bims-imicid 2024-09-22 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–09–22
fiveteen papers selected by
Dylan Ryan, University of Cambridge

Taurolithocholic acid protects against viral haemorrhagic fever via inhibition of ferroptosis.
Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation.
Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.
Integrated metabolic-transcriptomic network identifies immunometabolic modulations in human macrophages.
Gut microbiota-derived butyrate improved acute leptospirosis in hamster via promoting macrophage ROS mediated by HDAC3 inhibition.
TGFβ primes alveolar-like macrophages to induce type I IFN following TLR2 activation.
Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line.
Imaging immunometabolism in situ in live animals.
Breast cancer cell derived exosomes reduces glycolysis of activated CD8 + T cells in a AKT-mTOR dependent manner.
Activation induces shift in nutrient utilization that differentially impacts cell functions in human neutrophils.
Click-chemistry-based protocol for detecting 4-octyl-itaconate-alkylated proteins in primary mouse macrophages.
In situ chemoproteomic profiling reveals itaconate inhibits de novo purine biosynthesis in pathogens.
The gut microbiota and its metabolite butyrate shape metabolism and antiviral immunity along the gut-lung axis in the chicken.
VSV infection and LPS treatment alter serum bile acid profiles, bile acid biosynthesis, and bile acid receptors in mice.
Serum metabolomics profile identifies patients with community-acquired pneumonia infected by bacteria, fungi, and viruses.

Nat Microbiol. 2024 Sep 18.

Taurolithocholic acid protects against viral haemorrhagic fever via inhibition of ferroptosis.

Xiaojie Zheng, Yunfa Zhang, Lingyu Zhang, Tong Yang, Faxue Zhang, Xi Wang, Shu Jeffrey Zhu, Ning Cui, Hongdi Lv, Xiaoai Zhang, Hao Li, Wei Liu.

Bile acids are microbial metabolites that can impact infection of enteric and hepatitis viruses, but their functions during systemic viral infection remain unclear. Here we show that elevated levels of the secondary bile acid taurolithocholic acid (TLCA) are associated with reduced fatality rates and suppressed viraemia in patients infected with severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne haemorrhagic fever virus. TLCA inhibits viral replication and mitigates host inflammation during SFTSV infection in vitro, and indirectly suppresses SFTSV-mediated induction of ferroptosis by upregulating fatty acid desaturase 2 via the TGR5-PI3K/AKT-SREBP2 axis. High iron and ferritin serum levels during early infection were correlated with decreased TLCA levels and fatal outcomes in SFTSV-infected patients, indicating potential biomarkers. Furthermore, treatment with either ferroptosis inhibitors or TLCA protected mice from lethal SFTSV infection. Our findings highlight the therapeutic potential of bile acids to treat haemorrhagic fever viral infection.

DOI: https://doi.org/10.1038/s41564-024-01801-y
Cell Rep. 2024 Sep 13. pii: S2211-1247(24)01087-8. [Epub ahead of print]43(9): 114736

Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation.

Wei Wang, Alesja Dernst, Bianca Martin, Lucia Lorenzi, Maria Cadefau-Fabregat, Kshiti Phulphagar, Antonia Wagener, Christina Budden, Neil Stair, Theresa Wagner, Harald Färber, Andreas Jaensch, Rainer Stahl, Fraser Duthie, Susanne V Schmidt, Rebecca C Coll, Felix Meissner, Sergi Cuartero, Eicke Latz, Matthew S J Mangan.

  Short-chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through dietary fiber fermentation. Although generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) display poor tolerance to fiber-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of Toll-like receptor (TLR) agonists. In contrast to anti-inflammatory effects under steady-state conditions, we found that butyrate and propionate activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the presence of TLR agonists. Mechanistically, these SCFAs prevented transcription of FLICE-like inhibitory protein (cFLIP) and interleukin-10 (IL-10) through histone deacetylase (HDAC) inhibition, triggering caspase-8-dependent NLRP3 inflammasome activation. SCFA-driven NLRP3 activation was potassium efflux independent and did not result in cell death but rather triggered hyperactivation and IL-1β release. Our findings demonstrate that butyrate and propionate are bacterially derived danger signals that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.

Keywords:  CP: Immunology; HDAC; IL-10; NLRP3; SCFA; acetylation; butyrate; cFLIP; caspase-8; inflammasome; propionate

DOI:  https://doi.org/10.1016/j.celrep.2024.114736
Cell. 2024 Sep 12. pii: S0092-8674(24)00956-5. [Epub ahead of print]

Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.

Jeremy G Baldwin, Christoph Heuser-Loy, Tanmoy Saha, Roland C Schelker, Dragana Slavkovic-Lukic, Nicholas Strieder, Inmaculada Hernandez-Lopez, Nisha Rana, Markus Barden, Fabio Mastrogiovanni, Azucena Martín-Santos, Andrea Raimondi, Philip Brohawn, Brandon W Higgs, Claudia Gebhard, Veena Kapoor, William G Telford, Sanjivan Gautam, Maria Xydia, Philipp Beckhove, Sina Frischholz, Kilian Schober, Zacharias Kontarakis, Jacob E Corn, Matteo Iannacone, Donato Inverso, Michael Rehli, Jessica Fioravanti, Shiladitya Sengupta, Luca Gattinoni.

  Mitochondrial loss and dysfunction drive T cell exhaustion, representing major barriers to successful T cell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to T cells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with T cells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8+ T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8+ T cells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged T cells expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared with T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ T cells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.

Keywords:  CAR T therapy; CD8(+) T cells; TCR-T therapy; TIL therapy; Talin 2; bone marrow stromal cells; cancer immunotherapy; immune metabolism; mitochondrial transfer; nanotubes

DOI:  https://doi.org/10.1016/j.cell.2024.08.029
Cell Rep. 2024 Sep 13. pii: S2211-1247(24)01092-1. [Epub ahead of print]43(9): 114741

Integrated metabolic-transcriptomic network identifies immunometabolic modulations in human macrophages.

Hung-Jen Chen, Daniel C Sévin, Guillermo R Griffith, Johanna Vappiani, Lee M Booty, Cindy P A A van Roomen, Johan Kuiper, Jeroen den Dunnen, Wouter J de Jonge, Rab K Prinjha, Palwinder K Mander, Paola Grandi, Beata S Wyspianska, Menno P J de Winther.

  Macrophages exhibit diverse phenotypes and respond flexibly to environmental cues through metabolic remodeling. In this study, we present a comprehensive multi-omics dataset integrating intra- and extracellular metabolomes with transcriptomic data to investigate the metabolic impact on human macrophage function. Our analysis establishes a metabolite-gene correlation network that characterizes macrophage activation. We find that the concurrent inhibition of tryptophan catabolism by IDO1 and IL4I1 inhibitors suppresses the macrophage pro-inflammatory response, whereas single inhibition leads to pro-inflammatory activation. We find that a subset of anti-inflammatory macrophages activated by Fc receptor signaling promotes glycolysis, challenging the conventional concept of reduced glycolysis preference in anti-inflammatory macrophages. We demonstrate that cholesterol accumulation suppresses macrophage IFN-γ responses. Our integrated network enables the discovery of immunometabolic features, provides insights into macrophage functional metabolic reprogramming, and offers valuable resources for researchers exploring macrophage immunometabolic characteristics and potential therapeutic targets for immune-related disorders.

Keywords:  CP: Immunology; CP: Metabolism; Fc receptor; IDO1; IL4I1; cholesterol; glycolysis; immunometabolism; interferon; macrophage; metabolomics; tryptophan metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.114741
mBio. 2024 Sep 17. e0190624

Gut microbiota-derived butyrate improved acute leptospirosis in hamster via promoting macrophage ROS mediated by HDAC3 inhibition.

Xi Chen, Xufeng Xie, Ni Sun, Xin Liu, Jiuxi Liu, Wenlong Zhang, Yongguo Cao.

  Leptospirosis is a re-emerging worldwide zoonotic disease. Infected patients and animals often exhibit intestinal symptoms. Mounting evidence suggests that host immune responses to bacterial infection are closely associated with intestinal homeostasis. Our previous research has shown that the gut microbiota can protect the host from acute leptospirosis, while the specific bacterial metabolic mediators participating in the pathogenesis remain to be identified. Short-chain fatty acids (SCFAs) are metabolites produced mainly by the gut microbiota that play a role in immune regulation. However, whether SCFAs are the key to protecting the host against leptospirosis and the underlying regulatory mechanisms are unknown. In this study, our results showed that the SCFA butyrate is involved in ameliorating leptospirosis. The depletion of SCFAs by antibiotic cocktail treatment reduced survival time after Leptospira infection while supplementation with butyrate but not acetate or propionate significantly amelioration of leptospirosis. In vitro experiments showed that butyrate treatment enhanced the intracellular bactericidal activity mediated by reactive oxygen species (ROS) production. Mechanistically, butyrate functions as a histone deacetylase 3 inhibitor (HDAC3i) to promote ROS production via monocarboxylate transporter (MCT). The protection of butyrate against acute leptospirosis mediated by ROS was also proven in vivo. Collectively, our data provide evidence that the butyrate-MCT-HDAC3i-ROS signaling axis is a potential therapeutic target for acute leptospirosis. Our work not only interprets the microbial metabolite signaling involved in transkingdom interactions between the host and gut microbiota but also provides a possible target for developing a prevention strategy for acute leptospirosis.
IMPORTANCE: Leptospirosis is a worldwide zoonotic disease caused by Leptospira. An estimated 1 million people are infected with leptospirosis each year. Studies have shown that healthy gut microbiota can protect the host against leptospirosis but the mechanism is not clear. This work elucidated the mechanism of gut microbiota protecting the host against acute leptospirosis. Here, we find that butyrate, a metabolite of gut microbiota, can improve the survival rate of hamsters with leptospirosis by promoting the bactericidal activity of macrophages. Mechanistically, butyrate upregulates reactive oxygen species (ROS) levels after macrophage infection with Leptospira by inhibiting HDAC3. This work confirms the therapeutic potential of butyrate in preventing acute leptospirosis and provides evidence for the benefits of the macrophage-HDAC3i-ROS axis.

Keywords:  HDAC3; ROS; butyrate; leptospirosis; macrophage

DOI:  https://doi.org/10.1128/mbio.01906-24
bioRxiv. 2024 Sep 08. pii: 2024.09.04.611226. [Epub ahead of print]

TGFβ primes alveolar-like macrophages to induce type I IFN following TLR2 activation.

Sean M Thomas, Laurisa M Ankley, Kayla N Conner, Alexander W Rapp, Abigail P McGee, Francois LeSage, Christopher D Tanner, Taryn E Vielma, Eleanor C Scheeres, Joshua J Obar, Andrew J Olive.

Alveolar macrophages (AMs) are key mediators of lung function and are potential targets for therapies during respiratory infections. TGFβ is an important regulator of AM differentiation and maintenance, but how TGFβ directly modulates the innate immune responses of AMs remains unclear. This shortcoming prevents effective targeting of AMs to improve lung function in health and disease. Here we leveraged an optimized ex vivo AM model system, fetal-liver derived alveolar-like macrophages (FLAMs), to dissect the role of TGFβ in AMs. Using transcriptional analysis, we first globally defined how TGFβ regulates gene expression of resting FLAMs. We found that TGFβ maintains the baseline metabolic state of AMs by driving lipid metabolism through oxidative phosphorylation and restricting inflammation. To better understand inflammatory regulation in FLAMs, we next directly tested how TGFβ alters the response to TLR2 agonists. While both TGFβ (+) and TGFβ (-) FLAMs robustly responded to TLR2 agonists, we found an unexpected activation of type I interferon (IFN) responses in FLAMs and primary AMs in a TGFβ-dependent manner. Surprisingly, mitochondrial antiviral signaling protein and the interferon regulator factors 3 and 7 were required for IFN production by TLR2 agonists. Together, these data suggest that TGFβ modulates AM metabolic networks and innate immune signaling cascades to control inflammatory pathways in AMs.

DOI: https://doi.org/10.1101/2024.09.04.611226
Mitochondrion. 2024 Sep 12. pii: S1567-7249(24)00124-7. [Epub ahead of print] 101966

Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line.

Moris Sangineto, Martina Ciarnelli, Archana Moola, Vidyasagar Naik Bukke, Tommaso Cassano, Rosanna Villani, Antonino D Romano, Giuseppe Di Gioia, Carlo Avolio, Gaetano Serviddio.

  Metabolic reprogramming drives inflammatory activity in macrophages, including microglia, with Krebs cycle (KC) intermediates playing a crucial role as signaling molecules. Here, we show that the bioenergetic profile of LPS-activated human microglialclone 3 cell line (HMC3) is characterized by high levels of glycolysis and mitochondrial (mt) respiration, and the treatment with KC derivatives, namely dimethyl-fumarate (DMF) and itaconate (ITA), almost restores normal metabolism. However, despite comparable bioenergetic and anti-inflammatory effects, the mt hyper-activity was differentially modulated by DMF and ITA. DMF normalized complex I activity, while ITA dampened both complex I and II hyper-activity counteracting oxidative stress more efficiently.

Keywords:  Dimethyl fumarate; Immunometabolism; Itaconate; Krebs cycle; Microglia; Mitochondria

DOI:  https://doi.org/10.1016/j.mito.2024.101966
Immunometabolism (Cobham). 2024 Jul;pii: e00044. [Epub ahead of print]6(3):

Imaging immunometabolism in situ in live animals.

Nicole Molnar, Veronika Miskolci.

  Immunometabolism is a rapidly developing field that holds great promise for diagnostic and therapeutic benefits to human diseases. The field has emerged based on seminal findings from in vitro and ex vivo studies that established the fundamental role of metabolism in immune cell effector functions. Currently, the field is acknowledging the necessity of investigating cellular metabolism within the natural context of biological processes. Examining cells in their native microenvironment is essential not only to reveal cell-intrinsic mechanisms but also to understand how cross-talk between neighboring cells regulates metabolism at the tissue level in a local niche. This necessity is driving innovation and advancement in multiple imaging-based technologies to enable analysis of dynamic intracellular metabolism at the single-cell level, with spatial and temporal resolution. In this review, we tally the currently available imaging-based technologies and explore the emerging methods of Raman and autofluorescence lifetime imaging microscopy, which hold significant potential and offer broad applications in the field of immunometabolism.

Keywords:  FAD; FLIM; NAD(P)H; Raman; enzymatic activity assay; immune cells; lifetime imaging; optical redox ratio; spatial metabolomics

DOI:  https://doi.org/10.1097/IN9.0000000000000044
Cell Biol Int. 2024 Sep 16.

Breast cancer cell derived exosomes reduces glycolysis of activated CD8 + T cells in a AKT-mTOR dependent manner.

Abhishek Choudhury, Soumya Chatterjee, Shauryabrota Dalui, Pronabesh Ghosh, Altamas Hossain Daptary, Golam Kibria Mollah, Arindam Bhattacharyya.

  Cytotoxic CD8+ T cells plays a pivotal role in the adaptive immune system to protect the organism against infections and cancer. During activation and response, T cells undergo a metabolic reprogramming that involves various metabolic pathways, with a predominant reliance on glycolysis to meet their increased energy demands and enhanced effector response. Recently, extracellular vesicles (EVs) known as exosomes have been recognized as crucial signaling mediators in regulating the tumor microenvironment (TME). Recent reports indicates that exosomes may transfer biologically functional molecules to the recipient cells, thereby facilitate cancer progression, angiogenesis, metastasis, drug resistance, and immunosuppression by reprogramming the metabolism of cancer cells. This study sought to enlighten possible involvement of cancer-derived exosomes in CD8 + T cell glucose metabolism and discover a regulated signalome as a mechanism of action. We observed reduction in glucose metabolism due to downregulation of AKT/mTOR signalome in activated CD8 + T cells after cancer derived exosome exposure. In-vivo murine breast tumor studies showed better tumor control and antitumor CD8 + T cell glycolysis and effector response after abrogation of exosome release from breast cancer cells. Summarizing, the present study establishes an immune evasion mechanism of breast cancer cell secreted exosomes that will act as a foundation for future precision cancer therapeutics.

Keywords:  CD8 + T cells; breast cancer; effector response; exhaustion; exosomes; glycolysis

DOI:  https://doi.org/10.1002/cbin.12241
Proc Natl Acad Sci U S A. 2024 Sep 24. 121(39): e2321212121

Activation induces shift in nutrient utilization that differentially impacts cell functions in human neutrophils.

Emily C Britt, Xin Qing, James A Votava, Jorgo Lika, Andrew S Wagner, Simone Shen, Nicholas L Arp, Hamidullah Khan, Stefan M Schieke, Christopher D Fletcher, Anna Huttenlocher, Jing Fan.

  Neutrophils utilize a variety of metabolic sources to support their crucial functions as the first responders in innate immunity. Here, through in vivo and ex vivo isotopic tracing, we examined the contributions of different nutrients to neutrophil metabolism under specific conditions. Human peripheral blood neutrophils, in contrast to a neutrophil-like cell line, rely on glycogen storage as a major metabolic source under resting state but rapidly switch to primarily using extracellular glucose upon activation with various stimuli. This shift is driven by a substantial increase in glucose uptake, enabled by rapidly increased GLUT1 on cell membrane, that dominates the simultaneous increase in gross glycogen cycling capacity. Shifts in nutrient utilization impact neutrophil functions in a function-specific manner: oxidative burst depends on glucose utilization, whereas NETosis and phagocytosis can be flexibly supported by either glucose or glycogen, and neutrophil migration and fungal control are enhanced by the shift from glycogen utilization to glucose utilization. This work provides a quantitative and dynamic understanding of fundamental features in neutrophil metabolism and elucidates how metabolic remodeling shapes neutrophil functions, which has broad health relevance.

Keywords:  immunometabolism; neutrophil; nutrient dependence; nutrient preference switch

DOI:  https://doi.org/10.1073/pnas.2321212121
STAR Protoc. 2024 Sep 18. pii: S2666-1667(24)00479-9. [Epub ahead of print]5(4): 103314

Click-chemistry-based protocol for detecting 4-octyl-itaconate-alkylated proteins in primary mouse macrophages.

Chaofei Su, Tian Cheng, Hanyi Zhang, Hang Yin.

  4-Octyl itaconate (4-OI), a derivative of itaconate, inhibits inflammation by alkylating its target proteins. Here, we present a click-chemistry-based protocol for detecting 4-OI-alkylated proteins in mouse primary bone-marrow-derived macrophages (BMDMs) by using an itaconate-alkyne (ITalk) probe. We describe steps for culturing and treating BMDMs and details on using click chemistry in the cell lysate. We also detail procedures for detecting alkylated proteins by western blot. For complete details on the use and execution of this protocol, please refer to Su et al.1.

Keywords:  Cell-based Assays; Chemistry; Immunology; Molecular/Chemical Probes

DOI:  https://doi.org/10.1016/j.xpro.2024.103314
Cell Rep. 2024 Sep 13. pii: S2211-1247(24)01088-X. [Epub ahead of print]43(9): 114737

In situ chemoproteomic profiling reveals itaconate inhibits de novo purine biosynthesis in pathogens.

Zihua Liu, Dongyang Liu, Chu Wang.

  Itaconate serves as an immune-specific metabolite that regulates gene transcription and metabolism in both host and pathogens. S-itaconation is a post-translational modification that regulates immune response; however, its antimicrobial mechanism under the physiological condition remains unclear. Here, we apply a bioorthogonal itaconate probe to perform global profiling of S-itaconation in living pathogens, including S. Typhimurium, S. aureus, and P. aeruginosa. Some functional enzymes are covalently modified by itaconate, including those involved in the de novo purine biosynthesis pathway. Further biochemical studies demonstrate that itaconate suppresses this specific pathway to limit Salmonella growth by inhibiting the initiator purF to lower de novo purine biosynthesis and simultaneously targeting the guaABC cluster to block the salvage route. Our chemoproteomic study provides a global portrait of S-itaconation in multiple pathogens and offers a valuable resource for finding susceptible targets to combat drug-resistant pathogens in the future.

Keywords:  CP: Microbiology; bioorthogonal probe; chemoproteomics; de novo purine biosynthesis; itaconate; pathogens

DOI:  https://doi.org/10.1016/j.celrep.2024.114737
Commun Biol. 2024 Sep 20. 7(1): 1185

The gut microbiota and its metabolite butyrate shape metabolism and antiviral immunity along the gut-lung axis in the chicken.

Vincent Saint-Martin, Vanaique Guillory, Mélanie Chollot, Isabelle Fleurot, Emmanuel Kut, Ferdinand Roesch, Ignacio Caballero, Emmanuelle Helloin, Emilie Chambellon, Brian Ferguson, Philippe Velge, Florent Kempf, Sascha Trapp, Rodrigo Guabiraba.

The gut microbiota exerts profound influence on poultry immunity and metabolism through mechanisms that yet need to be elucidated. Here we used conventional and germ-free chickens to explore the influence of the gut microbiota on transcriptomic and metabolic signatures along the gut-lung axis in poultry. Our results demonstrated a differential regulation of certain metabolites and genes associated with innate immunity and metabolism in peripheral tissues of germ-free birds. Furthermore, we evidenced the gut microbiota's capacity to regulate mucosal immunity in the chicken lung during avian influenza virus infection. Finally, by fine-analysing the antiviral pathways triggered by the short-chain fatty acid (SCFA) butyrate in chicken respiratory epithelial cells, we found that it regulates interferon-stimulated genes (ISGs), notably OASL, via the transcription factor Sp1. These findings emphasize the pivotal role of the gut microbiota and its metabolites in shaping homeostasis and immunity in poultry, offering crucial insights into the mechanisms governing the communication between the gut and lungs in birds.

DOI: https://doi.org/10.1038/s42003-024-06815-0
Microbiol Spectr. 2024 Sep 17. e0083624

VSV infection and LPS treatment alter serum bile acid profiles, bile acid biosynthesis, and bile acid receptors in mice.

Yamei Li, Yan Luo, Chao Wang, Lei Xu, Xinhua Dai, Yunfei An, Lin He, Dongmei Zeng, Yangjuan Bai, Hua Zhang.

  Pathogen infections remain a significant public health problem worldwide. Accumulating evidence regarding the crosstalk between bile acid (BA) metabolism and immune response reveals that BA metabolism regulates host immunity and microbial pathogenesis, making it an attractive target for disease prevention and infection control. However, the effect of infection on circulating BA profiles, the biosynthesis-related enzymes, and their receptors remains to be depicted. Here, we investigated the effect of viral (vesicular stomatitis virus, VSV) and bacterial (lipopolysaccharide, LPS) infections on BA metabolism and signaling. Infection models were successfully established by intraperitoneally injecting VSV and LPS, respectively. VSV and LPS injection significantly changed the circulating BA profiles, with highly increased levels of taurine-conjugated BAs and significant decreases in unconjugated BAs. Consistent with the decreased levels of circulating cholic acid (CA) and chenodeoxycholic acid (CDCA), the expression of BA biosynthesis-related rate-limiting enzymes (Cyp7a1, Cyp27a1, Cyp8b1, and Hsd3b7) were significantly reduced. Furthermore, hepatic and pulmonary BA receptors (BARs) expression varied in different infection models. LPS treatment had an extensive impact on tested hepatic and pulmonary BARs, resulting in the upregulation of TGR5, S1PR2, and VDR, while VSV infection only promoted VDR expression. Our study provides insights into the involvement of BA metabolism in the pathophysiology of infection, which may provide potential clues for targeting BA metabolism and BAR signaling to boost innate immunity and control infection.
IMPORTANCE: This study focuses on the crosstalk between bile acid (BA) metabolism and immune response in VSV infection and LPS treatment models and depicts the effect of infection on circulating BA profiles, the biosynthesis-related enzymes, and their receptors. These findings provide insights into the effect of infection on BA metabolism and signaling, adding a more comprehensive understanding to the relationship between infection, BA metabolism and immune responses.

Keywords:  LPS treatment; VSV infection; bile acid biosynthesis; bile acid profiles; bile acid receptors

DOI:  https://doi.org/10.1128/spectrum.00836-24
Ann Med. 2024 Dec;56(1): 2399320

Serum metabolomics profile identifies patients with community-acquired pneumonia infected by bacteria, fungi, and viruses.

Li Chen, Jianbo Xue, Yukun He, Lili Zhao, Ying Zhang, Lu Yin, Shining Fu, Wenyi Yu, Xinqian Ma, Yu Wang, Yanfen Tang, Zhancheng Gao.

   PURPOSE: Patients with bacterial, fungal, and viral community-acquired pneumonia (CAP) were studied to determine their metabolic profiles.
METHODS: Loop-mediated isothermal amplification technology and nucleic acid sequence-dependent amplification combined with microfluidic chip technology were applied to screen multiple pathogens from respiratory tract samples. Eighteen patients with single bacterial infection (B-CAP), fifteen with single virus infection (V-CAP), twenty with single fungal infection (F-CAP), and twenty controls were enrolled. UHPLC-MS/MS analysis of untargeted serum samples for metabolic profiles. Multiple linear regression and Spearman's rank correlation analysis were used to determine associations between metabolites and clinical parameters. The sensitivity and specificity of the screened metabolites were also examined, along with their area under the curve.
RESULTS: The metabolic signatures of patients with CAP infected by bacteria, viruses, and fungi were markedly different from those of controls. The abundances of 45, 56, and 79 metabolites were significantly unbalanced. Among these differential metabolites, 11, 13, and 29 were unique to the B-CAP, V-CAP, and F-CAP groups, respectively. Bacterial infections were the only known causes of disturbances in the pentose and glucuronate and aldarate and ascorbate metabolism interconversions metabolic pathway.
CONCLUSIONS: Serum metabolomic techniques based on UHPLC-MS/MS may identify differences between individuals with CAP who have been infected by various pathogens, and they can also build a metabolite signature for early detection of the origin of infection and prompt care.

Keywords:  Metabolomics profiles; bacterial infection; community-acquired pneumonia; diagnosis; fungal infection; viral infection

DOI:  https://doi.org/10.1080/07853890.2024.2399320