bims-traimu 2024-10-06 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–10–06
seventeen papers selected by
Yantong Wan, Southern Medical University

Impact of Oil-in-Water Adjuvanted β-Glucan on Innate Immune Memory in Piglets.
Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection ameliorates secondary influenza A virus disease.
Trained immunity of synovial macrophages is associated with exacerbated joint inflammation and damage after Staphylococcus aureus infection.
Multi-Level Proteomics Reveals Epigenetic Signatures in BCG-mediated Macrophage Activation.
Biological evaluation of curdlan sulfate-based nanoparticles in trained immunity enhancement: In vitro and in vivo approaches.
Immunoresponsive Gene 1 Facilitates TLR4-agonist-Induced Augmentation of Innate Antimicrobial Immunity.
TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis-induced immune tolerance.
Non-Coding RNAs and Innate Immune Responses in Cancer.
Immune-response gene 1 deficiency aggravates inflammation-triggered cardiac dysfunction by inducing M1 macrophage polarization and aggravating Ly6Chigh monocyte recruitment.
The frequency of CD38+ alveolar macrophages correlates with early control of M. tuberculosis in the murine lung.
MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice.
Cancer cell-intrinsic biosynthesis of itaconate promotes tumor immunogenicity.
Immunometabolic Chaos in Septic Shock.
Bacillus Calmette-Guerin (BCG) Vaccine Impact on Dementia Risk in Bladder Cancer Patients: A Systematic Review and Meta-Analysis.
Single-cell RNA sequencing and immune repertoire analysis revealed dynamic immune characteristics associated with peripheral blood during sepsis.
Ornithine lipid is a partial TLR4 agonist and NLRP3 activator.
Enhanced Antimicrobial Peptide Response Following Bacillus Calmette-Guerin Vaccination in Elderly Individuals.

Vaccines (Basel). 2024 Aug 29. pii: 982. [Epub ahead of print]12(9):

Impact of Oil-in-Water Adjuvanted β-Glucan on Innate Immune Memory in Piglets.

Razieh Ardali, Obdulio Garcia-Nicolas, Catherine Ollagnier, José María Sánchez Carvajal, Maria Levy, Pauline Yvernault, Francisco de Aboim Borges Fialho de Brito, Artur Summerfield.

  The non-specific protective effects offered by the concept of "innate immune memory" might represent a promising strategy to tackle early-life threatening infections. Here we tested the potential of an in vitro selected β-glucan in inducing trained immunity using an in vivo porcine model. We assessed the leukocyte transcriptome using blood transcriptomic module (BTM), proinflammatory cytokines, and clinical scoring after a first "training" and a second "stimulation" phase. The possible induction of innate immune memory was tested during a "stimulation" by an LPS-adjuvanted Mycoplasma hyopneumoniae vaccine (Hyogen®) one day after weaning. Following the "training", no major group differences were found, with the exception of a plasma TNF that was only induced by Adj and Adj_BG treatment. After vaccination, all groups developed similar antibody responses. A significant induction of plasma TNF and IL-1β was found in groups that received Adj and Adj_BG. However, following vaccination, the expected early innate BTMs were only induced by the PBS group. In conclusion, the adjuvant alone, adjuvant-formulated β-glucan, or orally applied β-glucan were unable to enhance innate immune reactivity but rather appeared to promote innate immune tolerance. Such an immune status could have both positive and negative implications during this phase of the piglet's life.

Keywords:  adjuvant; innate immune memory; innate tolerance; piglets; β-glucan

DOI:  https://doi.org/10.3390/vaccines12090982
Immunity. 2024 Sep 27. pii: S1074-7613(24)00417-5. [Epub ahead of print]

Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection ameliorates secondary influenza A virus disease.

Alexander Lercher, Jin-Gyu Cheong, Michael J Bale, Chenyang Jiang, Hans-Heinrich Hoffmann, Alison W Ashbrook, Tyler Lewy, Yue S Yin, Corrine Quirk, Emma J DeGrace, Luis Chiriboga, Brad R Rosenberg, Steven Z Josefowicz, Charles M Rice.

  Pathogen encounter can result in epigenetic remodeling that shapes disease caused by heterologous pathogens. Here, we examined innate immune memory in the context of commonly circulating respiratory viruses. Single-cell analyses of airway-resident immune cells in a disease-relevant murine model of SARS-CoV-2 recovery revealed epigenetic reprogramming in alveolar macrophages following infection. Post-COVID-19 human monocytes exhibited similar epigenetic signatures. In airway-resident macrophages, past SARS-CoV-2 infection increased activity of type I interferon (IFN-I)-related transcription factors and epigenetic poising of antiviral genes. Viral pattern recognition and canonical IFN-I signaling were required for the establishment of this innate immune memory and augmented secondary antiviral responses. Antiviral innate immune memory mounted by airway-resident macrophages post-SARS-CoV-2 was necessary and sufficient to ameliorate secondary disease caused by influenza A virus and curtailed hyperinflammatory dysregulation and mortality. Our findings provide insights into antiviral innate immune memory in the airway that may facilitate the development of broadly effective therapeutic strategies.

Keywords:  SARS-CoV-2; alveolar macrophages; epigenetic memory; immunology; influenza; innate immune memory; lung disease; respiratory virus; trained immunity; viral infection

DOI:  https://doi.org/10.1016/j.immuni.2024.08.018
Inflamm Res. 2024 Sep 28.

Trained immunity of synovial macrophages is associated with exacerbated joint inflammation and damage after Staphylococcus aureus infection.

Peter Silva Rocha, Adryan Aparecido Silva, Celso Martins Queiroz-Junior, Amanda Dias Braga, Thaiane Pinto Moreira, Mauro Martins Teixeira, Flávio Almeida Amaral.

   OBJECTIVES: Investigate whether and which synoviocytes would acquire trained immunity characteristics that could exacerbate joint inflammation following a secondary Staphylococcus aureus infection.
METHODS: Lipopolysaccharide (LPS) and S. aureus were separately or double injected (21 days of interval) into the tibiofemoral joint cavity of male C57BL/6 mice. At different time points after these stimulations, mechanical nociception was analyzed followed by the analysis of signs of inflammation and damage in the affected joints. The trained immunity markers, including the glycolytic and mTOR pathway, were analyzed in whole tissue or isolated synoviocytes. A group of mice was treated with Rapamycin, an mTOR inhibitor before LPS or S. aureus stimulation.
RESULTS: The double LPS - S. aureus hit promoted intense joint inflammation and damage compared to single joint stimulation, including markers in synoviocyte activation, production of proinflammatory cytokines, persistent nociception, and bone damage, despite not reducing the bacterial clearance. The double LPS - S. aureus hit joints increased the synovial macrophage population expressing CX3CR1 alongside triggering established epigenetic modifications associated with trained immunity events in these cells, such as the upregulation of the mTOR signaling pathway (p-mTOR and HIF1α) and the trimethylation of histone H3. Mice treated with Rapamycin presented reduced CX3CR1+ macrophage activation, joint inflammation, and bone damage.
CONCLUSIONS: There is a trained immunity phenotype in CX3CR1+ synovial macrophages that contributes to the exacerbation of joint inflammation and damage during septic arthritis caused by S. aureus.

Keywords:   Staphylococcus aureus ; Arthritis; Inflammation; Septic arthritis; Synoviocytes; Trained Immunity

DOI:  https://doi.org/10.1007/s00011-024-01946-w
Mol Cell Proteomics. 2024 Oct 02. pii: S1535-9476(24)00141-5. [Epub ahead of print] 100851

Multi-Level Proteomics Reveals Epigenetic Signatures in BCG-mediated Macrophage Activation.

Zoe Schaefer, John Iradukunda, Evelyn Lumngwena, Kari Basso, Jonathan Blackburn, Ivana Parker.

The bacillus Calmette-Guérin BCG vaccine (Mycobacterium bovis) is primarily used to prevent tuberculosis (TB) infections but has wide-ranging immunogenic effects. One of its most notable properties is its ability to induce trained immunity, a memory-like response in innate immune cells such as macrophages. Through targeted analyses of well-established histone marks, prior research has shown that these changes are generated through epigenetic modification. Mass spectrometry-based proteomic approaches provide a way to globally profile various aspects of the proteome, providing data to further identify unexplored mechanisms of BCG-mediated immunomodulation. Here we use multi-level proteomics (total, histone, and phospho to identify networks and potential mechanisms that mediate BCG induced immunomodulation in macrophages. Histone-focused proteomics and total proteomics were performed at the University of Cape Town (data available via ProteomeXchange with identifier PXD051187), while phosphoproteomics data was retrieved from the ProteomeXchange Repository (identifier PXD013171). We identify several epigenetic mechanisms that may drive BCG-induced training phenotypes. Evidence across the proteomics and histone-focused proteomics data sets pair 6 epigenetic effectors (NuA4, NuRD, NSL, Sin3A, SIRT2, SIRT6) and their substrates.

DOI: https://doi.org/10.1016/j.mcpro.2024.100851
Int J Biol Macromol. 2024 Oct 01. pii: S0141-8130(24)07017-X. [Epub ahead of print] 136208

Biological evaluation of curdlan sulfate-based nanoparticles in trained immunity enhancement: In vitro and in vivo approaches.

Yipan Chen, Zuyi Li, Honglei Jiang, Longkun Wang, Yuhe Zhang, Xinke Zhang, Wenjie Jiang, Fengshan Wang.

   OBJECTIVES: Recently, more and more evidences suggest that β-glucans can induce trained immunity and non-specific protections against pathogens. However, most of the reports evaluated the immunological activities of β-glucans through injection route but no nasal inhalation. In this study, the effects of curdlan sulfate-based nanoparticles, CS/O-HTCC on trained immunity through intranasal administration were evaluated.
METHODS: Macrophages were treated with CS/O-HTCC and the metabolisms of the macrophages were detected. Mice were intranasal administered with CS/O-HTCC for 3 times with a 14 days interval, then the antitumor or infection prevention effects were assessed.
RESULTS: In vitro, CS/O-HTCC enhanced the macrophage metabolism significantly through upregulating glycolysis (26.1 ± 4.3 mpH/min) and oxidative phosphorylation (36.0 ± 9.0 pmol/min) compared with that of negative group (7.5 ± 2.3 mpH/min and 19.5 ± 4.9 pmol/min). In vivo, CS/O-HTCC inhibited lung metastasis of B16F10 tumor cells and improved the survival time (26.5 days) of the nmice compared with negative group (19.5 days). Moreover, CS/O-HTCC prevented the lung infections by Escherichia coli or Streptococcus pneumoniae (less bacterial residual) and reduced lung damages.
CONCLUSIONS: CS/O-HTCC can induce trained immunity through enhancing the metabolism of macrophages and enhance the non-specific protection against pathogens through intranasal immunization.

Keywords:  Curdlan sulfate; Mucosal adjuvant; Trained immunity

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136208
J Leukoc Biol. 2024 Oct 01. pii: qiae198. [Epub ahead of print]

Immunoresponsive Gene 1 Facilitates TLR4-agonist-Induced Augmentation of Innate Antimicrobial Immunity.

Margaret A McBride, Katherine R Caja, Tazeen K Patil, Allison M Owen, Liming Luan, Julia K Bohannon, Antonio Hernandez, Cody L Stothers, Irina A Trenary, Mohsin Rahim, Jamey D Young, M Wade Calcutt, Victoria R Stephens, Xenia Davis, Mary A Oliver, Dan Hao, Clara Si, Malik McRae, Kenny K Nguyen, Nicholas S Davis, Jingbin Wang, Naeem K Patil, Edward R Sherwood.

  Treatment with the toll-like receptor (TLR) 4 agonist monophosphoryl lipid A (MPLA) conditions innate immunocytes to respond robustly to subsequent infection, a phenotype termed innate immune memory. Our published studies show that metabolic reprogramming of macrophages is a prominent feature of the memory phenotype. We undertook studies to define the functional contributions of tricarboxylic acid (TCA) cycle reprogramming to innate immune memory. We observed that priming of wild type (WT) mice with MPLA potently facilitated accumulation of the TCA cycle metabolite itaconate at sites of infection and enhanced microbial clearance. Augmentation of itaconate accumulation and microbial clearance was ablated in immuneresponsive gene 1 (Irg1) -deficient mice. We further observed that MPLA potently induces expression of Irg1 and accumulation of itaconate in macrophages. Compared to WT macrophages, the ability of Irg1-deficient macrophages to kill Pseudomonas aeruginosa was impaired. We further observed that itaconate is directly antimicrobial against P. aeruginosa at pH 5, which is characteristic of the phagolysosome, and is facilitated by reactive oxygen species. MPLA-induced augmentation of glycolysis, oxidative phosphorylation and accumulation of the TCA cycle metabolites succinate and malate was decreased in Irg1 KO macrophages compared to WT controls. RNA sequencing revealed suppressed transcription of genes associated with phagolysosome function and increased expression of genes associated with cytokine production and chemotaxis in Irg1 deficient macrophages. This study identifies a contribution of itaconate to MPLA-induced augmentation of innate antimicrobial immunity via facilitation of microbial killing as well as impact on metabolic and transcriptional adaptations.

Keywords:  Immune Responsive Gene; Innate Immune Memory; Itaconate; Macrophages; Monophosphoryl Lipid A

DOI:  https://doi.org/10.1093/jleuko/qiae198
Proc Natl Acad Sci U S A. 2024 Oct 08. 121(41): e2404841121

TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis-induced immune tolerance.

Abhimanyu, Santiago Carrero Longlax, Tomoki Nishiguchi, Malik Ladki, Daanish Sheikh, Amera L Martinez, Emily M Mace, Sandra L Grimm, Thaleia Caldwell, Alexandra Portillo Varela, Rajagopal V Sekhar, Anna M Mandalakas, Mandla Mlotshwa, Sibuse Ginidza, Jeffrey D Cirillo, Robert S Wallis, Mihai G Netea, Reinout van Crevel, Cristian Coarfa, Andrew R DiNardo.

  Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all-cause postinfectious morbidity and mortality. Oncology studies identified metabolic drivers of the epigenetic landscape, with the tricarboxylic acid (TCA) cycle acting as a central hub. It is unknown if the TCA cycle also regulates epigenetics, specifically DNA methylation, after infection-induced immune tolerance. The following studies demonstrate that lipopolysaccharide and Mycobacterium tuberculosis induce changes in DNA methylation that are mediated by the TCA cycle. Infection-induced DNA hypermethylation is mitigated by inhibitors of cellular metabolism (rapamycin, everolimus, metformin) and the TCA cycle (isocitrate dehydrogenase inhibitors). Conversely, exogenous supplementation with TCA metabolites (succinate and itaconate) induces DNA hypermethylation and immune tolerance. Finally, TB patients who received everolimus have less DNA hypermethylation demonstrating proof of concept that metabolic manipulation can mitigate epigenetic scars.

Keywords:  DNA methylation; Rheostat; immune tolerance; sepsis; tuberculosis

DOI:  https://doi.org/10.1073/pnas.2404841121
Biomedicines. 2024 Sep 11. pii: 2072. [Epub ahead of print]12(9):

Non-Coding RNAs and Innate Immune Responses in Cancer.

Carlos Romero Díaz, María Teresa Hernández-Huerta, Laura Pérez-Campos Mayoral, Miriam Emily Avendaño Villegas, Edgar Zenteno, Margarito Martínez Cruz, Eduardo Pérez-Campos Mayoral, María Del Socorro Pina Canseco, Gabriel Mayoral Andrade, Manuel Ángeles Castellanos, José Manuel Matías Salvador, Eli Cruz Parada, Alexis Martínez Barras, Jaydi Nora Cruz Fernández, Daniel Scott-Algara, Eduardo Pérez-Campos.

  Non-coding RNAs (ncRNAs) and the innate immune system are closely related, acting as defense mechanisms and regulating gene expression and innate immunity. Both are modulators in the initiation, development and progression of cancer. We aimed to review the major types of ncRNAs, including small interfering RNAs (siRNAs), microRNAs (miRNAs), piwi-interacting RNAs (piRNAs), and long non-coding RNAs (lncRNAs), with a focus on cancer, innate immunity, and inflammation. We found that ncRNAs are closely related to innate immunity, epigenetics, chronic inflammation, and cancer and share properties such as inducibility, specificity, memory, and transfer. These similarities and interrelationships suggest that ncRNAs and modulators of trained immunity, together with the control of chronic inflammation, can be combined to develop novel therapeutic approaches for personalized cancer treatment. In conclusion, the close relationship between ncRNAs, the innate immune system, and inflammation highlights their importance in cancer pathways and their potential as targets for novel therapeutic strategies.

Keywords:  cancer; chronic inflammation; epimutation; immune-inducible; inheritance; miRNA; piRNA; siRNA; specificity; trained immunity; transfer

DOI:  https://doi.org/10.3390/biomedicines12092072
Biol Direct. 2024 Sep 30. 19(1): 86

Immune-response gene 1 deficiency aggravates inflammation-triggered cardiac dysfunction by inducing M1 macrophage polarization and aggravating Ly6Chigh monocyte recruitment.

Song Shen, Jianhui Li, Zhonghai Wei, Yihai Liu, Lina Kang, Rong Gu, Xuan Sun, Biao Xu, QiaoLing Li.

  The immune response gene 1 (IRG1) and its metabolite itaconate are implicated in modulating inflammation and oxidative stress, with potential relevance to sepsis-induced myocardial dysfunction (SIMD). This study investigates their roles in SIMD using both in vivo and in vitro models. Mice were subjected to lipopolysaccharide (LPS)-induced sepsis, and cardiac function was assessed in IRG1 knockout (IRG1-/-) and wild-type mice. Exogenous 4-octyl itaconate (4-OI) supplementation was also examined for its protective effects. In vitro, bone marrow-derived macrophages and RAW264.7 cells were treated with 4-OI following Nuclear factor, erythroid 2 like 2 (NRF2)-small interfering RNA administration to elucidate the underlying mechanisms. Our results indicate that IRG1 deficiency exacerbates myocardial injury during sepsis, while 4-OI administration preserves cardiac function and reduces inflammation. Mechanistic insights reveal that 4-OI activates the NRF2/HO-1 pathway, promoting macrophage polarization and attenuating inflammation. These findings underscore the protective role of the IRG1/itaconate axis in SIMD and suggest a therapeutic potential for 4-OI in modulating macrophage responses.

Keywords:  Itaconate; Macrophage polarization; Monocyte mobilization; NRF2; Septic myocardial injury

DOI:  https://doi.org/10.1186/s13062-024-00521-x
Nat Commun. 2024 Oct 02. 15(1): 8522

The frequency of CD38+ alveolar macrophages correlates with early control of M. tuberculosis in the murine lung.

Davide Pisu, Luana Johnston, Joshua T Mattila, David G Russell.

Tuberculosis, caused by Mycobacterium tuberculosis, remains an enduring global health challenge due to the limited efficacy of existing treatments. Although much research has focused on immune failure, the role of host macrophage biology in controlling the disease remains underappreciated. Here we show, through multi-modal single-cell RNA sequencing in a murine model, that different alveolar macrophage subsets play distinct roles in either advancing or controlling the disease. Initially, alveolar macrophages that are negative for the CD38 marker are the main infected population. As the infection progresses, CD38+ monocyte-derived and tissue-resident alveolar macrophages emerge as significant controllers of bacterial growth. These macrophages display a unique chromatin organization pre-infection, indicative of epigenetic priming for pro-inflammatory responses. Moreover, intranasal BCG immunization increases the numbers of CD38+ macrophages, enhancing their capability to restrict Mycobacterium tuberculosis growth. Our findings highlight the dynamic roles of alveolar macrophages in tuberculosis and open pathways for improved vaccines and therapies.

DOI: https://doi.org/10.1038/s41467-024-52846-w
Nat Commun. 2024 Oct 04. 15(1): 8624

MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice.

Kelvin Ka-Lok Wu, Xiaofan Xu, Manyin Wu, Xiaomu Li, Moinul Hoque, Gloria Hoi Yee Li, Qizhou Lian, Kekao Long, Tongxi Zhou, Hailong Piao, Aimin Xu, Hannah Xiaoyan Hui, Kenneth King-Yip Cheng.

M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Mechanistically, MDM2 triggers the ubiquitination and degradation of E3 ligase, SPSB2, to stabilize iNOS and increases production of NO, which s-nitrosylates and activates HIF-1α for triggering the glycolytic and pro-inflammatory programs in M1 macrophages. Myeloid-specific haplodeletion of MDM2 in mice not only blunts LPS-induced endotoxemia and NO production, but also alleviates obesity-induced adipose tissue-resident macrophage inflammation. By contrast, MDM2 haplodeletion induces higher mortality, tissue damage and bacterial burden, and also suppresses M1 macrophage response, in the cecal ligation and puncture-induced sepsis mouse model. Our findings thus identify MDM2 as an activator of glycolytic and inflammatory responses in M1 macrophages by connecting the iNOS-NO and HIF-1α pathways.

DOI: https://doi.org/10.1038/s41467-024-53006-w
EMBO J. 2024 Sep 30.

Cancer cell-intrinsic biosynthesis of itaconate promotes tumor immunogenicity.

Zining Wang, Lei Cui, Yanxun Lin, Bitao Huo, Hongxia Zhang, Chunyuan Xie, Huanling Zhang, Yongxiang Liu, Huan Jin, Hui Guo, Mengyun Li, Xiaojuan Wang, Penghui Zhou, Peng Huang, Jinyun Liu, Xiaojun Xia.

  The Krebs cycle byproduct itaconate has recently emerged as an important metabolite regulating macrophage immune functions, but its role in tumor cells remains unknown. Here, we show that increased tumor-intrinsic cis-aconitate decarboxylase (ACOD1 or CAD, encoded by immune-responsive gene 1, Irg1) expression and itaconate production promote tumor immunogenicity and anti-tumor immune responses. Furthermore, we identify thimerosal, a vaccine preservative, as a specific inducer of IRG1 expression in tumor cells but not in macrophages, thereby enhancing tumor immunogenicity. Mechanistically, thimerosal induces itaconate production through a ROS-RIPK3-IRF1 signaling axis in tumor cells. Further, increased IRG1/itaconate upregulates antigen presentation-related gene expression via promoting TFEB nuclear translocation. Intratumoral injection of thimerosal induced itaconate production, activated the tumor immune microenvironment, and inhibited tumor growth in a T cell-dependent manner. Importantly, IRG1 deficiency markedly impaired tumor response to thimerosal treatment. Furthermore, itaconate induction by thimerosal potentiates the anti-tumor efficacy of adoptive T-cell therapy and anti-PD1 therapy in a mouse lymphoma model. Hence, our findings identify a new role for tumor intrinsic IRG1/itaconate in promoting tumor immunogenicity and provide a translational means to increase immunotherapy efficacy.

Keywords:  Immunogenicity; Immunotherapy; Itaconate; Thimerosal

DOI:  https://doi.org/10.1038/s44318-024-00217-y
J Leukoc Biol. 2024 Sep 28. pii: qiae211. [Epub ahead of print]

Immunometabolic Chaos in Septic Shock.

Deepmala Shrestha, Bishnu Pant, Sanjoy Roychowdhury, Anugraha Gandhirajan, Emily Cross, Mamta Chhabria, Seth Bauer, Margaret Jeng, Megan Mitchell, Omar Mehkri, Fatima Zaidi, Akash Ahuja, Xiaofeng Wang, Yuxin Wang, Christine McDonald, Michelle Longworth, Thaddeus Stappenbeck, George R Stark, Rachel Scheraga, Vidula Vachharajani.

  Septic shock is associated with over 40% mortality. The immune response in septic shock is tightly regulated by cellular metabolism and transitions from early hyper-inflammation to later hypo-inflammation. Patients are susceptible to secondary infections during hypo-inflammation. The magnitude of the metabolic dysregulation and the effect of plasma metabolites on the circulating immune cells in septic shock are not reported. We hypothesized that the accumulated plasma metabolites affect the immune response in septic shock during hypo-inflammation. Our study took a unique approach. Using peripheral blood from adult septic shock patients and healthy controls, we studied: 1. Whole blood stimulation ± E. Coli lipopolysaccharide (LPS: endotoxin) to analyze plasma TNF protein, and 2. Plasma metabolomic profile by Metabolon. Inc. 3. We exposed peripheral blood mononuclear cells (PBMCs) from healthy controls to commercially available carbohydrate, amino acid, and fatty acid metabolites and studied the response to LPS. We report that: 1. The whole blood stimulation of the healthy control group showed a significantly upregulated TNF protein, while the septic shock group remained endotoxin tolerant, a biomarker for hypo-inflammation. 2. A significant accumulation of carbohydrate, amino acid, fatty acid, ceramide, sphingomyelin, and TCA cycle pathway metabolites in septic shock plasma. 3. In vitro exposure to five metabolites repressed while two metabolites upregulated the inflammatory response of PBMCs to LPS. We conclude that the endotoxin-tolerant phenotype of septic shock is associated with a simultaneous accumulation of plasma metabolites from multiple metabolic pathways, and these metabolites fundamentally influence the immune response profile of circulating cells.

Keywords:  Metabolism; Monocytes; Sepsis; Septic shock

DOI:  https://doi.org/10.1093/jleuko/qiae211
J Prev Alzheimers Dis. 2024 ;11(5): 1355-1362

Bacillus Calmette-Guerin (BCG) Vaccine Impact on Dementia Risk in Bladder Cancer Patients: A Systematic Review and Meta-Analysis.

M Ibrahim, P Kim, R Marawar, K I Avgerinos.

   BACKGROUND: The BCG vaccine has been traditionally administered to prevent TB. It has been additionally used in bladder cancer patients as a therapy with success. Some observational studies found that bladder cancer patients receiving BCG may have reduced dementia risk, however, the evidence is not conclusive.
OBJECTIVE: To investigate the impact of BCG vaccine on dementia risk in bladder cancer patients.
METHODS: Six databases were searched from inception to January 13, 2024, for published and unpublished studies that examine the association between BCG and dementia risk in bladder cancer patients. We conducted meta-analyses using a random-effects model.
RESULTS: Eight retrospective cohort studies were included in the systematic review and seven in the meta-analyses. Because there were studies with overlapping populations, two separate main analyses were performed reassuring the avoidance of overlap. The first analysis showed that compared to controls, BCG did not reduce dementia risk [5 studies pooled, n=88,852, HR = 0.65, 95% CI (0.40, 1.06), I2 = 85%] whereas there was a marginally significant risk reduction in the second analysis [6 studies pooled, n=70,025, HR = 0.63, 95% CI (0.40, 0.97), I2 = 83%]. Sensitivity analysis excluding the unpublished studies did not affect the outcome importantly. Additional meta-analysis showed that BCG did not reduce the risk of Alzheimer's disease.
CONCLUSION: This meta-analysis of observational studies found that BCG administration in bladder cancer patients has likely a minimally positive impact on dementia risk if any. To better understand the effect of BCG on dementia, randomized controlled trials are needed.

Keywords:   dementia; Alzheimer’s; BCG; immune system; vaccines

DOI:  https://doi.org/10.14283/jpad.2024.94
Biochem Biophys Res Commun. 2024 Sep 27. pii: S0006-291X(24)01287-7. [Epub ahead of print]734 150751

Single-cell RNA sequencing and immune repertoire analysis revealed dynamic immune characteristics associated with peripheral blood during sepsis.

Lijun Wang, Yao Xiao, Xiaoyong Zhang, Kai Zhu, Wanyi Chen, Lian Zhao, Qingjie Zhao, Hong Zhou, Gan Chen.

  Sepsis is a potentially fatal condition arising from an abnormal immune response to an infection, which can result in organ failure and even death. To explore the mechanism underlying the dysregulated immune response during sepsis and identify potential therapeutic targets, single-cell RNA sequencing (scRNA-seq) and immune repertoire analysis were conducted to depict the cellular landscape of peripheral blood cells in septic mice. We observed significant alterations in the number and proportion of peripheral blood cell populations driven by sepsis. By combining single-cell gene expression profiles and B cell receptor (BCR) repertoire analysis, we discerned that infection inflicted serious damage on the antigen presentation ability of B cells and the diversity of BCR in a short time. In addition, we found that the cecal ligation and puncture procedure in mice inhibited the communication signals of CD4+ and CD8+ T cells and decreased the interactions between B cells and other cells. Our study provides detailed insights into the dynamic changes in the biological characteristics of peripheral blood cells driven by sepsis and provides important advances in our understanding of immune disorders during sepsis.

Keywords:  B cell receptor (BCR) repertoires; Immune disorders; Peripheral blood cells; Sepsis; Single-cell RNA-sequencing

DOI:  https://doi.org/10.1016/j.bbrc.2024.150751
Cell Rep. 2024 Sep 26. pii: S2211-1247(24)01139-2. [Epub ahead of print]43(10): 114788

Ornithine lipid is a partial TLR4 agonist and NLRP3 activator.

Malvina Pizzuto, Laura Hurtado-Navarro, Cristina Molina-Lopez, Jalal Soubhye, Michel Gelbcke, Silvia Rodriguez-Lopez, Jean-Marie Ruysschaert, Kate Schroder, Pablo Pelegrin.

  Gram-negative bacterial lipopolysaccharides (LPSs) trigger inflammatory reactions through Toll-like receptor 4 (TLR4) and prime myeloid cells for inflammasome activation. In phosphate-limited environments, bacteria reduce LPS and other phospholipid production and synthesize phosphorus-free alternatives such as amino-acid-containing lipids like the ornithine lipid (OL). This adaptive strategy conserves phosphate for other essential cellular processes and enhances bacterial survival in host environments. While OL is implicated in bacterial pathogenicity, the mechanism is unclear. Using primary murine macrophages and human mononuclear cells, we elucidate that OL activates TLR4 and induces potassium efflux-dependent nucleotide-binding domain and leucine-rich repeat-containing pyrin protein 3 (NLRP3) activation. OL upregulates the expression of NLRP3 and pro-interleukin (IL)-1β and induces cytokine secretion in primed and unprimed cells. By contrast, in the presence of LPS, OL functions as a partial TLR4 antagonist and reduces LPS-induced cytokine secretion. We thus suggest that in phosphate-depleted environments, OL replaces LPS bacterial immunogenicity, while constitutively present OL may allow bacteria to escape immune surveillance.

Keywords:  CP: Immunology; CP: Microbiology; IL-1β; NLRP3; TLR; Toll-like receptor; bacteria; caspase; inflammasome; ionizable lipid; lipopolysaccharide; ornithine lipids

DOI:  https://doi.org/10.1016/j.celrep.2024.114788
Vaccines (Basel). 2024 Sep 18. pii: 1065. [Epub ahead of print]12(9):

Enhanced Antimicrobial Peptide Response Following Bacillus Calmette-Guerin Vaccination in Elderly Individuals.

Arul Nancy Pandiarajan, Nathella Pavan Kumar, Anuradha Rajamanickam, Perumal Kannabiran Bhavani, Bharathi Jeyadeepa, Nandhini Selvaraj, Dinesh Asokan, Srikanth Tripathy, Chandrasekharan Padmapriyadarsini, Subash Babu.

   BACKGROUND: Antimicrobial peptides are an important component of host defense against Mycobacterium tuberculosis. However, the ability of BCG to induce AMPs as part of its mechanism of action has not been investigated in detail.
METHODS: We investigated the impact of Bacillus Calmette-Guerin (BCG) vaccination on circulating plasma levels and TB-antigen stimulated plasma levels of AMPs in a healthy elderly population. We assessed the association of AMPs, including Human Beta Defensin 2 (HBD-2), Human Neutrophil Peptide 1-3 (HNP1-3), Granulysin, and Cathelicidin (LL37), in circulating plasma and TB-antigen stimulated plasma (using IGRA supernatants) at baseline (pre-vaccination) and at Month 1 and Month 6 post vaccination.
RESULTS: Post BCG vaccination, both circulating plasma levels and TB-antigen stimulated plasma levels of AMPs significantly increased at Month 1 and Month 6 compared to pre-vaccination levels in the elderly population. However, the association of AMP levels with latent TB (LTB) status did not exhibit statistical significance.
CONCLUSION: Our findings indicate that BCG vaccination is linked to heightened circulating levels of AMPs in the elderly population, which are also TB-antigen-specific. This suggests a potential mechanism underlying the immune effects of BCG in enhancing host defense against TB.

Keywords:  BCG; antimicrobial peptides; tuberculosis

DOI:  https://doi.org/10.3390/vaccines12091065