Disruption of glucose homeostasis by bacterial infection orchestrates host innate immunity through NAD+/NADH balance.

Metabolic reprogramming is crucial for activating innate immunity in macrophages, and the accumulation of immunometabolites is essential for effective defense against infection. The NAD+/NADH (ratio of nicotinamide adenine dinucleotide and its reduced counterpart) redox couple serves as a critical node that integrates metabolic pathways and signaling events, but how this metabolite couple engages macrophage activation remains unclear. Here, we show that the NAD+/NADH ratio serves as a molecular signal that regulates proinflammatory responses and type I interferon (IFN) responses divergently. Salmonella Typhimurium infection leads to a decreased NAD+/NADH ratio by inducing the accumulation of NADH. Further investigation shows that an increased NAD+/NADH ratio correlates with attenuated proinflammatory responses and enhanced type I IFN responses. Conversely, a decreased NAD+/NADH ratio is linked to intensified proinflammatory responses and restrained type I IFN responses. These results show that the NAD+/NADH ratio is an essential cell-intrinsic factor that orchestrates innate immunity, which enhances our understanding of how metabolites fine-tune innate immunity.

Immunometabolites in viral infections: Action mechanism and function.

The interplay between viral pathogens and host metabolism plays a pivotal role in determining the outcome of viral infections. Upon viral detection, the metabolic landscape of the host cell undergoes significant changes, shifting from oxidative respiration via the tricarboxylic acid (TCA) cycle to increased aerobic glycolysis. This metabolic shift is accompanied by elevated nutrient accessibility, which is vital for cell function, development, and proliferation. Furthermore, depositing metabolites derived from fatty acids, TCA intermediates, and amino acid catabolism accelerates the immunometabolic transition, facilitating pro-inflammatory and antimicrobial responses. Immunometabolites refer to small molecules involved in cellular metabolism regulating the immune response. These molecules include nutrients, such as glucose and amino acids, along with metabolic intermediates and signaling molecules adenosine, lactate, itaconate, succinate, kynurenine, and prostaglandins. Emerging evidence suggests that immunometabolites released by immune cells establish a complex interaction network within local niches, orchestrating and fine-tuning immune responses during viral diseases. However, our current understanding of the immense capacity of metabolites to convey essential cell signals from one cell to another or within cellular compartments remains incomplete. Unraveling these complexities would be crucial for harnessing the potential of immunometabolites in therapeutic interventions. In this review, we discuss specific immunometabolites and their mechanisms of action in viral infections, emphasizing recent findings and future directions in this rapidly evolving field.

Spermidine - an old molecule with a new age-defying immune function.

Polyamines - putrescine, spermidine, and spermine - are widely distributed aliphatic compounds known to regulate important biological processes in prokaryotic and eukaryotic cells. Therefore, spermidine insufficiency is associated with various physio-pathological processes, such as aging and cancers. Recent advances in immuno-metabolism and immunotherapy shed new light on the role of spermidine in immune cell regulation and anticancer responses. Here, we review novel works demonstrating that spermidine is produced by collective metabolic pathways of gut bacteria, bacteria-host co-metabolism, and by the host cells, including activated immune cells. We highlight the effectiveness of spermidine in enhancing antitumor responses in aged animals otherwise nonresponsive to immune checkpoint therapy and propose that spermidine supplementation could be used to enhance the efficacy of anti-PD-1 treatment.

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development.

Despite meritorious attempts, a S. aureus vaccine that prevents infection or mitigates severity has not yet achieved efficacy endpoints in prospective, randomized clinical trials. This experience underscores the complexity of host-S. aureus interactions, which appear to be greater than many other bacterial pathogens against which successful vaccines have been developed. It is increasingly evident that S. aureus employs strategic countermeasures to evade or exploit human immune responses. From entering host cells to persist in stealthy intracellular reservoirs, to sensing the environmental milieu and leveraging bacterial or host metabolic products to reprogram host immune responses, S. aureus poses considerable challenges for the development of effective vaccines. The fact that this pathogen causes distinct types of infections and can undergo transient genetic, transcriptional or metabolic adaptations in vivo that do not occur in vitro compounds challenges in vaccine development. Notably, the metabolic versatility of both bacterial and host immune cells as they compete for available substrates within specific tissues inevitably impacts the variable repertoire of gene products that may or may not be vaccine antigens. In this respect, S. aureus has chameleon phenotypes that have alluded vaccine strategies thus far. Nonetheless, a number of recent studies have also revealed important new insights into pathogenesis vulnerabilities of S. aureus. A more detailed understanding of host protective immune defenses versus S. aureus adaptive immune evasion mechanisms may offer breakthroughs in the development of effective vaccines, but at present this goal remains a very high bar. Coupled with the recent advances in human genetics and epigenetics, newer vaccine technologies may enable such a goal. If so, future vaccines that protect against or mitigate the severity of S. aureus infections are likely to emerge at the intersection of precision and personalized medicine. For now, the development of S. aureus vaccines or alternative therapies that reduce mortality and morbidity must continue to be pursued.

Immunometabolism Modulation in Therapy.

The study of cancer biology should be based around a comprehensive vision of the entire tumor ecosystem, considering the functional, bioenergetic and metabolic state of tumor cells and those of their microenvironment, and placing particular importance on immune system cells. Enhanced understanding of the molecular bases that give rise to alterations of pathways related to tumor development can open up new therapeutic intervention opportunities, such as metabolic regulation applied to immunotherapy. This review outlines the role of various oncometabolites and immunometabolites, such as TCA intermediates, in shaping pro/anti-inflammatory activity of immune cells such as MDSCs, T lymphocytes, TAMs and DCs in cancer. We also discuss the extraordinary plasticity of the immune response and its implication in immunotherapy efficacy, and highlight different therapeutic intervention possibilities based on controlling the balanced systems of specific metabolites with antagonistic functions.

Haemophilus influenzae Glucose Catabolism Leading to Production of the Immunometabolite Acetate Has a Key Contribution to the Host Airway-Pathogen Interplay.

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and impaired airway immunity, which provides an opportunistic platform for nontypeable Haemophilus influenzae (NTHi) infection. Clinical evidence supports that the COPD airways present increased concentrations of glucose, which may facilitate proliferation of pathogenic bacteria able to use glucose as a carbon source. NTHi metabolizes glucose through respiration-assisted fermentation, leading to the excretion of acetate, formate, and succinate. We hypothesized that such specialized glucose catabolism may be a pathoadaptive trait playing a pivotal role in the NTHi airway infection. To find out whether this is true, we engineered and characterized bacterial mutant strains impaired to produce acetate, formate, or succinate by inactivating the ackA, pflA, and frdA genes, respectively. While the inactivation of the pflA and frdA genes only had minimal physiological effects, the inactivation of the ackA gene affected acetate production and led to reduced bacterial growth, production of lactate under low oxygen tension, and bacterial attenuation in vivo. Moreover, bacterially produced acetate was able to stimulate the expression of inflammatory genes by cultured airway epithelial cells. These results back the notion that the COPD lung supports NTHi growth on glucose, enabling production of fermentative end products acting as immunometabolites at the site of infection. Thus, glucose catabolism may contribute not only to NTHi growth but also to bacterially driven airway inflammation. This information has important implications for developing nonantibiotic antimicrobials, given that airway glucose homeostasis modifying drugs could help prevent microbial infections associated with chronic lung disease.

A readily 16O-/18O-isotopically-paired chiral derivatization approach for the quantification of 2-HG metabolic panel by liquid chromatography-Tandem mass spectrometry.

With the rapid development of immunometabolism, 2-hydroxyglutarate (2-HG) is being promoted as a key immunometabolite to regulate the immune system. Based on the well-established crosstalk between 2-HG and other immunometabolites, here we firstly constructed a 2-HG metabolic panel by mapping the related metabolic pathways. Quantitative methods to globally monitor 2-HG metabolic panel are of great importance for immunometabolism study. However, the existence of enantiomer hampers the accurate measurement of these immunometabolites. This study addressed an original isotopically-paired chiral derivatization approach for UPLC-MS/MS quantification of 2-HG metabolic panel. To achieve better chromatographic separation, N-(p-toluenesulfonyl)-L-phenylalanyl chloride (TSPC) was utilized as an optical resolving reagent to form diastereomers. For accurate quantitation, an 18O2-labeled-TSPC reagent was designed and readily synthesized to produce one-to-one internal standards. The developed approach enabled an accurate quantification of 13 immunometabolites in 2-HG metabolic panel with good linearity (R2 > 0.99) and high sensitivity (0.5-120 fmol for LLOQ). With this method, we were able to simultaneously monitor the specific alterations of 2-HG metabolic panel in collagen-induced rheumatoid arthritis (CIA) rats. The measured levels of this panel ranged from 0.02 to 85.14 µg g-1 for synovium tissue and 0.012 to 87.75 µmol L-1 for serum samples. We envisage that the present isotopically-paired chiral derivatization approach will be practicable for different bio-samples to quantitatively profile the amino- and hydroxyl acids submetabolome, especially for the endogenous enantiomers. By virtue of the low cost of reagents and the simple procedure used in the assay, this method could be readily implemented.