bims-ainimu 2025-12-14 papers

bims-ainimu

Biomed News

on AI & infection immunometabolism

Issue of 2025–12–14
seven papers selected by
Pedro Escoll Guerrero, Institut Pasteur

Intracellular C. neoformans infection stimulates increased glycolytic activity in fetal liver-derived alveolar-like macrophages.
From Gatekeepers to Mitochondrial Mischief: How Bacterial Outer Membrane Proteins Crash the Host Cell Party.
PPARγ mediated enhanced lipid biogenesis fuels Mycobacterium tuberculosis growth in a drug-tolerant hepatocyte environment.
Host-directed insights into mycobacterial infections: Toward targeted immunomodulation.
The dual implications of iron homeostasis as a bacterial threat: its roles in virulence and antimicrobial resistance.
A surprising new hiding place for a dangerous pathogen.
Sequestration of the phagocyte metabolite itaconate by Pseudomonas aeruginosa RpoN promotes successful pulmonary infection.

bioRxiv. 2025 Dec 02. pii: 2025.11.28.690224. [Epub ahead of print]

Intracellular C. neoformans infection stimulates increased glycolytic activity in fetal liver-derived alveolar-like macrophages.

Derek A Wiggins, Josh B Griggs, Andrew M England, Emily N Callison, Cedra H Kamel, Cathrine A Hasan, Anna E Davis, Morgan E Chappell, Kayla N Conner-Halim, Andrew J Olive, Erin E McClelland, Rachel N Leander, Rebecca L Seipelt-Thiemann, David E Nelson.

Alveolar macrophages (AMs) serve as a first line of defense against respiratory pathogens, including Cryptococcus neoformans , the primary causative agent of cryptococcosis, a deadly pulmonary mycosis which commonly afflicts immunocompromised individuals. While these innate immune cells are thought to play a pivotal role in controlling the outcome of C. neoformans infections, this critical host-pathogen interaction is more commonly studied in vitro using bone marrow-derived macrophages (BMDM) or immortalized macrophage cell lines that differ in ontogeny and phenotype from AMs. In this work, we characterized fetal liver-derived alveolar-like macrophages (FLAMs) as an alternate model to study the earliest stages of C. neoformans infection. Here, we show that the FLAM steady state transcriptome is more similar to primary AMs than peritoneal macrophages and the macrophage cell lines, RAW264.7 and J774, and that FLAMs exhibit distinct transcriptional responses to IFNγ stimulation and C. neoformans infection compared to J774 cells. Specifically, transcriptome profiling and gene ontology analysis indicate that C. neoformans infection of FLAMs, but not J774 cells, increases the expression of canonical glycolytic genes, including Slc2a1, Pgk1, and Ldha , which is accompanied by a metabolic shift favoring glycolysis. Furthermore, activation or inhibition of hypoxia inducible factor 1 (HIF1) activity utilizing dimethyloxalylglycine (DMOG) and echinomycin, respectively, indicates that the expression of select glycolytic genes in C. neoformans -infected FLAMs is HIF1-dependent. Collectively, our results suggest that FLAMs serve as an appropriate tool for modeling AM: C. neoformans interactions and investigating the effects of this pathogen on host AM immunometabolism.

DOI: https://doi.org/10.1101/2025.11.28.690224
FEMS Microbiol Rev. 2025 Dec 12. pii: fuaf062. [Epub ahead of print]

From Gatekeepers to Mitochondrial Mischief: How Bacterial Outer Membrane Proteins Crash the Host Cell Party.

Paloma Osset-Trenor, Markus Proft, Amparo Pascual-Ahuir.

  Gram-negative bacteria are equipped with a unique cell envelope structure that includes an outer membrane populated by diverse outer membrane proteins (OMPs). These OMPs are not only essential for bacterial survival, mediating critical functions such as nutrient transport, antibiotic resistance, and structural integrity, but they also play pivotal roles as virulence factors during host-pathogen interactions. Recent research highlights the ability of OMPs to manipulate host cellular processes, often targeting mitochondria to induce cell death or modulate immune responses. This review explores the multifunctional roles of bacterial OMPs, emphasizing their structural features, biogenesis, and pathogenic mechanisms. Furthermore, it delves into how bacterial OMPs exploit host cell machinery, particularly mitochondria, to promote infection, as well as their potential as targets for innovative antimicrobial strategies. Specifically, this review focuses on β-barrel OMPs that reach host mitochondria, detailing their delivery routes and mechanisms of organelle manipulation, while excluding non-β-barrel toxins and secretion-system effectors, to provide a defined perspective on mitochondria-targeting OMP virulence mechanisms.

Keywords:  Apoptosis; Bacterial virulence; Mitochondrial subversion; Outer membrane proteins; Outer membrane vesicles; β-barrel proteins

DOI:  https://doi.org/10.1093/femsre/fuaf062
Elife. 2025 Dec 08. pii: RP103817. [Epub ahead of print]14

PPARγ mediated enhanced lipid biogenesis fuels Mycobacterium tuberculosis growth in a drug-tolerant hepatocyte environment.

Binayak Sarkar, Jyotsna Singh, Mohit Yadav, Priya Sharma, Raman Deep Sharma, Shweta Singh, Aakash Chandramouli, Kritee Mehdiratta, Ashwani Kumar, Siddhesh S Kamat, Devram S Ghorpade, Debasisa Mohanty, Dhiraj Kumar, Rajesh S Gokhale.

  Mycobacterium tuberculosis (Mtb) infection of the lungs, besides producing prolonged cough with mucus, also causes progressive fatigue and cachexia with debilitating loss of muscle mass. While anti-tuberculosis (TB) drug therapy is directed toward eliminating bacilli, the treatment regimen ignores the systemic pathogenic derailments that probably dictate TB-associated mortality and morbidity. Presently, it is not understood whether Mtb spreads to metabolic organs and brings about these impairments. Here, we show that Mtb creates a replication-conducive milieu of lipid droplets in hepatocytes by upregulating transcription factor PPARγ and scavenging lipids from the host cells. In hepatocytes, Mtb shields itself against the common anti-TB drugs by inducing drug-metabolizing enzymes. Infection of the hepatocytes in the in vivo aerosol mice model can be consistently observed post-week, 4 along with enhanced expression of PPARγ and drug-metabolizing enzymes. Moreover, histopathological analysis indeed shows the presence of Mtb in hepatocytes along with granuloma-like structures in human biopsied liver sections. Hepatotropism of Mtb during the chronic infectious cycle results in immuno-metabolic dysregulation that could magnify local and systemic pathogenicity, altering clinical presentations.

Keywords:  Mycobacterium tuberculosis; human; infectious disease; microbiology; mouse

DOI:  https://doi.org/10.7554/eLife.103817
Microb Pathog. 2025 Dec 08. pii: S0882-4010(25)00958-1. [Epub ahead of print]211 108233

Host-directed insights into mycobacterial infections: Toward targeted immunomodulation.

Arjun M Menon, Abhinand Kuniyil, Shwetha Susan Thomas, S Salini, Lekshmi K Edison, P C Parvathi Mohanan, K B Arun, Pradeesh Babu, Geetha B Kumar, Bipin G Nair, Aravind Madhavan.

Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a significant worldwide health threat, especially in resource-limited environments. This review emphasizes that manipulating host metabolic and epigenetic pathways can bolster immune defences and potentially shorten the duration of tuberculosis treatment. The growing prevalence of multidrug-resistant TB and the protracted nature of standard treatments underscore the urgent need for alternative therapeutic approaches. Host-directed treatment has arisen as a promising approach that aims to enhance or redirect the host's innate and adaptive responses rather than targeting the pathogen directly. This strategy focuses on counteracting M. tuberculosis-induced subversion of immune and cellular processes. Approaches under investigation include modulation of host metabolic pathways, stimulation of autophagy, epigenetic reprogramming, and strengthening of immune defense mechanisms to control or eliminate infection. These interventions hold potential for not only overcoming traditional drug resistance but also for accelerating recovery and reducing immunopathology. In this review, we explore recent advances in host-directed therapy research, with particular emphasis on mechanisms involving immunometabolic regulation, epigenetic remodeling, and enhancement of intercellular antimicrobial responses. The advancement of these methodologies may facilitate the creation of more accurate and efficacious tuberculosis treatments. We highlight recent work on three linked areas-immunometabolic regulation, epigenetic control, and autophagy driven antimicrobial activity drawing out the main advances and remaining debates that guide future host-directed approaches. Viewing host-directed therapy through this integrated lens outline a path toward more targeted, durable, and resistance-resilient interventions for tuberculosis.

DOI: https://doi.org/10.1016/j.micpath.2025.108233
Arch Microbiol. 2025 Dec 09. 208(1): 51

The dual implications of iron homeostasis as a bacterial threat: its roles in virulence and antimicrobial resistance.

Naveenraj Rajasekar, Vijaya Bharathi Srinivasan, Karthikeyan Krishnan, Chankit Giri, Mahesh Kumar, Balvinder Singh, Govindan Rajamohan.

  Antimicrobial resistance (AMR) is a global health concern that requires innovative therapeutic strategies to improve clinical outcomes. Bacterial priority pathogens have developed multiple mechanisms for AMR. To develop therapeutics to overcome AMR, it is essential to explore, understand, and identify effective molecular targets. Iron is crucial for survival and pathogenesis in bacterial physiology. Reports indicate that iron supports vital cellular functions and modulates bacterial virulence and pathogenicity. Due to the bacterial requirement for iron during infection, antimicrobials are being developed by targeting iron homeostasis pathways in pathogens. In this review, we explore the virulence, AMR, and iron homeostatic mechanisms in bacterial pathogens, as well as the functional role of iron in regulating virulence, antimicrobial resistance, and other aspects of bacterial physiology, to elucidate potential therapeutic strategies against drug-resistant pathogens. This review briefly discusses therapeutic interventions based on iron homeostasis mechanisms and the associated translational challenges.

Keywords:  Antimicrobial resistance; Critical pathogen; Iron regulation; Virulence

DOI:  https://doi.org/10.1007/s00203-025-04594-8
Elife. 2025 Dec 08. pii: e109706. [Epub ahead of print]14

A surprising new hiding place for a dangerous pathogen.

Sheetal Gandotra, Yogendra Singh.

  The bacterium that causes TB can hide in liver cells called hepatocytes, and reprogram their metabolism for its own benefit.

Keywords:  Mycobacterium tuberculosis; hepatocytes; human; infectious disease; metabolism; microbiology; mouse; tuberculosis

DOI:  https://doi.org/10.7554/eLife.109706
Nat Commun. 2025 Dec 13.

Sequestration of the phagocyte metabolite itaconate by Pseudomonas aeruginosa RpoN promotes successful pulmonary infection.

Ayesha Z Beg, Zihua Liu, Ying-Tsun Chen, Absar Talat, Griffin Gowdy, Jake Miller, Lindsey Florek, Lars Dietrich, Chu Wang, Ian Lewis, Tania Wong Fok Lung, Sebastian Riquelme, Alice Prince.

Inhaled opportunistic pathogens such as Pseudomonas aeruginosa actively modify gene expression to meet the challenges of a new environment. In the infected airway the bacteria must respond to the immunometabolite itaconate, which is abundantly produced by macrophages and has anti-inflammatory and anti-oxidant functions that protect the host from airway damage and causes toxicity to bacteria. As a dicarboxylate that targets cysteine residues, itaconate can modify both bacterial and host proteins often altering metabolic activity. We demonstrate that itaconate promotes a global metabolic response in P. aeruginosa by enhancing the activity of the major alternative transcription factor RpoN. Itaconate is actively transported into the bacteria, induces σ54 rpoN expression and covalently binds cysteine residues 218 and 275 on RpoN helping to neutralize its toxicity. The S-itaconated RpoN exhibits a gain of function driving increased glucose catabolism and enhanced utilization of the bioenergetically efficient Entner-Doudoroff pathway. Thus, the accumulation of itaconate in the infected airway promotes the adaptation of P. aeruginosa to the lung by optimizing its metabolic activity and ability to cause pneumonia.

DOI: https://doi.org/10.1038/s41467-025-67153-1