive responses. This review explores how mitochondrial dysfunction shapes immune dysregulation, influencing thymocyte maturation, regulatory T cells, and B cell function while also driving innate immune activation through mitochondrial DNA instability and type I interferon signaling. Additionally, MtD highlight an emerging overlap between inborn errors of metabolism and inborn errors of immunity, revealing shared pathways that connect mitochondrial dysfunction to immune deficiencies and inflammatory disease. Studying MtD not only advances our understanding of immunometabolism but also provides critical insights into more common inflammatory and autoimmune conditions, offering potential therapeutic targets that extend beyond rare mitochondrial disorders. • Mitochondrial diseases reveal links between metabolism and immune function. • Inborn errors of metabolism and immunity share pathways of immune dysregulation. • Oxidative phosphorylation defects impair thymocyte maturation and T cell responses. • Heteroplasmy influences immune cell function through purifying selection of mtDNA. • Mitochondrial DNA instability triggers innate immune activation and inflammation.

cGAS-STING dependent type I IFN protects against <i>Leptospira interrogans</i> renal colonization in mice

bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-04

Abstract Leptospira interrogans is the major causative agent of leptospirosis. Humans, canines and livestock animals are susceptible to Leptospira species and can develop fulminant disease. Rodents serve as reservoir hosts in which the bacteria colonize the renal tubules and are excreted in the urine. The host immune response to Leptospira spp. remains poorly defined. We show that L. interrogans induces a robust type I interferon (IFN) response in human and murine macrophages that is dependent on the cytosolic dsDNA sensor Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of IFN Genes (STING) signaling pathway. Further, we show that mice deficient in the IFNα/β receptor subunit 1 (IFNAR1) or STING had higher bacterial burdens and increased renal colonization following infection in vivo suggesting that cGAS-STING-driven type I IFN is required for the host defense against L. interrogans . These findings demonstrate the significance of cGAS-STING-dependent type I IFN signaling in mammalian innate immune responses to L. interrogans . Author Summary Leptospirosis is a globally distributed zoonotic disease caused by spirochetes belonging to the genus Leptospira . While humans, livestock, and dogs can develop severe or even fatal illness upon infection, rodents typically serve as asymptomatic reservoir hosts. A defining feature of the leptospiral life cycle is the ability of the pathogen to colonize the kidney in these reservoir host species, leading to prolonged urinary shedding and environmental dissemination. Despite the significant global burden of leptospirosis, the innate immune pathways that detect this pathogen and prevent renal colonization remain poorly understood. In this study we demonstrate that L. interrogans induces a robust type I IFN cytokine response from macrophages. The induction of this type I IFN response is dependent on sensing cytosolic DNA by the cGAS-STING pathway. Using in vivo mouse models of L. interrogans infection we further show that activation of this pathway is required to control bacterial burdens and reduce long-term kidney colonization. This study is the first to demonstrate a critical role for cGAS-STING and type I IFN in controlling L. interrogans infection.