bims-ainimu 2025-11-09 papers

bims-ainimu

Biomed News

on AI & infection immunometabolism

Issue of 2025–11–09
nine papers selected by
Pedro Escoll Guerrero, Institut Pasteur

Intracellular Salmonella hijacks the mitochondrial citrate carrier to evade host oxidative defenses.
Metabolic reprogramming of immune cells in the battle against intracellular bacterial chronic infections: novel mechanisms and breakthroughs.
NLRP3 is crucial for macrophage metabolic reprogramming during Vibrio vulnificus infection.
Glucose Metabolic Reprogramming of Macrophages Against Mycobacterium tuberculosis Infection.
"Gut microbiome-mediated nutrients alter opportunistic bacterial growth in peritonitis".
Mitoxantrone elicits ROS-dependent elimination of dysfunctional mitochondria through mitophagy to control viability of intracellular mycobacteria in human macrophages.
Porcine reproductive and respiratory syndrome virus activates the pentose phosphate pathway via the ROS/HIF-1α/G6PD axis to promote viral replication.
Regulation of mitochondria functions by Mycobacterium tuberculosis infection.
A Single-Cell Methodology for Energy Metabolism Analysis in Parasitic Protozoa.

Nat Commun. 2025 Nov 06. 16(1): 9806

Intracellular Salmonella hijacks the mitochondrial citrate carrier to evade host oxidative defenses.

Chieh-Hua Fu, Yu-Ting Hsu, Shao-Chun Hsu, Nai-Shu Chen, Hsueh-Wen Hu, Ting-Yin Wu, Yi-Jou Huang, Ying-Chu Chen, An-Chi Luo, Yu-Tsung Huang, Shu-Jung Chang.

Intracellular vacuolar pathogens replicate within membrane-bound compartments known as pathogen-containing vacuoles (PCVs). Maintaining the integrity of these vacuoles is essential for creating a permissive niche that supports pathogen survival and proliferation. In this study, we show that Salmonella enterica serovar Typhimurium co-opts the host mitochondrial citrate carrier (CIC) to promote its intracellular replication by detoxifying the Salmonella-containing vacuole (SCV). Loss of CIC significantly impairs Salmonella growth within host cells, as CIC recruitment to SCVs regulates local citrate levels and mitigates the production of reactive oxygen species (ROS), thereby reducing oxidative stress. Mechanistically, we identify the SPI-2 effector SseF as a critical factor that interacts with CIC and the GTPase RAB7, enabling CIC recruitment to the SCV membrane. These findings reveal a previously unrecognized strategy by which an intracellular pathogen hijacks a mitochondrial metabolite transporter to modulate the vacuolar environment and evade host antimicrobial defenses. Notably, pharmacological inhibition of CIC sensitizes Salmonella to host immune pressures, highlighting CIC as a potential target for host-directed antimicrobial therapy.

DOI: https://doi.org/10.1038/s41467-025-64779-z
Mol Biol Rep. 2025 Nov 01. 53(1): 37

Metabolic reprogramming of immune cells in the battle against intracellular bacterial chronic infections: novel mechanisms and breakthroughs.

Rongrong Jiang, Xiao Liu, Fangtao Xing, Yurong Fu, Zhengjun Yi.

  Chronic intracellular bacterial infections persist within host cells by evading immune clearance, imposing prolonged metabolic stress on the host. In response, the immune system undergoes metabolic reprogramming to sustain prolonged defense. A key feature of this reprogramming is the shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, which enhances pro-inflammatory and antimicrobial responses. Concurrently, fatty acid and amino acid catabolism provide additional metabolic support. Beyond shaping immune function, these metabolic shifts also influence the trajectory of infection by altering the host-pathogen metabolic interplay. In this review, we focus primarily on Mycobacterium tuberculosis (Mtb) infection and integrate quantitative flux analyses of carbon and nitrogen distribution, emphasizing how these metabolic changes connect to epigenetic regulation. We also explore metabolic reprogramming in five representative immune cell types-comprising both innate and adaptive immune cells-to elucidate how their distinct metabolic profiles influence host defense mechanisms and disease progression. Building on these foundations, we propose an innovative metabolic competition model between host and pathogen, offering new insights into the intricate interplay of metabolic networks in chronic intracellular infections.

Keywords:  Immune cells; Infection; Intracellular bacterial; Metabolic reprogramming

DOI:  https://doi.org/10.1007/s11033-025-11218-3
Microbiol Spectr. 2025 Nov 05. e0023025

NLRP3 is crucial for macrophage metabolic reprogramming during Vibrio vulnificus infection.

Ye-Lin Jiang, Xian-Hui Huang, Wen-Hui Zhu, Si-Qi Wei, Jing-Jing Li, Hao-Nan Lin, Huang-Kai Bian, Chen-Lin Wu, Xin-Jun Miao, Yong-Liang Lou, Lu Tang, Dan-Li Xie.

  Vibrio vulnificus is notorious for inducing rapidly progressive infections with high lethality and significant morbidity. Macrophages, being essential components of the innate immune system, play a vital role in combating infections, and their activation and effector functions are closely intertwined with metabolic reprogramming processes. However, the mechanisms governing macrophage glycolytic metabolism in response to V. vulnificus infection remain poorly elucidated. Based on our current data, we propose that NOD-like receptor 3 (NLRP3) could potentially contribute to the regulation of glycolytic metabolism in macrophages infected with V. vulnificus, though further validation is needed to confirm this relationship in both in vivo and in vitro. Upon V. vulnificus infection, NLRP3 was shown to augment glucose uptake, upregulate the aerobic glycolytic pathway, facilitate lactate release, and enhance reactive oxygen species (ROS) production. Notably, these metabolic alterations were abolished in NLRP3 knockout (KO) macrophages, as observed in both NLRP3-deficient macrophage cell lines and primary cells. We also found that the abundances of fructose 1,6-bisphosphate and 3-phosphoglyceric acid in glycolytic metabolism were decreased in V. vulnificus-infected NLRP3 KO macrophages by non-targeted metabolic flux analysis, which might be due to the reduction of PFKL that converts fructose 6-phosphate to fructose 1,6-bisphosphate in V. vulnificus-infected NLRP3 KO macrophage. These findings suggest that NLRP3 may promote inflammation in macrophages during V. vulnificus infection by driving glycolysis and increasing ROS production. The absence of these metabolic changes in NLRP3 KO macrophages underlines the crucial role of NLRP3 in modulating the immunometabolic response to V. vulnificus infection.IMPORTANCEThe results of this study demonstrate that NOD-like receptor 3 (NLRP3) is critical for metabolic reprogramming in macrophages during Vibrio vulnificus infection. NLRP3 enhances glucose uptake, upregulates glycolysis, reprograms metabolic flux, and promotes reactive oxygen species production. These findings are significant, as they reveal a previously unrecognized role of NLRP3 in regulating immune function in V. vulnificus-infected macrophages. This study identifies NLRP3 as a central mediator linking immune cell metabolism to defense against infections, providing novel insights into how innate immunity controls pathogenic bacteria and suggesting potential strategies for improving treatment or prevention of severe infections. However, further research is required to fully elucidate its impact on macrophage glycolysis in V. vulnificus-induced sepsis.

Keywords:  NLRP3; Vibrio vulnificus; glycolysis; macrophage; metabolism; single-cell sequencing

DOI:  https://doi.org/10.1128/spectrum.00230-25
Immunotargets Ther. 2025 ;14 1209-1221

Glucose Metabolic Reprogramming of Macrophages Against Mycobacterium tuberculosis Infection.

Tianhui Liu, Zeliang Yang, Jing Tong, Mengqiu Gao, Yu Pang.

  Tuberculosis (TB) is a global infectious disease caused by Mycobacterium tuberculosis (Mtb). Serving as the primary effector cells, macrophages play a crucial role in host immune responses against Mtb. During Mtb infection, macrophages undergo extensive metabolic reprogramming, notably glycolysis, the pentose phosphate pathway (PPP) and the tricarboxylic acid (TCA) cycle, to adapt to the challenges posed by the pathogen, with glucose metabolic rewiring being particularly critical. This review focuses on the dynamic reprogramming of glucose metabolism in macrophages during Mtb infection, highlighting how metabolic adjustments influence the activation state, polarization, and functional capacity of macrophages. Furthermore, we explore the role of glucose metabolic reprogramming in shaping the immune responses against Mtb, particularly its contribution to granuloma formation and maintenance. By understanding the intricate interplay between metabolic rewiring and immune function, we discuss the therapeutic potential of targeting glucose metabolic pathways in macrophages as a novel strategy for TB treatment. Overall, this review emphasizes the need for a deeper understanding of the relationship between glucose metabolism reprogramming and the biological function of Mtb-infected macrophages and the development of novel immunometabolic therapies-such as metformin (AMPK activator) or PKM2 modulators already used in oncology- to improve the outcomes of TB patients.

Keywords:  Mycobacterium tuberculosis; glucose metabolic reprogramming; macrophages

DOI:  https://doi.org/10.2147/ITT.S552746
Am J Physiol Gastrointest Liver Physiol. 2025 Nov 05.

"Gut microbiome-mediated nutrients alter opportunistic bacterial growth in peritonitis".

Kale S Bongers, Thomas L Flott, Larisa Yeomans, Lilian Maynard, Mark D Adame, Nicole R Falkowski, Roderick A McDonald, Annastasia Petouhoff, Jennifer M Baker, Michael McLellan, Lauren L Aragones, JaKyla Kaniaru, Benjamin H Singer, Robert P Dickson, Kathleen A Stringer.

  Peritonitis is a well-known complication of bowel perforation and abdominal surgery, leading to sepsis and high mortality. Despite its prevalence and severity, the pathogenesis of peritonitis remains incompletely understood, limiting our ability to develop targeted medical therapies. Specifically, little is known about the determinants of the peritoneal nutrient environment for pathogens. The gut microbiome is a well-established source of infectious bacteria in peritonitis, but whether it also modulates levels of nutrients that enable and sustain these infections remains unknown. Using multiple murine models of peritonitis (lipopolysaccharide, cecal slurry), multiple methods of microbiome modulation (germ-free mice and antibiotic-treated mice), novel ex vivo modeling of peritonitis, and nuclear magnetic resonance (NMR) metabolomics of the peritoneal microenvironment, we performed a series of experiments to determine how the gut microbiome influences peritoneal metabolite concentration during peritonitis. We found that both lipopolysaccharide and cecal slurry peritonitis caused consistent changes in high-abundance peritoneal metabolites, and that many of these changes were blunted or completely abrogated in antibiotic-treated and germ-free mice. Moreover, we found that peritoneal washings from septic, microbiome-depleted animals supported less bacterial growth of common intra abdominal pathogens compared to washings from septic conventional animals. We identified the peritoneal nutrients consumed by two common pathogens from the Enterobacteriaceae family, and found that supplementation of gut microbiome-mediated nutrients was sufficient to alter bacterial growth in an ex vivo model. Taken together, we identify the gut microbiome as a key driver of the peritoneal nutrient environment, mediating pathogen growth. These findings suggest microbiome-targeted therapies could mitigate peritonitis risk.

Keywords:  critical illness; metabolomics; microbiome; peritonitis; sepsis

DOI:  https://doi.org/10.1152/ajpgi.00132.2025
Biochem Pharmacol. 2025 Nov 02. pii: S0006-2952(25)00777-4. [Epub ahead of print]243(Pt 1): 117512

Mitoxantrone elicits ROS-dependent elimination of dysfunctional mitochondria through mitophagy to control viability of intracellular mycobacteria in human macrophages.

Mousumi Das, Dev Kiran Nayak, Salina Patel, Ashish Kumar, Mustafeez Ali Quaderi, Pramathesh Kumar Dandsena, Lincoln Naik, Abtar Mishra, Amit Mishra, Ramandeep Singh, Sujit Kumar Bhutia, Assirbad Behura, Rohan Dhiman.

  Autophagy plays a critical role in clearance of Mycobacterium tuberculosis. It has emerged as a promising target for host-directed therapies against drug-resistant tuberculosis (TB). This insight opens up promising therapeutic avenues, suggesting that pharmacological activation of autophagy could effectively combat this highly persistent and harmful bacterium. The current study investigates the anti-mycobacterial properties of the anthracene-dione compound Mitoxantrone (MTX) through the activation of autophagy in differentiated THP-1 cells. The non-cytotoxic dose of MTX reduced the intracellular viability of mycobacteria compared to the control cells, and inhibition of autophagy reversed the effect of MTX on intracellular bacterial burden. Through multiparametric approaches, our investigation established the effect of MTX on mitochondria, the principal source of endogenous reactive oxygen species (ROS), acting as essential signal transducers that promote autophagy. Further, we have demonstrated that MTX decreased ATP production, which caused disruption of mitochondrial membrane proteins and increased mitochondrial ROS generation, resulting in mitochondrial fission and accelerating the initiation of mitophagy, leading to the elimination of intracellular mycobacteria. Our findings collectively demonstrated that MTX-induced mitochondrial dysfunction triggered interplay between two selective autophagic responses, diminishing mycobacterial infection and promoting its clearance. This study highlights MTX as a potential host-directed therapeutic candidate against TB through modulation of mitochondrial signaling pathways and autophagic responses.

Keywords:  Autophagy; Mitochondria; Mitophagy; Mitoxantrone; Mycobacteria

DOI:  https://doi.org/10.1016/j.bcp.2025.117512
Virulence. 2025 Dec;16(1): 2585639

Porcine reproductive and respiratory syndrome virus activates the pentose phosphate pathway via the ROS/HIF-1α/G6PD axis to promote viral replication.

Ying-Xian Ma, Jia-Ming Yang, Hang-Tian Mei, Lei Zeng, Guo-Yu Yang, Jiang Wang, Sheng-Li Ming, Bei-Bei Chu.

  Porcine reproductive and respiratory syndrome virus (PRRSV), a highly contagious pathogen in swine, poses significant economic challenges to global pork production. This study elucidated the regulatory interplay between PRRSV infection and the pentose phosphate pathway (PPP), a critical metabolic axis for anabolism. Comparative metabolomic profiling of porcine alveolar macrophages (PAMs) pre- and post-PRRSV infection demonstrated marked upregulation of PPP activity, concomitant with elevated levels of nucleotide biosynthesis. This metabolic shift was driven by PRRSV-induced upregulation of glucose-6-phosphate dehydrogenase (G6PD), the PPP's rate-limiting enzyme. Mechanistic investigations revealed that PRRSV infection stimulated hypoxia-inducible factor 1α (HIF-1α) expression, which transcriptionally activates G6PD. Genetic silencing of HIF-1α abolished PRRSV-mediated G6PD induction. Furthermore, reactive oxygen species (ROS) accumulation was identified as the upstream regulator of HIF-1α activation during PRRSV infection. Pharmacological ROS scavenging disrupted the ROS/HIF-1α/G6PD signaling cascade, diminished NADPH and reduced glutathione production, and consequently attenuated viral proliferation. These results established that PRRSV exploited the ROS/HIF-1α axis to reprogram host glucose metabolism through PPP potentiation, creating a biosynthetic environment conducive to viral propagation.

Keywords:  G6PD; HIF-1α; PPP; PRRSV; ROS

DOI:  https://doi.org/10.1080/21505594.2025.2585639
Future Microbiol. 2025 Nov 04. 1-10

Regulation of mitochondria functions by Mycobacterium tuberculosis infection.

Jing Wang, Caixing Cao, Jiale Hua, Yahui Zhang, Changxin Wu, Li Xing.

  Tuberculosis, a leading killer among infectious diseases worldwide, is caused by Mycobacterium tuberculosis (Mtb). Mtb has strong ability to manipulate the intracellular environment of macrophages for successful surviving. Mitochondrion is a key organelle involved in diverse physiological processes, including Ca2+ fluxes, ATP synthesis, bioenergetic metabolism, and cell death, which are pivotal to cellular and organismal homeostasis. Mitochondrion is also targeted by Mtb to control various physiological responses of the host. Mtb has evolved a series of strategies to manipulate mitochondrial functions in favor of their survival, replication, and dissemination. In mitochondrion, Mtb regulates cell energy metabolism and cell death pathway. Herein, we reviewed the latest advances in the interactions between Mtb and mitochondria and discussed multiple aspects of the influence of Mtb on mitochondrial metabolism to shed light on the Mtb-induced pathogenesis.

Keywords:  Mycobacterium tuberculosis; Tuberculosis; cell death pathway; energy metabolism; mitochondria

DOI:  https://doi.org/10.1080/17460913.2025.2582374
Methods Mol Biol. 2026 ;2982 339-351

A Single-Cell Methodology for Energy Metabolism Analysis in Parasitic Protozoa.

Salomé C Vilchez-Larrea, Rafael J Argüello, Guillermo D Alonso.

  The metabolic adaptability of Trypanosoma cruzi, the causative agent of Chagas disease, and other trypanosomatids across their life cycle stages is a defining feature of their biology and pathogenicity. Studying parasite and host cell metabolic profiles during infections is crucial to understanding disease progression and developing targeted therapeutic interventions. Traditionally, researchers have faced limitations in effectively capturing the dynamic nature of metabolic shifts in real time, hindering our ability to unravel the complex interplay between the host and the pathogen. Approaching these questions requires a high-throughput technique capable of assessing the metabolic changes and preferences of both the parasite and the host cell under physiological conditions in infected cells and tissues. A novel analytical technique that promises to push forward our understanding of metabolic profiles during Trypanosoma cruzi infections has now been developed. Here, we describe the potential to exploit the Single-Cell Energetic Metabolism by Profiling Translation Inhibition (SCENITH™) to examine the energetic metabolism of T. cruzi during its distinct developmental stages-epimastigote, trypomastigote, and amastigote-allowing to unveil the metabolic shifts that underpin their survival and proliferation in diverse host environments. Additionally, SCENITH allows to study how infected host cells' metabolism changes in the presence of parasites. The variability in metabolic pathways offers a unique perspective for identifying and developing stage-specific drug targets, presenting opportunities for more effective therapeutic interventions.

Keywords:  Flow Cytometry; Host–Parasite interaction; Metabolic profile; SCENITH; Trypanosoma cruzi

DOI:  https://doi.org/10.1007/978-1-0716-4848-3_22