bims-bac4me 2025-08-03 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–08–03
29 papers selected by
Chun-Chi Chang, Lunds universitet

Trained immunity in the lung.
Heparin-Binding Hemagglutinin-Induced Trained Immunity in Macrophages: Implications for Antimycobacterial Defense.
Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia.
C-Reactive Protein as a Potential Signpost to Trained Immunity.
Immune dysfunction during S. aureus biofilm-associated implant infections: opportunities for novel therapeutic strategies.
Macrophages: Subtypes, Distribution, Polarization, Immunomodulatory Functions, and Therapeutics.
A promising Staphylococcus aureus vaccine adjuvant candidate to overcome Staphylococcal infection based on innate immunity.
A combination of phenotypic responses and genetic adaptations enables Staphylococcus aureus to withstand inhibitory molecules secreted by Pseudomonas aeruginosa.
Trained immunity: novel perspectives in diabetes and associated complications.
Myeloid cells as IFNα producers in systemic lupus erythematosus.
Environmental cues in different host niches shape the survival fitness of Staphylococcus aureus.
Pseudomonas aeruginosa-derived extracellular vesicles enhance macrophage aerobic glycolysis that fuels inflammation.
Immunization with Complete Freund's Adjuvant Reveals Trained Immunity-like Features in A/J Mice.
Lactobacillus murinus Reduces Susceptibility to Secondary MRSA Infection in IAV-Infected Mice Through Promoting a T Cell-Independent IgA Response.
Staphylococcus aureus biofilm-associated component PNAG stimulates the secretion of the immunomodulatory chemokine CXCL10 via Dectin-1 signaling.
BCG Vaccination Potentially Modulates the Transcriptome of Infant CD4 T Cells in Addition to Age-Dependent Immune Ontogeny-Associated Changes.
Respiratory microbiota, host immunity, respiratory viral infections and malignant tumors.
Epicutaneous Staphylococcus aureus initiates cross-tissue IL-36R signaling for neutrophilic lung inflammation in a model of the atopic march.
Immune priming in the insect gut: a dynamic response revealed by ultrastructural and transcriptomic changes.
How leukocytes push their way through tissues.
Microbiome-Based Products: Therapeutic Potential for Inflammatory Skin Diseases.
Decidual macrophage subsets and polarization puzzle during the human early pregnancy.
A microbiota-epigenetic circuit controls systematic circadian programs in the gut epithelium.
Simvastatin Administration Prohibits Staphylococcus aureus Anti-ROS Adaptation In Vivo and Alleviates Bone Infections.
How lactate and lactylation shape the immunity system in atherosclerosis (Review).
Rethinking approaches to overcome infectious disease.
Bufei Jiedu Formula enhances CD40 activation and macrophage polarization to eliminate intracellular MRSA persisters.
Lactylation and viral infections: A novel link between metabolic reprogramming and immune regulation.
NOD2 (Nucleotide-Binding Oligomerization Domain-Containing Protein 2)-Mediated Modulation of the Immune Response Induced by BCG (Bacillus Calmette-Guérin) Bacilli.

Elife. 2025 Aug 01. pii: e104918. [Epub ahead of print]14

Trained immunity in the lung.

Elina Idiiatullina, Dane Parker.

  Trained immunity represents a recent concept that elucidates the long-term reprogramming of innate immune cells, enabling them to adapt and respond more effectively to subsequent encounters with diverse pathogens. Initially recognized through the Bacillus Calmette-Guérin vaccine, Candida albicans infection, and β-glucan administration, this phenomenon challenges the traditional view that immune memory is exclusive to the adaptive immune system. Trained immunity is characterized by epigenetic and metabolic modifications in innate immune cells that facilitate enhanced responses to infections through mechanisms like chromatin remodeling and altered gene expression. This review focuses on the implications of trained immunity within the lung environment, which is constantly exposed to a plethora of pathogens and environmental irritants. We discuss the roles of various immune cell types, including alveolar macrophages and dendritic cells, in mediating trained immunity and how these adaptations may influence pulmonary insults and disease. Furthermore, we highlight the potential for leveraging trained immunity to enhance vaccine efficacy and develop novel therapeutic strategies for immune-related lung conditions. As research progresses, understanding trained immunity in the lung could pave the way for innovative interventions that improve lung health and resilience against infections.

Keywords:  airway; alveolar macrophage; immunology; infectious disease; inflammation; innate immune memory; lung; microbiology; trained immunity

DOI:  https://doi.org/10.7554/eLife.104918
Biomolecules. 2025 Jul 04. pii: 959. [Epub ahead of print]15(7):

Heparin-Binding Hemagglutinin-Induced Trained Immunity in Macrophages: Implications for Antimycobacterial Defense.

Yongqiang Li, Xiuping Jia, Jinhua Tang, Huilian Qiao, Jiani Zhou, Yueyun Ma.

  Tuberculosis (TB) is a major global health threat, with the current Bacillus Calmette-Guérin (BCG) vaccine having limited efficacy against adult pulmonary disease. Trained immunity (TI) is a form of innate immune memory that enhances antimicrobial defense. It is characterized by the epigenetic and metabolic reprogramming of innate immune cells and holds promise as a promising approach to prevent TB. In this study, we investigated the capacity of heparin-binding hemagglutinin (HBHA), a methylated antigen of Mycobacterium tuberculosis, to induce TI in murine RAW264.7 macrophages, human-derived THP-1 macrophages, and human peripheral blood mononuclear cells (hPBMCs). HBHA-trained macrophages exhibited the enhanced expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) following secondary lipopolysaccharide stimulation. The epigenetic profiling indicated elevated levels of H3K4me1 and H3K4me3 histone marks at cytokine gene loci. Further, metabolic analysis revealed heightened lactate production and the increased expression of glycolytic enzymes. Functionally, HBHA-trained macrophages exhibited improved control of intracellular mycobacteria, as evidenced by a significant reduction in colony-forming units following BCG infection. These findings elucidate that HBHA induces a functional TI phenotype via coordinated epigenetic and metabolic changes, and suggest HBHA may serve as a valuable tool for studying TI and its relevance to host defense against mycobacterial infections, pending further in vivo and clinical validation.

Keywords:  epigenetic reprogram; heparin-binding hemagglutinin; macrophage; trained immunity; tuberculosis

DOI:  https://doi.org/10.3390/biom15070959
Nat Commun. 2025 Aug 01. 16(1): 7050

Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia.

Ying-Tsun Chen, Zihua Liu, Dario Fucich, Stefano G Giulieri, Zhe Liu, Ridhima Wadhwa, Gustavo Rios, Henning Henschel, Nupur Tyagi, Françios A B Olivier, Ian R Monk, Shivang S Shah, Shwetha H Sridhar, Marija Drikic, Colleen Bianco, Gaurav K Lohia, Ayesha Z Beg, Paul J Planet, Ian A Lewis, Robert Sebra, Ana Traven, Abderrahman Hachani, Timothy P Stinear, Benjamin P Howden, Jeffrey M Boyd, Sebastian A Riquelme, Chu Wang, Alice Prince, Tania Wong Fok Lung.

Staphylococcus aureus is a leading cause of healthcare-associated pneumonia, contributing significantly to morbidity and mortality worldwide. As a ubiquitous colonizer of the upper respiratory tract, S. aureus must undergo substantial metabolic adaptation to achieve persistent infection in the distinctive microenvironment of the lung. We observed that fumC, which encodes the enzyme that converts fumarate to malate, is highly conserved with low mutation rates in S. aureus isolates from chronic lung infections. Fumarate, a pro-inflammatory metabolite produced by macrophages during infection, is regulated by the host fumarate hydratase (FH) to limit inflammation. Here, we demonstrate that fumarate, which accumulates in the chronically infected lung, is detrimental to S. aureus, blocking primary metabolic pathways such as glycolysis and oxidative phosphorylation (OXPHOS). This creates a metabolic bottleneck that drives staphylococcal FH (FumC) activity for airway adaptation. FumC not only degrades fumarate but also directs its utilization into critical pathways including the tricarboxylic acid (TCA) cycle, gluconeogenesis and hexosamine synthesis to maintain metabolic fitness and form a protective biofilm. Itaconate, another abundant immunometabolite in the infected airway enhances FumC activity, in synergy with fumarate. In a mouse model of pneumonia, a ΔfumC mutant displays significant attenuation compared to its parent and complemented strains, particularly in fumarate- and itaconate-replete conditions. Our findings underscore the pivotal role of immunometabolites in promoting S. aureus pulmonary adaptation.

DOI: https://doi.org/10.1038/s41467-025-62453-y
JACC Basic Transl Sci. 2025 Jul;pii: S2452-302X(25)00269-4. [Epub ahead of print]10(7): 101319

C-Reactive Protein as a Potential Signpost to Trained Immunity.

Robin P Choudhury.



Keywords:  hsCRP; inflammatory risk; monocyte; trained immunity; unstable angina

DOI:  https://doi.org/10.1016/j.jacbts.2025.101319
NPJ Biofilms Microbiomes. 2025 Jul 25. 11(1): 144

Immune dysfunction during S. aureus biofilm-associated implant infections: opportunities for novel therapeutic strategies.

Nichole D Brandquist, Tammy Kielian.

Staphylococcus aureus is a common cause of biofilm infections, particularly on implanted medical devices. Biofilms are heterogeneous bacterial communities contained in a self-produced matrix that are poorly cleared by the immune system. This review discusses mechanisms employed by the biofilm, such as alterations in bacterial metabolism and toxin production, to induce immune dysfunction by highlighting recent bacterial single-cell sequencing studies. Additionally, the role of immune recognition and metabolism in biofilm containment is examined with an emphasis on the role of granulocytic myeloid-derived suppressor cells and how responses are tailored to distinct tissue niches. We also address emerging evidence revealing the importance of the infection microenvironment, host genetic variability, and bacterial heterogeneity in shaping immune responses during S. aureus biofilm infections.

DOI: https://doi.org/10.1038/s41522-025-00782-y
MedComm (2020). 2025 Aug;6(8): e70304

Macrophages: Subtypes, Distribution, Polarization, Immunomodulatory Functions, and Therapeutics.

Mengyuan Peng, Niannian Li, Hongbo Wang, Yaxu Li, Hui Liu, Yanhua Luo, Bao Lang, Weihang Zhang, Shilong Li, Liujun Tian, Bin Liu.

  Macrophages are heterogeneous immune cells with diverse subtypes and tissue-specific distributions, displaying dynamic polarization states that critically govern their immunomodulatory functions and responses to environmental cues. As key regulators of innate and adaptive immunity, they originate from either embryonic progenitors or bone marrow-derived monocytes and exhibit remarkable plasticity in response to microenvironmental cues. Tissue-resident macrophages (e.g., Langerhans cells, Kupffer cells, microglia) display unique organ-specific functions, while inflammatory stimuli drive their polarization into proinflammatory (M1) or anti-inflammatory (M2) phenotypes along a functional continuum. This review systematically examines macrophage subtypes, their anatomical distribution, and the signaling pathways (e.g., NF-κB, STATs, PPARγ) underlying polarization shifts in acute and chronic inflammation. We highlight how polarization imbalances contribute to pathologies including neuroinflammation, liver fibrosis, and impaired tissue repair, particularly in aging contexts. Furthermore, we discuss emerging therapeutic strategies targeting macrophage plasticity, such as cytokine modulation, metabolic reprogramming, and subtype-specific interventions. By integrating recent advances in macrophage biology, this work provides a comprehensive framework for understanding their dual roles in immune regulation and tissue homeostasis, offering insights for treating inflammatory and age-related diseases through macrophage-centered immunomodulation.

Keywords:  immune; inflammation; macrophages; polarization; therapeutics; tissue‐resident macrophages

DOI:  https://doi.org/10.1002/mco2.70304
Clin Exp Vaccine Res. 2025 Jul;14(3): 189-202

A promising Staphylococcus aureus vaccine adjuvant candidate to overcome Staphylococcal infection based on innate immunity.

Xinrui Mao, Thomas Söderhäll, Gi-Sub Choi, Jin-Han Kang, Cunwei Cao, Qinghua Yuan.

  Staphylococcus aureus-mediated human disease ranges from minor skin infection to life threatening diseases. In the past, infections caused by this bacterium could be treated with antibiotics. However, this species has become increasingly resistant to antibiotics. Therefore, vaccines as alternative therapeutic tools is urgently required for controlling this troubles pathogen. But thus far, all vaccines in human clinical trials for preventing S. aureus infections have failed. Three major reasons for this failure can be summarized: 1) An effective antigen has not yet been identified; 2) Host protective immune responses against S. aureus are unclear; 3) Good animal model is not yet identified. The most critical challenge is that despite robust serum immunoglobulin G titers, vaccinated hosts fail to eliminate intracellular S. aureus. To solve this problem, a vaccine inducing both humoral- and cellular-immunity should be designed and developed. Based on our research experiences and recent other groups' published data, we propose that microbial glycopolymers, which are activating host innate immunity, should be considered as a new S. aureus vaccine adjuvant. Here, our review aims at highlighting how the latest advances in carbohydrates immunobiology can guide the design and development of better S. aureus vaccines and adjuvants.

Keywords:  Adjuvant; Humoral- and cellular-immunity; Microbial glycopolymers; Staphylococcus aureus; Vaccines

DOI:  https://doi.org/10.7774/cevr.2025.14.e27
mSystems. 2025 Jul 31. e0026225

A combination of phenotypic responses and genetic adaptations enables Staphylococcus aureus to withstand inhibitory molecules secreted by Pseudomonas aeruginosa.

Lukas Schwyter, Selina Niggli, Natalia Zajac, Lucy Poveda, Witold Eryk Wolski, Christian Panse, Ralph Schlapbach, Rolf Kümmerli, Jonas Grossmann.

  Staphylococcus aureus and Pseudomonas aeruginosa frequently co-occur in infections, and there is evidence that their interactions can negatively affect disease outcomes. P. aeruginosa is known to be dominant, often compromising S. aureus through the secretion of inhibitory compounds. We previously demonstrated that S. aureus can become resistant to growth-inhibitory compounds during experimental evolution. While resistance arose rapidly, the underlying mechanisms were not obvious as only a few genetic mutations were associated with resistance, while ample phenotypic changes occurred. We thus hypothesize that resistance may result from a combination of phenotypic responses and genetic adaptation. Here, we tested this hypothesis using proteomics. We first focused on an evolved strain that acquired a single mutation in tcyA (encoding a transmembrane transporter unit) upon exposure to P. aeruginosa supernatant. We show that this mutation leads to a complete abolishment of transporter synthesis, which confers moderate protection against Pseudomonas quinolone signal and selenocystine, two toxic compounds produced by P. aeruginosa. However, this genetic effect was minor compared to the fundamental phenotypic changes observed at the proteome level when both ancestral and evolved S. aureus strains were exposed to P. aeruginosa supernatant. Major changes involved the downregulation of virulence factors, metabolic pathways, and membrane transporters, and the upregulation of reactive oxygen species scavengers and an efflux pump. Our results suggest that the observed multivariate phenotypic response is a powerful adaptive strategy, offering instant protection against competitors in fluctuating environments and reducing the need for hard-wired genetic adaptations.IMPORTANCEDifferent bacterial pathogens can co-occur in infections, where they interact with one another and influence disease severity. Previous research showed that pathogens can evolve and adapt to co-infecting species. Here, we show that evolution through genetic mutations and selection is not necessarily required to change pathogen behavior. Instead, we found that the human pathogen Staphylococcus aureus is able to plastically respond to the presence of Pseudomonas aeruginosa, a competing pathogen. Through proteomics and metabolomics, we demonstrate that S. aureus undergoes substantial proteomic alterations in response to P. aeruginosa by downregulating virulence factor expression, changing metabolism, and mounting protective measures against toxic compounds. Our work highlights that pathogens possess sophisticated mechanisms to respond to competitors to secure growth and survival in polymicrobial infections. We predict such plastic responses to have significant impacts on infection outcomes.

Keywords:  Pseudomonas aeruginosa; Staphylococcus aureus; evolutionary biology; metabolomics; pathogen interaction; proteomics; stress adaptation; virulence

DOI:  https://doi.org/10.1128/msystems.00262-25
Front Immunol. 2025 ;16 1613602

Trained immunity: novel perspectives in diabetes and associated complications.

Yukun Liu, Yanqi Lei, Zhuojun Dai, Changfang Luo, Qiming Gong, Yanqun Li, Yong Xu, Wei Huang.

  Recent studies have revealed that the innate immune system possesses the capacity to develop "trained immunity" via metabolic and epigenetic reprogramming, leading to non-specific memory responses distinct from the memory traditionally attributed exclusively to adaptive immunity. Hyperglycemia, acting as an initiating stimulus, drives myeloid progenitor cell proliferation and monocyte-derived macrophage expansion, which leads to a sustained pro-inflammatory phenotype that is closely associated with the pathogenesis of diabetes and its related complications. The paradigm of trained immunity provides a novel perspective on explaining the "metabolic memory" phenomenon in diabetes. Here, we summarize the research progress on trained immunity, diabetes, and related complications to explore novel insights into diabetes prevention and treatment.

Keywords:  diabetes; epigenetics; hyperglycemia; inflammation; metabolism; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1613602
Front Immunol. 2025 ;16 1562221

Myeloid cells as IFNα producers in systemic lupus erythematosus.

Taiga Kuga, Asako Chiba, Goh Murayama, Sachiko Miyake.

  Type I interferons (IFNs) play crucial roles in the pathogenesis of systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) stimulated by Toll-like receptor (TLR) pathways have been thought to be the major producers of IFNα in patients with SLE. However, the responsiveness of pDCs from SLE patients to stimuli that produce IFNα differs depending on the type of TLR pathway involved. In addition to pDCs, monocytes from SLE patients were found to produce IFNα when responding to the cGAS-STING pathway. Here, we outline the major pathways that induce IFNα production by myeloid cells in SLE, and the possible mechanisms by which IFNα overproduction occurs by these cells. Finally, we discuss the current and future therapeutic strategies to regulate IFNα production in patients with SLE.

Keywords:  SLE; TLR; cGAS-STING; cellular senescence; interferon; monocyte; pDC

DOI:  https://doi.org/10.3389/fimmu.2025.1562221
Nat Commun. 2025 Jul 28. 16(1): 6928

Environmental cues in different host niches shape the survival fitness of Staphylococcus aureus.

JuOae Chang, ChaeYoung Lee, Inseo Kim, Jihyeon Kim, Ji-Hoon Kim, Taegwan Yun, David C Hooper, Suzanne Walker, Wonsik Lee.

The ability of Staphylococcus aureus to adapt and thrive in diverse host niches adds to the challenge in combating this ubiquitous pathogen. While extensive research has been pursued on the adaptive mechanisms of methicillin-resistant S. aureus (MRSA) in various infection models, a comprehensive analysis of its fitness across different host niches is lacking. In this study, we employ transposon sequencing to analyze the adaptive strategies of MRSA in various infection niches. Our analysis encompasses a cell model that mimics an intracellular niche, human blood, which represents a major extracellular environment as well as a major intermediary route encountered by bacteria during systemic infection, and a male murine sepsis model that recapitulates intra-organ environments. Our findings reveal substantial differences in the genetic determinants essential for bacterial survival in intracellular and blood environments. Moreover, we show that each organ imposes unique growth constraints, thus fostering heterogeneity within the mutant population that can enter and survive in each organ of the mouse. By comparing genes important for survival across all examined host environments, we identify 27 core genes that represent potential therapeutic targets for treating S. aureus infections. Additionally, our findings aid in understanding how bacteria adapt to diverse host environments.

DOI: https://doi.org/10.1038/s41467-025-62292-x
Front Microbiol. 2025 ;16 1619101

Pseudomonas aeruginosa-derived extracellular vesicles enhance macrophage aerobic glycolysis that fuels inflammation.

Chun Li, Jing Peng, Lihua Xiao, Haiying Wu, Jing Chen, Nian Chen.

  Outer membrane vesicles (OMVs) derived from Pseudomonas aeruginosa drive inflammation by metabolically reprogramming macrophages to favor aerobic glycolysis. This study shows that OMVs trigger this metabolic shift via Toll-like receptors 2 and 4 (TLR2/4)-dependent activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. OMV-stimulated macrophages exhibited increased glucose uptake, lactate production, and expression of key glycolytic enzymes, resulting in a higher extracellular acidification rate and a lower oxygen consumption rate. Inhibition of the PI3K/Akt pathway reversed these metabolic changes. Crucially, this metabolic reprogramming was required for OMV-induced secretion of pro-inflammatory cytokines, as inhibition of glycolysis via 2-deoxy-D-glucose treatment attenuated the inflammatory response both in vitro and in vivo. These findings reveal that P. aeruginosa OMVs control metabolism in macrophages through the TLR2/4-PI3K/Akt axis to promote a pro-inflammatory state and identifies glycolysis as a potential therapeutic target for bacteria-associated inflammatory diseases.

Keywords:  Pseudomonas aeruginosa; aerobic glycolysis; inflammation; outer membrane vesicle; toll-like receptor

DOI:  https://doi.org/10.3389/fmicb.2025.1619101
Vaccines (Basel). 2025 Jul 21. pii: 768. [Epub ahead of print]13(7):

Immunization with Complete Freund's Adjuvant Reveals Trained Immunity-like Features in A/J Mice.

Kiruthiga Mone, Shraddha Singh, Fatema Abdullatif, Meghna Sur, Mahima T Rasquinha, Javier Seravalli, Denise K Zinniel, Indranil Mukhopadhyay, Raul G Barletta, Teklab Gebregiworgis, Jay Reddy.

   BACKGROUND/OBJECTIVES: Freund's adjuvants induce different immunomodulatory effects, but their underlying molecular mechanisms are unclear. In this study, we investigated whether the immune-stimulating effects of the complete Freund's adjuvant (CFA) involve the mechanisms of trained immunity (TI).
METHODS: We examined bone marrow cells (BMCs) isolated from CFA-immunized A/J mice to address this question. Incomplete Freund's adjuvant (IFA) and Mycobacterium tuberculosis var. bovis Bacillus Calmette-Guérin (BCG) served as negative and positive controls, respectively. We evaluated cytokine profiles, metabolic, and epigenetic changes.
RESULTS: First, BMCs from all groups except saline showed varied levels of IL-1β, IL-6, and TNF-α. But expression of CCL5 and CXCL10 was significantly elevated only in the CFA and BCG groups. Transcriptionally, significant elevations were noted for TNF-α and IL-1β in the CFA and BCG groups, whereas CXCL10, IL-6, and IL-10 were upregulated in the CFA and BCG groups, respectively. Second, while BMCs from the BCG group expressed the markers of both the M1 and M2 macrophages, no clear trends were noted in the CFA and IFA groups. Third, cell lysates from the CFA group revealed metabolic reprogramming in the BMCs. Specifically, we observed an increased level of lactate, indicative of aerobic glycolysis, which is implicated in TI, and this was also detected in the IFA group. Fourth, epigenetic analysis revealed histone enrichment in the promoter region of TNF-α, in the CFA group, but to a lesser degree than the BCG group. However, no epigenetic changes were observed in the IFA group.
CONCLUSIONS: Our data provide new insights into the mechanisms of Freund's adjuvants and the immunomodulatory effects of CFA could involve the features of TI.

Keywords:  CFA; Freund’s adjuvants; IFA; adjuvants; complete Freund’s adjuvant; epigenetics; immunometabolism; incomplete Freund’s adjuvant; innate immune memory; metabolomics; trained immunity; vaccine adjuvants

DOI:  https://doi.org/10.3390/vaccines13070768
Microorganisms. 2025 Jul 21. pii: 1709. [Epub ahead of print]13(7):

Lactobacillus murinus Reduces Susceptibility to Secondary MRSA Infection in IAV-Infected Mice Through Promoting a T Cell-Independent IgA Response.

Qichao Chen, Yanfeng Lin, Kaiying Wang, Jinhui Li, Peng Li, Hongbin Song.

  Secondary methicillin-resistant Staphylococcus aureus (MRSA) infection causes high mortality in patients with influenza A virus (IAV). Our previous study observed that the relative abundance of Lactobacillus murinus (L. murinus) was significantly reduced in both the respiratory tract and gut of IAV-infected mice and negatively correlated with the severity of IAV-MRSA coinfection pneumonia, but the role of L. murinus remains unclear. Here, we supplemented the respiratory tract and gut of IAV-infected mice with live L. murinus and performed a secondary MRSA infection challenge to investigate the effects and potential mechanisms further. Data showed that L. murinus supplementation significantly reduced mortality and pathogen loads in IAV-MRSA coinfected mice and upregulated the lung T cell-independent (TI) IgA response in IAV-infected mice. The 16S rRNA gene sequencing results showed that L. murinus supplementation ameliorated microbiota composition disorder and regulated metabolic dysfunction in the gut of IAV-infected mice. The correlation analysis and antibiotic cocktail treatment experiment showed that the TI IgA response in lungs is dependent on gut microbiota. These findings demonstrated that L. murinus supplementation reduces susceptibility to secondary MRSA infection in IAV-infected mice by promoting the TI IgA response, and provide a new perspective on the use of probiotics to prevent secondary bacterial infection following IAV infection.

Keywords:  Lactobacillus murinus; T cell-independent IgA response; gut microbiota; secondary methicillin-resistant Staphylococcus aureus infection following influenza A virus

DOI:  https://doi.org/10.3390/microorganisms13071709
Commun Biol. 2025 Jul 31. 8(1): 1136

Staphylococcus aureus biofilm-associated component PNAG stimulates the secretion of the immunomodulatory chemokine CXCL10 via Dectin-1 signaling.

Reza Gheitasi, Daniel Weiss, Mario M Müller, Karolin Sommer, Daniela Röll, Alexander Mosig, Mathias W Pletz, Oliwia Makarewicz.

Staphylococcus aureus is a common human pathogen associated with many infections. The key factor contributing to the virulence of S. aureus is its ability to form difficult-to-treat and recalcitrant biofilms. One of the major staphylococcal biofilms matrix compounds is poly-N-acetylglucosamine (PNAG). In previous study, we observed an increased secretion of various cytokines and chemokines when immune cells were stressed by S. aureus biofilms. In this study, we aimed to analyze the effect of PNAG on the secretion of the CXCL10 chemokine subfamily by peripheral blood mononuclear cells and monocytes and studied the connection to the Dectin-1-Syk-CARD9 signaling pathway, as Dectin-1 is the major pattern recognized by polysaccharide structures. We showed that, in contrast to the major virulence factor surface protein A, PNAG primarily elevates the secretion of CXCL10. This secretion was interrupted by blocking the Dectin-1 receptor or tyrosine kinase Syk. PNAG exposure resulted in increased Dectin-1 and CARD9 expression as well as increased NF-κB and CXCL10 expression, which may be related to the long-term memory processes of T cells. We also showed that PNAG induces the formation of CD14 + CXCL10+ monocytes that can migrate to the site of infection, triggering an innate immune response against S. aureus. This study provides insights into the complex interaction of the staphylococcal biofilms matrix with immune chemotaxis and shows that immunologic processes leading to bacterial infections should be viewed in a more differentiated manner, as biofilms are the preferred formation of microorganisms.

DOI: https://doi.org/10.1038/s42003-025-08503-z
Vaccines (Basel). 2025 Jun 29. pii: 706. [Epub ahead of print]13(7):

BCG Vaccination Potentially Modulates the Transcriptome of Infant CD4 T Cells in Addition to Age-Dependent Immune Ontogeny-Associated Changes.

Vidya Vijayan Karuvan Kandiyil, Eunchong Kang, Emily Coates, Portia Kamthunzi, Gerald Tegha, Mina Hosseinipour, Di Wu, Fei Zou, Kristina De Paris.

   BACKGROUND: The Bacille Calmette-Guérin (BCG) vaccine is part of the Extended Programme on Immunization (EPI) and as such is generally administered at birth. The global introduction of BCG not only protected many vaccinated infants against severe complications of tuberculosis but also resulted in markedly reduced overall childhood mortality. Studies in human adults determined that BCG vaccination induces epigenetic reprogramming of innate immune cells (also known as trained immunity) and can also enhance T cell responses to both mycobacterial and non-mycobacterial antigens.
GOAL AND METHODS: The current study tested the hypothesis that BCG immunization similarly impacts the functionally distinct infant immune system. Towards this goal, we applied RNA sequencing to assess transcriptome changes in circulating CD4+ T cells of Malawian infants prior to and 2 to 13 weeks after BCG immunization.
RESULTS: In the first three months of life, transcriptome changes of infant CD4 T cells implied a functional shift towards T helper 1 and Th17 immunity. Vaccination with BCG resulted in additional modulation of the CD4 T cell transcriptome and differentially expressed genes could be linked to metabolomic function.
CONCLUSIONS: These findings are consistent with data reported in BCG vaccinated adults and contribute to the understanding of molecular changes in infant CD4 T cells that may explain the improved capacity of the infant immune system to respond to pathogens after BCG vaccination.

Keywords:  BCG vaccination; immune ontogeny; infant CD4 T cell transcriptome; signaling pathways

DOI:  https://doi.org/10.3390/vaccines13070706
Front Microbiol. 2025 ;16 1626077

Respiratory microbiota, host immunity, respiratory viral infections and malignant tumors.

Xinjie Jiang, Sujiang Zhang.

  In recent years, the role of the respiratory tract microbiota in respiratory tract infections has attracted considerable attention. Respiratory microbiota have important effects on respiratory physiology, immune regulation, and the occurrence and development of various respiratory viral infectious diseases. The microbial composition in the different parts of the respiratory tract, such as the nose, oropharynx, and lower respiratory tract, varies. Under physiological conditions, the respiratory microbiota remains relatively stable; however, when this homeostatic balance is disrupted, respiratory microbiota imbalance occurs, increasing the risk of infection. An increasing number of studies have revealed the complex relationship between bacterial dysregulation and respiratory viral infections. Dysregulation of the respiratory tract microbiota plays an important role in both innate and adaptive immune responses. In this study, changes in respiratory microbes and their interactions with host immunity, respiratory viral infections and malignant tumors were reviewed. Future studies should further explore the interaction mechanism between respiratory microbiota and host immunity, develop new diagnostic and therapeutic strategies, and improve the current level of clinical treatment for respiratory diseases.

Keywords:  airway dysbiosis; immune; interaction; respiratory tract microbiota; viral infection

DOI:  https://doi.org/10.3389/fmicb.2025.1626077
Cell Rep. 2025 Jul 24. pii: S2211-1247(25)00825-3. [Epub ahead of print]44(8): 116054

Epicutaneous Staphylococcus aureus initiates cross-tissue IL-36R signaling for neutrophilic lung inflammation in a model of the atopic march.

Sabrina N Kline, Laine E Feller, Yoshine Saito, Dustin Dikeman, Christine Youn, Yu Wang, Zhiyang Li, Meng-Jen Wu, Jing Zhang, Cristina Pontaza, Junela C Hunat, Christine T N Pham, Xinzhong Dong, Nathan K Archer.

  Patients with atopic dermatitis exhibit abundant Staphylococcus aureus skin colonization and an increased risk of atopic march diseases, including allergic rhinitis, food allergies, and asthma. We have previously shown that S. aureus skin exposure exacerbates allergic lung inflammation in an interleukin-36 receptor (IL-36R)-dependent manner. However, the cellular and molecular mechanisms by which S. aureus skin exposure and IL-36R signaling orchestrate the progression from skin to lung inflammation are unclear. Using a preclinical model of the atopic march, we found that S. aureus skin exposure promoted robust neutrophilic lung inflammation via keratinocyte- and lung epithelia-specific IL-36R signaling. Unexpectedly, neutrophil IL-36R signaling triggered neutrophil extracellular trap (NET) formation and augmented lung pathology. Importantly, anti-IL-36R monoclonal antibody (mAb) treatment prevented the development of neutrophilic lung inflammation. Collectively, our findings suggested that S. aureus skin exposure exacerbates lung inflammation via distinct IL-36R signaling mechanisms on epithelia and neutrophils, which has therapeutic potential in halting the progression of the atopic march.

Keywords:  CP: Immunology; CP: Microbiology; IL-36; NETs; Staphylococcus aureus; atopic dermatitis; atopic march; immunotherapeutic; inflammation; lung; neutrophilic asthma; skin

DOI:  https://doi.org/10.1016/j.celrep.2025.116054
BMC Biol. 2025 Jul 28. 23(1): 227

Immune priming in the insect gut: a dynamic response revealed by ultrastructural and transcriptomic changes.

Moritz Baur, Nora K E Schulz, Lilo Greune, Zoe M Länger, Jürgen Eirich, Iris Finkemeier, Robert Peuß, Petra Dersch, Joachim Kurtz.

   BACKGROUND: Research on forms of memory in innate immune systems has recently gained momentum with the study of trained immunity in vertebrates and immune priming in invertebrates. Immune priming is an evolutionary ancient process that confers protection against previously encountered pathogens. However, despite the existence of immune priming across many invertebrate taxa, evolution and mechanisms of immune priming are still not well understood. Moreover, it is unclear how natural pathogens might elicit immune priming in their hosts.
RESULTS: Here we combine RNA sequencing with transmission electron microscopy to investigate the dynamic processes during priming in the gut of a well-established model for oral immune priming, consisting of the host Tribolium castaneum and its natural pathogen Bacillus thuringiensis tenebrionis (Btt). We show that priming with specific, pathogen-derived virulence-relevant factors induces gut damage in T. castaneum larvae, triggering an early physiological stress response and upregulation of a distinct set of immune genes. This response diminishes over time yet enables the gut to upregulate genes known to interfere with Btt virulence when later exposed to infectious Btt spores.
CONCLUSIONS: Our findings demonstrate that pathogen-derived factors inducing gut damage and stress responses prime gut tissue to provide more efficient protection against infection. These insights deepen our understanding of the mechanisms driving innate immune memory, which likely evolved as an adaptive response to natural pathogens.

Keywords:   Bacillus thuringiensis ; Evolution of immunity; Innate immune memory; Insect; Invertebrate; Pathogen; Virulence

DOI:  https://doi.org/10.1186/s12915-025-02334-4
Nat Immunol. 2025 Aug;26(8): 1225-1226

How leukocytes push their way through tissues.

DOI: https://doi.org/10.1038/s41590-025-02242-3
Int J Mol Sci. 2025 Jul 14. pii: 6745. [Epub ahead of print]26(14):

Microbiome-Based Products: Therapeutic Potential for Inflammatory Skin Diseases.

Anamarija Rušanac, Zara Škibola, Mario Matijašić, Hana Čipčić Paljetak, Mihaela Perić.

  Maintaining a balanced skin microbiota is essential for skin health, whereas disruptions in skin microbiota composition, known as dysbiosis, can contribute to the onset and progression of various skin disorders. Microbiota dysbiosis has been associated with several inflammatory skin conditions, including atopic dermatitis, seborrheic dermatitis, acne, psoriasis, and rosacea. Recent advances in high-throughput sequencing and metagenomic analyses have provided a deeper understanding of the skin microbial communities in both health and disease. These discoveries are now being translated into novel therapeutic approaches aimed at restoring microbial balance and promoting skin health through microbiome-based interventions. Unlike conventional therapies that often disrupt the microbiota and lead to side effects or resistance, microbiome-based products offer a more targeted strategy for preventing and managing inflammatory skin diseases. These products, which include probiotics, prebiotics, postbiotics, and live biotherapeutic agents, are designed to modulate the skin ecosystem by enhancing beneficial microbial populations, suppressing pathogenic strains, and enhancing immune tolerance. As a result, they represent a promising class of products with the potential to prevent, manage, and even reverse inflammatory skin conditions. However, realizing the full therapeutic potential of microbiome-based strategies in dermatology will require continued research, robust clinical validation, and clear regulatory frameworks.

Keywords:  dysbiosis; human microbiota; inflammatory skin disease; microbiome-based products

DOI:  https://doi.org/10.3390/ijms26146745
Front Immunol. 2025 ;16 1610891

Decidual macrophage subsets and polarization puzzle during the human early pregnancy.

Huiling Liu, Liping Zhang.

  At the maternal-fetal interface from human early pregnancy, decidual macrophages (dMφs) comprise approximately 20% of the leukocyte population, displaying a distinct immunophenotype characterized by hybrid functional features that transcend conventional M1/M2 polarization paradigms. The dynamic balance between M1-like dMφs and M2-like dMφs in human early pregnancy is closely related to the success of pregnancy. However, the comprehensive subsets profiling of dMφs and the factors influencing polarization haven't been elucidated until recent years. In this review, we first delineate the dMφs compositional proportion and subsets profiling during early gestation. Second, we clarify the mechanisms underlying dMφs recruitment and tissue residency. Finally, we comprehensively synthesize molecular drivers of dMφs polarization and the functional specialization of polarized dMφs in sustaining successful pregnancy. A comprehensive understanding of the molecular network governing dMφs polarization dynamics and their functional contributions to gestational processes will provide crucial insights for developing targeted therapeutic strategies to address pregnancy-related complications.

Keywords:  M1-like dMφs; M2-like dMφs; decidual macrophages; human early pregnancy; polarization

DOI:  https://doi.org/10.3389/fimmu.2025.1610891
Front Syst Biol. 2023 ;pii: 1175306. [Epub ahead of print]3

A microbiota-epigenetic circuit controls systematic circadian programs in the gut epithelium.

Junjie Ma, Jianglin Zhang, Zheng Kuang.

  The intestinal microbiota is an important factor that regulates mammalian circadian rhythms and health. We previously reported that the microbiota synchronizes lipid uptake and metabolism in the intestinal epithelium through histone deacetylase 3 (HDAC3). However, the breadth and significance of microbiota-circadian crosstalk in the intestine are not well understood. Here, we show that the gut microbiota programs the rhythmic expression of a broad range of biological processes, and temporally orchestrates epithelial functions and physiology in accordance with the rhythmic gut environment. Protein synthesis, cell proliferation, and metabolic and immune activities are differentially expressed in the daytime and nighttime respectively, indicating a daily alternation of "working" and "recharging" themes in the gut. The rhythms of gene expression are dampened or altered in germ-free mice, suggesting that the microbiota helps to structure the timing of host gene expression. Further analysis showed that HDAC3 drives a vast majority of these microbiota-dependent circadian programs, likely through rhythmic deacetylation of histones. Motif enrichment analysis revealed that HDAC3 could differentially control distinct rhythmic pathways, most likely by recruiting different transcription factors. These findings provide a systematic view of how the commensal microbiota exploits an epigenetic factor to program just-in-time functions in the intestinal epithelium and maintain host homeostasis.

Keywords:  HDAC3; cell proliferation; circadian rhythm; histone acetylation; intestinal epithelial cells; metabolism and immunity; microbiome

DOI:  https://doi.org/10.3389/fsysb.2023.1175306
ACS Infect Dis. 2025 Jul 31.

Simvastatin Administration Prohibits Staphylococcus aureus Anti-ROS Adaptation In Vivo and Alleviates Bone Infections.

Guoliang Chen, Ziwei Fan, Mengxian Jia, Ruini Li, Yaozhi He, Xiaowu Lin, Honglin Teng.

  Bone infections in diabetic patients often result in devastating outcomes, highlighting the need for effective treatment strategies. Our study aims to explore how Staphylococcus aureus adapts to the diabetic microenvironment. This study found increased bacterial resistance to reactive oxygen species (ROS) and a higher expression of the crtOPQMN operon among strains isolated from diabetic patients. Mechanistically, S. aureus was found to increase its staphyloxanthin (STX) level through genomic changes in the locus of rsbU, rsbW, and sigB. Both in vitro and in vivo experiments demonstrated that genomic changes were due to bacterial adaptation to the ROS pressure. Moreover, by adopting simvastatin, a representative STX synthesis inhibitor, we found that statins can inhibit the frequency of S. aureus genomic changes under the pressure of ROS. A mouse infection model demonstrated that simvastatin can reduce bacterial loads, alleviate bone infection outcomes, and increase the cure rate of vancomycin in treating bone infections. These findings suggest that by inhibiting bacterial adaptation toward ROS pressure, simvastatins could be a promising adjunctive therapy for bone infection treatment, especially among diabetic patients.

Keywords:  Bone Infections; Diabetes Mellitus; Reactive Oxygen Species (ROS); Simvastatins; Staphylococcus aureus; Staphyloxanthin (Stx)

DOI:  https://doi.org/10.1021/acsinfecdis.5c00309
Int J Mol Med. 2025 Oct;pii: 163. [Epub ahead of print]56(4):

How lactate and lactylation shape the immunity system in atherosclerosis (Review).

Yan Xiong, Jie Zhou, Junru Wang, Hui Huang.

  Atherosclerosis is a leading cause of cardiovascular diseases, causing significant morbidity and mortality. This review article examines the role of lactate and lactylation in atherosclerosis, a chronic inflammatory disease closely linked to lipid metabolism and immune system activation. Lactate, a metabolic byproduct and signaling molecule, has emerged as a key regulator of immune cell functions and epigenetic modifications. The article explores the mechanisms through which lactate and lactylation influence macrophage polarization, T‑cell differentiation and B‑cell metabolism, highlighting their complex dual roles in the progression of atherosclerosis. By modulating metabolic reprogramming, functional polarization and epigenetic regulation, lactate and lactylation significantly impact plaque formation and stability. These findings provide a foundation for developing novel therapeutic strategies targeting lactate metabolism and lactylation pathways.

Keywords:  atherosclerosis; epigenetic modifications; immune system; lactate; lactylation; metabolic reprogramming

DOI:  https://doi.org/10.3892/ijmm.2025.5604
Nat Microbiol. 2025 Aug;10(8): 1791-1792

Rethinking approaches to overcome infectious disease.

DOI: https://doi.org/10.1038/s41564-025-02093-6
Front Immunol. 2025 ;16 1623182

Bufei Jiedu Formula enhances CD40 activation and macrophage polarization to eliminate intracellular MRSA persisters.

Shaoyan Zhang, Jiajun Chen, Lei Qiu, Xianwei Wu, Wei Zhou, Ruoqing Peng, Ya Feng, Rui Zhou, Xing Huang, Dingzhong Wu, Zhenhui Lu.

   Background: Intracellular methicillin-resistant Staphylococcus aureus (MRSA) represents a complex infection in clinical practice, characterized by its refractory and recurrent nature, rendering it challenging to treat with conventional antibiotics. Bufei Jiedu Formula (BFJD) is a traditional Chinese medicine compound utilized for treating chronic lung infections; however, its mechanisms against intracellular MRSA infection are not yet fully understood.
Methods: An animal model with persistent MRSA infection was used to evaluate the efficacy of BFJD against chronic bacterial infections. Flow cytometry was employed to assess the regulatory effects of BFJD on macrophages. Transcriptomic sequencing and molecular biological experiments were utilized to explore and validate the regulatory targets and pathways of BFJD. Flow cytometry and molecular docking were used to clarify the possible binding mode of bioactive compounds with CD40.
Results: BFJD reduced bacterial loads in the lungs, liver, and kidneys of mice with persistent MRSA infection and promoted M1 polarization of macrophages in the lungs. In vitro, BFJD decreased intracellular MRSA persisters loads and enhanced macrophage M1 polarization and M2-to-M1 repolarization. Multi-time point cellular sequencing data revealed the transcriptomic characteristics of intracellular persistent MRSA infections, including the downregulation of cytokine activity and TNF signaling pathways. GO-KEGG enrichment analysis revealed that BFJD regulated signaling pathways related to response to reactive oxygen species (ROS), IL-1β and IL-6 production, NF-κB and TNF signaling. Further intersection analysis found that genes down-regulated in the persistence state were up-regulated by BFJD, among which pro-inflammatory genes including Il1b, Il6, Ccl2, and Cd40 were all reversed. Furthermore, we found BFJD enhanced the host-mediated intracellular killing of MRSA by macrophages via the CD40-ROS-NF-κB signaling cascade. Multiplex cytokine analysis showed that BFJD increased the levels of IL-1β, CCL-2, IL-6, and TNF-α in the serum of persistently infected mice. Further screening of active compounds revealed that atractylenolide II and formononetin exhibit high affinity with CD40 and decreased intracellular bacterial loads.
Conclusion: BFJD decreased organ bacterial loads in mice with persistent MRSA infection by regulating the CD40-ROS-NF-κB signaling pathway, thereby modulating macrophage immunophenotypes and exerting anti-MRSA persister effects.

Keywords:  CD40; MRSA infection; atractylenolide II; intracellular; macrophage polarization; persistent

DOI:  https://doi.org/10.3389/fimmu.2025.1623182
PLoS Pathog. 2025 Jul;21(7): e1013366

Lactylation and viral infections: A novel link between metabolic reprogramming and immune regulation.

Shanshan Chen, Tongxue Qin, Shengrui Luo, Fengyi Wang, Feirong Chen, Hailun Wei, Yuting Wu, Rongfeng Chen, Wudi Wei, Jingzhen Lai, Hao Liang, Li Ye, Zongxiang Yuan, Junjun Jiang.

Post-translational modifications (PTMs) regulate protein structure, function, and interactions, playing pivotal roles in cellular processes and disease progression. Lactate, a byproduct of the Warburg effect, accumulates excessively during viral infections and functions as a signaling molecule, disrupting mitochondrial antiviral-signaling protein activity and facilitating viral immune evasion. Lactylation, a recently identified PTM derived from lactate metabolism, links cellular metabolism and immune regulation by modulating gene expression and metabolic reprogramming. It also serves as a mechanism for viruses to modulate host immunity. Despite its emerging importance, its role with respect to viruses infecting humans and animals remains poorly understood. Investigating its impact on metabolic, protein modifications, and immune signaling may reveal novel immune evasion strategies and therapeutic targets. This review aims to provide an overview of the fundamental features and regulatory functions of lactylation, explore its association with viral infections, and offer insights into how lactylation influences metabolic and immune responses during virus-host interactions.

DOI: https://doi.org/10.1371/journal.ppat.1013366
Pathogens. 2025 Jul 11. pii: 683. [Epub ahead of print]14(7):

NOD2 (Nucleotide-Binding Oligomerization Domain-Containing Protein 2)-Mediated Modulation of the Immune Response Induced by BCG (Bacillus Calmette-Guérin) Bacilli.

Magdalena Jurczak, Joanna Kaczmarek, Magdalena Kowalewska-Pietrzak, Paulina Stelmach, Magdalena Druszczynska.

  The Bacillus Calmette-Guérin (BCG) vaccine confers broad, non-specific immunity that may bolster defenses against respiratory viruses. While NOD2 (nucleotide-binding oligomerization domain-containing protein 2)-driven pathways are central to innate immune responses, the contribution of surface receptor modulation on monocytes to shaping these responses remains underexplored. We analyzed whole-blood cultures from BCG-vaccinated Polish children, stratified by serostatus to SARS-CoV-2 and RSV, and stimulated for 48 h with live BCG, purified viral antigens, or both. RT-qPCR quantified mRNA levels of NOD2 and key cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF), while flow cytometry assessed CD14, HLA-DR, CD11b, and CD206 expression. Co-stimulation with BCG + RSV elicited the strongest transcriptional response, notably a 2-4-fold upregulation of NOD2, IL-1β, and IL-6 versus RSV alone. In SARS-CoV-2(+) donors, RSV alone induced higher NOD2 expression than BCG or BCG + RSV, while IL-2 peaked following BCG + SARS-CoV-2. Across conditions, NOD2 positively correlated with IL-4 and IL-6 but negatively correlated with IL-1β in SARS-CoV-2 cultures. Viral antigens increased CD14 and HLA-DR on monocytes, suggesting activation; CD206 rose only in dual-seropositive children. Our findings indicate that BCG stimulation affects pediatric antiviral immunity through NOD2-related cytokine production and induction of a CD14+HLA-DR+ phenotype, supporting its potential role in boosting innate defenses against respiratory pathogens.

Keywords:  Bacillus Calmette-Guérin; respiratory syncytial virus; severe acute respiratory syndrome coronavirus 2

DOI:  https://doi.org/10.3390/pathogens14070683