bims-bac4me 2025-01-12 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–01–12
37 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Orally Administered Lactobacilli Strains Modulate Alveolar Macrophages and Improve Protection Against Respiratory Superinfection.
Dendritic cell immunometabolism - a potential therapeutic target for allergic diseases.
Importance of Lactobacilli for Human Health.
Exploring the mechanism and crosstalk between IL-6 and IL- 1β on M2 macrophages under metabolic stress conditions.
HCAR2 Modulates the Crosstalk between Mammary Epithelial Cells and Macrophages to Mitigate Staphylococcus aureus Infection in the Mouse Mammary Gland.
Weakened Airway Epithelial Junctions and Enhanced Neutrophil Elastase Release Contribute to Age-Dependent Bacteremia Risk Following Pneumococcal Pneumonia.
Helminth infection induces innate immune priming in plasmacytoid dendritic cells.
Intranasal exposure to commensal bacterium Rothia mucilaginosa protects against influenza A virus infection.
Clec12a controls colitis by tempering inflammation and restricting expansion of specific commensals.
β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus.
HCMV infection downregulates GPX4 and stimulates lipid peroxidation but does not induce ferroptosis.
MAP Kinase Signaling at the Crossroads of Inflammasome Activation.
Directional and Strain-Specific Interaction Between Lactobacillus plantarum and Staphylococcus aureus.
Staphylococcus aureus: Current perspectives on molecular pathogenesis and virulence.
Pharmacological inhibition of key metabolic pathways attenuates Leishmania spp infection in macrophages.
Immunomodulatory Properties of Multi-Strain Postbiotics on Human CD14+ Monocytes.
Immune crosstalk between respiratory and intestinal mucosal tissues in respiratory infections.
Crosstalk between ferroptosis and autophagy: broaden horizons of cancer therapy.
The Cellular and Transcriptomic Early Innate Immune Response to BCG Vaccination in Mice.
CCL4 Affects Eosinophil Survival via the Shedding of the MUC1 N-Terminal Domain in Airway Inflammation.
Ferroptosis and tumor immunity.
Commensal fungi, a force to be reckoned with.
Iron Regulatory Protein 2 (IRP2) Deficiency Is Protective Against Resistive Breathing-induced Pulmonary Inflammation.
Heightened innate immune state induced by viral vector leads to enhanced response to challenge and prolongs malaria vaccine protection.
Granulocyte macrophage colony stimulating factor in virus-host interactions and its implication for immunotherapy.
IRF1 cooperates with ISGF3 or GAF to form innate immune de novo enhancers in macrophages.
Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine.
Regulation of cGAS-STING signalling and its diversity of cellular outcomes.
Protocol for generating and characterizing a nasal epithelial model using imaging with application for respiratory viruses.
Bovine Lactoferrin Enhances Toll-like Receptor 7 Response in Plasmacytoid Dendritic Cells and Modulates Cellular Immunity.
Effects of Lacticaseibacillus paracasei L9 on Oral Microbiota and Cariogenic Factors in Streptococcus mutans-Infected Mice.
Monocyte-derived macrophages act as reinforcements when microglia fall short in Alzheimer's disease.
Mechanisms of metabolism-coupled protein modifications.
Targeted Antibacterial Endolysin to Treat Infected Wounds on 3D Full-Thickness Skin Model: XZ.700 Efficacy.
NLRP3 promotes inflammatory signaling and IL-1β cleavage in acute lung injury caused by cell wall extract of Lactobacillus casei.
The Ability of SOCS1 to Cross-Regulate GM-CSF Signaling is Dose Dependent.
Harnessing gut microbial communities to unravel microbiome functions.

Biomolecules. 2024 Dec 14. pii: 1600. [Epub ahead of print]14(12):

Orally Administered Lactobacilli Strains Modulate Alveolar Macrophages and Improve Protection Against Respiratory Superinfection.

Leonardo Albarracin, Stefania Dentice Maidana, Kohtaro Fukuyama, Mariano Elean, Julio Nicolás Argañaraz Aybar, Yoshihito Suda, Keita Nishiyama, Haruki Kitazawa, Julio Villena.

  Orally administered immunomodulatory lactobacilli can stimulate respiratory immunity and enhance the resistance to primary infections with bacterial and viral pathogens. However, the potential beneficial effects of immunomodulatory lactobacilli against respiratory superinfection have not been evaluated. In this work, we showed that the feeding of infant mice with Lacticaseibacillus rhamnosus CRL1505 or Lactiplantibacillus plantarum MPL16 strains can reduce susceptibility to the secondary pneumococcal infection produced after the activation of TLR3 in the respiratory tract or after infection with RVS. The treatment of mice with CRL1505 or MPL16 strains by the oral route improved the production of interferons in the respiratory tract, differentially modulated the balance of pro- and anti-inflammatory cytokines, reduced bacterial replication, and diminished lung damage. Additionally, we demonstrated that orally administered lactobacilli confer longstanding protection against secondary Streptococcus pneumoniae infection and that this effect would be mediated by the stimulation of trained alveolar macrophages. This work contributes to revealing the mechanisms involved in the modulation of the gut-lung axis by beneficial microbes by demonstrating that specific lactobacilli strains, through the stimulation of the common mucosal immune system, would be able to support the development of trained alveolar macrophages that would confer longstanding protection against secondary bacterial challenges produced after a primary inflammatory event in the respiratory mucosa.

Keywords:  Lacticaseibacillus rhamnosus CRL1505; alveolar macrophages; probiotic lactobacilli; respiratory immunity; superinfection

DOI:  https://doi.org/10.3390/biom14121600
Int J Med Sci. 2025 ;22(2): 417-431

Dendritic cell immunometabolism - a potential therapeutic target for allergic diseases.

Chuang Ouyang, Jiaying Huang, Gonghua Huang, Yanyan Wang.

  Allergic diseases are a group of chronic inflammatory disorders driven by abnormal immune responses. Dendritic cells (DCs) play a pivotal role in the initiation and progression of allergic diseases by modulating T cell responses. Extensive progress has been made in characterizing crucial roles of metabolic reprogramming in the regulation of immune cell functions. As the critical upstream regulators and effectors in allergic responses, the activation, migration, and function of DCs are reliant on metabolic reprogramming. In this review, we summarize the metabolic characteristics of DCs, and how the cellular microenvironment shapes DC function. We also elucidate the metabolic regulation of DC biology in the context of allergic diseases and targeted therapeutic strategies based on DC metabolism regulation. Understanding the functional alterations in DCs during allergic responses and the underlying mechanisms governing its metabolic regulation is crucial for the development of effective strategies for the prevention and treatment of allergic diseases.

Keywords:  Allergic disease; Dendritic cell; Gut microbiota; Immunometabolism; T cell response; Targeted therapy

DOI:  https://doi.org/10.7150/ijms.105532
Microorganisms. 2024 Nov 21. pii: 2382. [Epub ahead of print]12(12):

Importance of Lactobacilli for Human Health.

Piotr B Heczko, Milena Giemza, Weronika Ponikiewska, Magdalena Strus.

  As an extraordinarily diverse group of bacteria, lactobacilli are now classified into several genera, many of which still include "Lactobacillus" in their names. Despite their names, this group of lactic acid bacteria comprises microorganisms that are crucial for human health, especially during the early development of the human microbiota and immune system. The interactions between lactobacilli and components of the mucosal immunity lead to its shaping and development, which is possibly considered a prime mover in the advancement of the human immune system. Although much of the evidence backing the pivotal role of lactobacilli in maintaining human health comes from studies on probiotics aiming to elucidate the mechanisms of their functional activities and studies on mucosal immunity in germ-free mice, it is justifiable to extend observations on the properties of the individual probiotic Lactobacillus that are related to health benefits onto other strains sharing common characteristics of the species. In this review, we will discuss the acquisition, presence, and functions of lactobacilli in different human microbiota throughout their whole life, including those arising in the amnion and their interactions with mucosal and immune cells. Examples of immune system modulation by probiotic lactobacilli include their colonic competition for available nutrients, interference with colonization sites, competition for binding sites on gut epithelial cells, bacteriocin production, reduction of colonic pH, and nonspecific stimulation of the immune system.

Keywords:  Lactobacillus; gut–vaginal microbiota; innate immunity; neonates

DOI:  https://doi.org/10.3390/microorganisms12122382
Cytokine. 2025 Jan 06. pii: S1043-4666(24)00356-9. [Epub ahead of print]186 156852

Exploring the mechanism and crosstalk between IL-6 and IL- 1β on M2 macrophages under metabolic stress conditions.

Shawna Yadav, Anusha Prasannan, Kaliyamurthi Venkatachalam, Ambika Binesh.

  Macrophages are highly variable immune cells that are important in controlling inflammation and maintaining tissue balance. The ability to polarize into two major types-M1, promoting inflammation, and M2, resolving inflammation and contributing to tissue repair-determines their specific roles in health and disease. M2 macrophages are particularly important for reducing inflammation and promoting tissue regeneration, but their function is shaped mainly by surrounding cells. This is evident in obesity, diabetes, and chronic inflammation. Although many cytokines regulate macrophage polarization, interleukin-6 (IL-6) and interleukin-1β (IL-1β) are major players, but their effects on M2 macrophage behavior under metabolic stress remain unclear. This study describes the intricacies within M2 macrophages concerning IL-6 and IL-1β signaling when under metabolic stress. Though, more frequently than not, IL-6 is labelled as pro-inflammatory, it can also behave as an anti-inflammatory mediator. On the other hand, IL-1β is the main pro-inflammatory agent, particularly in metabolic disorders. The relationship between these cytokines and the macrophages is mediated through important pathways such as JAK/STAT and NFκB, which get perturbed by metabolic stress. Therefore, metabolic stress also alters the functional parameters of macrophages, including alterations in mitochondrial metabolism, glycolytic and oxidative metabolism. Phosphorylation alters the kinetics involved in energy consumption and affects their polarization and their function. However, it has been suggested that IL-6 and IL-1β may work in concert or competition when inducing M2 polarization and, importantly, implicate cytokine release, phagocytic activity, and tissue repair processes. In this review, we discuss the recent literature on the participation of IL-6 and IL-1β cytokines in macrophage polarization and how metabolic stress changes cytokine functions and synergistic relations. A better understanding of these cytokines would serve as an important step toward exploring alternative antiviral strategies directed against metabolic disturbance and, hence, approve further endeavors.

Keywords:  Interleukin-6; Interleulin-1β; Macrophage polarization and inflammation; Macrophages; Metabolic stress

DOI:  https://doi.org/10.1016/j.cyto.2024.156852
Adv Sci (Weinh). 2025 Jan 10. e2411947

HCAR2 Modulates the Crosstalk between Mammary Epithelial Cells and Macrophages to Mitigate Staphylococcus aureus Infection in the Mouse Mammary Gland.

Xin Ran, Kefei Li, Yutao Li, Weiwei Guo, Xiaoxuan Wang, Wenjin Guo, Bao Yuan, Juxiong Liu, Shoupeng Fu.

  Staphylococcus aureus (S. aureus) is a major zoonotic pathogen, with mammary gland infections contributing to mastitis, a condition that poses significant health risks to lactating women and adversely affects the dairy industry. Therefore, understanding the immune mechanisms underlying mammary infections caused by S. aureus is essential for developing targeted therapeutic strategies against mastitis. This study identified hydroxycarboxylic acid receptor 2 (HCAR2) as a potential regulator of S. aureus infection in mammary glands. It is demonstrated that HCAR2 deficiency exacerbates the inflammatory response and disrupts the blood-milk barrier in the mammary gland during S. aureus infection, with NLRP3 inflammasome-mediated pyroptosis playing a central role. Activation of HCAR2, on the other hand, suppressed CMPK2 expression, thereby mitigating mitochondrial damage and pyroptosis in mouse mammary epithelial cells (mMECs) induced by S. aureus. Additionally, mitochondrial DNA (mtDNA) released from S. aureus-infected mMECs activates the cGAS/STING signaling pathway in macrophages, impairing their bactericidal activity. In conclusion, this study highlights the critical role of HCAR2 in S. aureus infection of the mammary gland and provides a theoretical basis for identifying potential therapeutic targets for such infections.

Keywords:  CMPK2; HCAR2; S. aureus; mastitis; pyroptosis

DOI:  https://doi.org/10.1002/advs.202411947
Aging Cell. 2025 Jan 08. e14474

Weakened Airway Epithelial Junctions and Enhanced Neutrophil Elastase Release Contribute to Age-Dependent Bacteremia Risk Following Pneumococcal Pneumonia.

Shuying Xu, Tianmou Zhu, Hongmei Mou, Shumin Tan, John M Leong.

  Streptococcus pneumoniae (Sp; pneumococcus), the most common agent of community-acquired pneumonia, can spread systemically, particularly in the elderly, highlighting the need for adjunctive therapies. The airway epithelial barrier defends against bacteremia and is dependent upon apical junctional complex (AJC) proteins such as E-cadherin. After mouse lung challenge, pneumolysin (PLY), a key Sp virulence factor, stimulates epithelial secretion of an inflammatory eicosanoid, triggering the infiltration of polymorphonuclear leukocytes (PMNs) that secrete high levels of neutrophil elastase (NE), thus promoting epithelial damage and systemic infection. Here, pulmonary E-cadherin staining of intratracheally (i.t.) inoculated mice revealed PLY-mediated disruption of AJC independently of PMNs. Apical infection of air-liquid interface (ALI) respiratory epithelial monolayers similarly showed that PLY disrupts AJCs. This epithelial damage promoted PMN transmigration and bacterial apical-to-basolateral translocation, and pharmacologically fortifying epithelial barrier function diminished both barrier breach in vitro and bacteremia in vivo. E-cadherin staining after Sp i.t. inoculation of > 20-month-old mice, or apical infection of ALI monolayers derived from these mice, revealed an age-associated vulnerability to PLY-mediated AJC disruption, which in turn enhanced PMN migration and bacteremia. In addition, we found that PMNs from aged mice secrete increased levels of tissue-damaging NE. Simultaneous pharmacological inhibition of tissue-destructive NE and fortification of pulmonary epithelial barrier function was required to reduce the level of Sp bacteremia in aged mice to that of young mice. This work underscores the importance of fully characterizing the multifactorial sources of age-associated susceptibility in devising adjunctive therapies to mitigate invasive pneumococcal disease in the elderly.

Keywords:   Streptococcus pneumoniae ; E‐cadherin; aging; neutrophil transmigration; pneumolysin

DOI:  https://doi.org/10.1111/acel.14474
J Infect Dis. 2025 Jan 07. pii: jiaf009. [Epub ahead of print]

Helminth infection induces innate immune priming in plasmacytoid dendritic cells.

Lamin B Cham, Bradley Whitehead, Marvin Werner, Frederikke Jensen, Mads Zippor, Trine H Mogensen, Mihai G Netea, Andrew R Williams, Peter Nejsum.

  Heligmosomoides polygyrus co-infection is reported to have protective antiviral effects against pulmonary viral infections. To investigate a potential underlying mechanism, we infected C57BL/6 mice with H. polygyrus larvae for two weeks. Bone marrow (BM)-derived plasmacytoid dendritic cells (pDCs) were generated and stimulated with TLR agonists. We found increased expression of type 1 interferon genes (Ifnα1, Ifnα4, Ifnβ1, Mx1, Isg15), increased TNF, IL-6, IL-10 secretion, and higher expression of antigen presentation markers in BM-derived-pDCs from infected mice compared to naïve control. Our findings may partly explain the mechanism of the antiviral protection previously reported in acute helminth infections.

Keywords:   H. polygyrus ; Bone marrow; antiviral; helminth; plasmacytoid dendritic cells

DOI:  https://doi.org/10.1093/infdis/jiaf009
Antiviral Res. 2025 Jan 02. pii: S0166-3542(25)00001-4. [Epub ahead of print]234 106076

Intranasal exposure to commensal bacterium Rothia mucilaginosa protects against influenza A virus infection.

Ana Raquel Maia, Loïc Gonzalez, Badreddine Bounab, Lucia Grassi, Coralie Mousset, Gaëlle Fromont-Hankard, Adeline Cezard, Pieter Hiemstra, Thomas Baranek, Christophe Paget, Aurélie Crabbé, Mustapha Si-Tahar.

  The respiratory tract hosts a diverse microbial community whose composition varies with anatomical location and throughout life. Rothia mucilaginosa, a common commensal of the upper respiratory tract and oral cavity, has recently been recognized for its ability to inhibit bacteria-triggered pro-inflammatory responses. However, its role in modulating the immune response to viral infections such as influenza A virus (IAV) pneumonia, remains unknown. Here, we demonstrate that R. mucilaginosa enhances protection against IAV, promoting viral clearance, reducing inflammation, preserving bronchial and alveolar structures, and improving survival in a mouse model of influenza pneumonia. The enhanced viral clearance observed in R. mucilaginosa-treated mice is associated with the recruitment of innate immune cells to the lungs, including PD-L1-expressing neutrophils, alongside the production of the anti-inflammatory cytokine IL-10, both of which are known to play regulatory roles in the context of IAV infection. Together, these findings highlight R. mucilaginosa-mediated innate immune priming as a key protective mechanism in the respiratory tract against IAV infection.

Keywords:  Antiviral; Commensal; Influenza virus; Microbiota; Protection; Respiratory tract; Rothia mucilaginosa

DOI:  https://doi.org/10.1016/j.antiviral.2025.106076
Cell Host Microbe. 2025 Jan 08. pii: S1931-3128(24)00474-8. [Epub ahead of print]33(1): 89-103.e7

Clec12a controls colitis by tempering inflammation and restricting expansion of specific commensals.

Tyson R Chiaro, Morgan Greenewood, Kaylyn M Bauer, Kyla S Ost, Emmanuel Stephen-Victor, Michaela Murphy, Allison M Weis, Morgan C Nelson, Jennifer H Hill, Rickesha Bell, Warren Voth, Taylor Jackson, Kendra A Klag, Ryan M O'Connell, W Zac Stephens, June L Round.

  Microbiota composition regulates colitis severity, yet the innate immune mechanisms that control commensal communities and prevent disease remain unclear. We show that the innate immune receptor, Clec12a, impacts colitis severity by regulating microbiota composition. Transplantation of microbiota from a Clec12a-/- animal is sufficient to worsen colitis in wild-type mice. Clec12a-/- mice have expanded Faecalibaculum rodentium, and treatment with F. rodentium similarly exacerbates disease. However, Clec12a-/- animals are resistant to colitis development when rederived into an 11-member community, underscoring the role of specific species. Colitis in Clec12a-/- mice is dependent on monocytes, and cytokine and sequencing analysis in Clec12a-/- macrophages and serum shows enhanced inflammation with a reduction in phagocytic genes. F. rodentium specifically binds to Clec12a, and Clec12a-/--deficient macrophages are impaired in their ability to phagocytose F. rodentium. Thus, Clec12a contributes to an innate-immune-surveillance mechanism that controls the expansion of potentially harmful commensals while limiting inflammation.

Keywords:  C-Type Lectin; Clec12a; F. rodentium; immune regulation; intestine; macrophage; microbiota; phagocytosis

DOI:  https://doi.org/10.1016/j.chom.2024.12.009
Nat Immunol. 2025 Jan 08.

β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus.

Nargis Khan, Kim A Tran, Raphael Chevre, Veronica Locher, Mathis Richter, Sarah Sun, Mina Sadeghi, Erwan Pernet, Andrea Herrero-Cervera, Alexandre Grant, Ahmed Saif, Jeffrey Downey, Eva Kaufmann, Shabaana Abdul Khader, Philippe Joubert, Luis B Barreiro, Bryan G Yipp, Oliver Soehnlein, Maziar Divangahi.

Disease tolerance is an evolutionarily conserved host defense strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant (β-glucan) can reprogram innate immunity to provide protection against influenza A virus (IAV) infection. β-Glucan treatment reduces the morbidity and mortality against IAV infection, independent of host resistance. The enhanced survival is the result of increased recruitment of neutrophils via RoRγt+ T cells in the lung tissue. β-Glucan treatment promotes granulopoiesis in a type 1 interferon-dependent manner that leads to the generation of a unique subset of immature neutrophils utilizing a mitochondrial oxidative metabolism and producing interleukin-10. Collectively, our data indicate that β-glucan reprograms hematopoietic stem cells to generate neutrophils with a new 'regulatory' function, which is required for promoting disease tolerance and maintaining lung tissue integrity against viral infection.

DOI: https://doi.org/10.1038/s41590-024-02041-2
J Virol. 2025 Jan 07. e0185124

HCMV infection downregulates GPX4 and stimulates lipid peroxidation but does not induce ferroptosis.

Madison Martin, Rinki Kumar, Nicholas J Buchkovich, Christopher C Norbury.

  Human cytomegalovirus (HCMV) modulates numerous cellular pathways to facilitate infection, including key components in cellular iron homeostasis. Iron is essential to many cellular processes but, if present in excess, drives cell death through ferroptosis. Ferroptosis is a process that is dependent upon the accumulation of oxidatively damaged phospholipids (lipid peroxides); when these lipid peroxides accumulate in membranes, this culminates in plasma membrane rupture and eventual cell lysis. Here, we demonstrate that HCMV infection downregulates the expression of a key modulator of lipid peroxidation, glutathione peroxidase 4 (GPX4). HCMV infection also markedly increased levels of lipid peroxides within infected cells. Despite the marked downregulation of GPX4 by HCMV, further inhibition of GPX4 impaired virus replication. Interestingly, overexpression of GPX4 did not reduce the production of lipid peroxides within infected cells. In contrast, lipid peroxide levels were reduced by treatment with ferrostatin-1, a ferrous iron-dependent scavenger of alkoxyl radicals, indicating a role for iron in the production of lipid peroxides. HCMV-infected cells became less sensitive to GPX4 inhibition as infection progressed, requiring substantially higher levels of GPX4 inhibitors to induce ferroptosis compared to uninfected cells. This observed difference in sensitivity to ferroptosis upon infection correlated with a large increase in lipid production by infected cells. Therefore, the marked stimulation of lipid peroxidation by HCMV likely proceeds through a pathway that is independent of GPX4 regulation, but the ability of lipid peroxides to stimulate ferroptosis by modulating plasma membrane rupture is likely blunted by the massive increase in lipid production during HCMV infection.
IMPORTANCE: Human cytomegalovirus (HCMV) infection is intimately linked with countless host cell pathways that are modulated in a coordinated fashion to facilitate infection. Here, we describe HCMV-induced regulation of lipid peroxidation, a precursor of the iron-regulated cell death pathway known as ferroptosis, during human cytomegalovirus infection. These studies reveal hitherto unidentified changes in metabolism mediated by HCMV that decrease sensitivity to ferroptosis, despite increases in lipid peroxidation and transient increases in intracellular iron levels in infected cells.

Keywords:  HCMV; ferroptosis; iron; lipid peroxides

DOI:  https://doi.org/10.1128/jvi.01851-24
Immunol Rev. 2025 Jan;329(1): e13436

MAP Kinase Signaling at the Crossroads of Inflammasome Activation.

Alex Vervaeke, Mohamed Lamkanfi.

  Inflammasomes are crucial mediators of both antimicrobial host defense and inflammatory pathology, requiring stringent regulation at multiple levels. This review explores the pivotal role of mitogen-activated protein kinase (MAPK) signaling in modulating inflammasome activation through various regulatory mechanisms. We detail recent advances in understanding MAPK-mediated regulation of NLRP3 inflammasome priming, licensing and activation, with emphasis on MAPK-induced activator protein-1 (AP-1) signaling in NLRP3 priming, ERK1 and JNK in NLRP3 licensing, and TAK1 in connecting death receptor signaling to NLRP3 inflammasome activation. Furthermore, we discuss novel insights into MAPK signaling in human NLRP1 inflammasome activation, focusing on the MAP3K member ZAKα as a key kinase linking ribosomal stress to inflammasome activation. Lastly, we review recent work elucidating how Bacillus anthracis lethal toxin (LeTx) manipulates host MAPK signaling to induce macrophage apoptosis as an immune evasion strategy, and the counteraction of this effect through genotype-specific Nlrp1b inflammasome activation in certain rodent strains.

Keywords:  JNK; MAP kinase; TAK1; inflammasome; inflammation; p38; pyroptosis

DOI:  https://doi.org/10.1111/imr.13436
Microorganisms. 2024 Nov 26. pii: 2432. [Epub ahead of print]12(12):

Directional and Strain-Specific Interaction Between Lactobacillus plantarum and Staphylococcus aureus.

Sandeep Kondakala, Sunghyun Yoon, Soumana Daddy Gaoh, Ohgew Kweon, Seong-Jae Kim, Mark E Hart.

  The interaction between Lactobacillus plantarum and Staphylococcus aureus strains FRI-1169 and MN8, two original isolated strains from menstrual toxic shock syndrome (mTSS) cases, is a key focus for developing non-antibiotic strategies to control S. aureus-related infections. While the antagonistic effects of Lactobacilli species on S. aureus through mechanisms like organic acid and bacteriocin production are known, the molecular dynamics of these interactions remain underexplored. This study employs a proteomic approach to analyze the interactions between L. plantarum WCFS1 and S. aureus strains, FRI-1169 and MN8, during co-culture. We profiled differentially expressed proteins (DEPs) found in the spent media and cytosols of both bacteria, revealing distinct directional and strain-specific responses. The findings demonstrate that L. plantarum exerts a more pronounced effect on S. aureus, with more DEPs and upregulated proteins, while S. aureus showed fewer DEPs and more downregulated proteins. These strain-specific interactions highlight the complex metabolic and regulatory adjustments between these bacterial species. This research provides valuable insights into the molecular mechanisms of Lactobacillus-S. aureus antagonism and underscores the potential of proteomic analysis as a powerful tool for studying bacterial dynamics in co-culture systems.

Keywords:  Lactobacillus plantarum; Staphylococcus aureus infection; antagonism; non-antibiotic biocontrol agent; proteomics

DOI:  https://doi.org/10.3390/microorganisms12122432
Cell Surf. 2025 Jun;13 100137

Staphylococcus aureus: Current perspectives on molecular pathogenesis and virulence.

Abayeneh Girma.

  Staphylococcus aureus has evolved a sophisticated regulatory system to control its virulence. One of the main roles of this interconnected network is to sense and respond to diverse environmental signals by altering the synthesis of virulence components required for survival in the host, including cell surface adhesins, extracellular enzymes and toxins. The accessory gene regulator (agr), a quorum sensing system that detects the local concentration of a cyclic peptide signaling molecule, is one of the well-studied of these S. aureus regulatory mechanisms. By using this system, S. aureus is able to sense its own population density and translate this information into a specific pattern of gene expression. In addition to Agr, this pathogen senses specific stimuli through various two-component systems and synchronizes responses with alternative sigma factors and cytoplasmic regulators of the SarA protein family. These different regulatory mechanisms combine host and environmental information into a network that guarantees the best possible response of pathogens to changing circumstances. In this article, an overview of the most significant and thoroughly studied regulatory systems of S. aureus is provided, along with a summary of their roles in host interactions.

Keywords:  Anti-virulence strategies; Molecular pathogenesis; Staphylococcus aureus; Virulence

DOI:  https://doi.org/10.1016/j.tcsw.2024.100137
PLoS Negl Trop Dis. 2025 Jan 07. 19(1): e0012763

Pharmacological inhibition of key metabolic pathways attenuates Leishmania spp infection in macrophages.

Elaine Carvalho de Oliveira, Rafael Tibúrcio, Gabriela Duarte, Amanda Lago, Léon de Melo, Sara Nunes, Gustavo Gastão Davanzo, Ana Júlia Martins, Bruno Vinagre Ribeiro, Deborah Mothé, Juliana B P Menezes, Patrícia Veras, Natalia Tavares, Pedro M Moraes-Vieira, Cláudia Ida Brodskyn.

Macrophages represent a fundamental component of the innate immune system that play a critical role in detecting and responding to pathogens as well as danger signals. Leishmania spp. infections lead to a notable alteration in macrophage metabolism, whereby infected cells display heightened energy metabolism that is linked to the integrity of host mitochondria. However, little is known about how different species of Leishmania manipulate host metabolism. Here, we demonstrate that despite differences in their mechanisms for evading host immune responses, L. amazonensis and L. braziliensis induce comparable disruptions in key metabolic pathways. We found that infected macrophages exhibited an overall elevation in energy metabolism regardless of the parasite strain, evidenced by the elevation in glycolysis and oxygen consumption rates, along with increased proton leak and decreased ATP production. We also analyzed the effects of both Leishmania spp. strain infection on mitochondria function, further revealing that infected cells display heightened mitochondrial mass and membrane potential. To investigate the metabolic pathways required for Leishmania amastigotes to persist in BMDMs, we pre-treated cells with small molecule drugs that target major metabolic pathways, revealing that perturbations in several metabolic processes affected parasite survival in a strain-independent manner. Treatments with inhibitors of the oxidative phosphorylation and glycolysis substantially reduced parasite loads. Collectively, our findings suggest that L.amazonensis and L.braziliensis exploit host cell metabolic pathways similarly to survive in macrophages.

DOI: https://doi.org/10.1371/journal.pntd.0012763
Life (Basel). 2024 Dec 17. pii: 1673. [Epub ahead of print]14(12):

Immunomodulatory Properties of Multi-Strain Postbiotics on Human CD14+ Monocytes.

Kyle D Roberts, Sadia Ahmed, Erin San Valentin, Luca Di Martino, Thomas S McCormick, Mahmoud A Ghannoum.

  The ability of probiotics, comprising live microbiota, to modulate the composition of intestinal microbiomes has been connected to modulation of the central nervous system (Gut-Brain axis), neuroendocrine system (Gut-Skin axis), and immune response (Gut-Immune axis). Less information is known regarding the ability of postbiotics (cell wall components and secreted metabolites derived from live organisms) to regulate host immunity. In the present study, we tested postbiotics comprising single strains of bacteria and yeast (Lactobacillus acidophilus 16axg, Lacticaseibacillus rhamnosus 18fx, Saccharomyces cerevisiae var. boulardii 16mxg) as well as combinations of multiple strains for their ability to stimulate cytokine production by human CD14+ monocytes. We quantified cytokine gene and protein expression levels in monocytes following stimulation with postbiotics. Both heat-killed L. acidophilus and L. rhamnosus stimulated naïve monocytes without significant differences between them. Heat-killed S. boulardii stimulated less cytokine production compared to postbiotic bacteria at the same concentration. Interestingly, the addition of heat-killed yeast to heat-killed L. acidophilus and L. rhamnosus resulted in an enhancement of immune stimulation. Thus, heat-killed postbiotics have immune-modulating potential, particularly when bacteria and yeast are combined. This approach may hold promise for developing targeted interventions that can be fine-tuned to modulate host immune response with beneficial health impact.

Keywords:  Lacticaseibacillus rhamnosus; Lactobacillus acidophilus; Saccharomyces boulardii; immunomodulation; postbiotics

DOI:  https://doi.org/10.3390/life14121673
Mucosal Immunol. 2025 Jan 02. pii: S1933-0219(24)00136-3. [Epub ahead of print]

Immune crosstalk between respiratory and intestinal mucosal tissues in respiratory infections.

Min Zhao, Lei Zhou, Shuo Wang.

Mucosal tissues, including those in the respiratory and gastrointestinal tracts, are critical barrier surfaces for pathogen invasion. Infections at these sites not only trigger local immune response, but also recruit immune cells from other tissues. Emerging evidence in mouse models and human samples indicate that the immune crosstalk between lung and gut critically impact and determine the course of respiratory disease. Here we summarize the current knowledge of the immune crosstalk between respiratory and gastrointestinal tracts during respiratory infections, discussing how immune cells are recruited and migrated between these tissues, and how commensal bacteria contribute to these processes. Understanding of immune regulation between respiratory and intestinal mucosal tissues will be critical for developing therapeutic strategies against infection.

DOI: https://doi.org/10.1016/j.mucimm.2024.12.013
J Transl Med. 2025 Jan 06. 23(1): 18

Crosstalk between ferroptosis and autophagy: broaden horizons of cancer therapy.

Xingyu Liu, Halahati Tuerxun, Yixin Zhao, Yawen Li, Shuhui Wen, Xi Li, Yuguang Zhao.

  Ferroptosis and autophagy are two main forms of regulated cell death (RCD). Ferroptosis is a newly identified RCD driven by iron accumulation and lipid peroxidation. Autophagy is a self-degradation system through membrane rearrangement. Autophagy regulates the metabolic balance between synthesis, degradation and reutilization of cellular substances to maintain intracellular homeostasis. Numerous studies have demonstrated that both ferroptosis and autophagy play important roles in cancer pathogenesis and cancer therapy. We also found that there are intricate connections between ferroptosis and autophagy. In this article, we tried to clarify how different kinds of autophagy participate in the process of ferroptosis and sort out the common regulatory pathways between ferroptosis and autophagy in cancer. By exploring the complex crosstalk between ferroptosis and autophagy, we hope to broaden horizons of cancer therapy.

Keywords:  Autophagy; Cancer therapy; Crosstalk; Ferroptosis

DOI:  https://doi.org/10.1186/s12967-024-06059-w
Cells. 2024 Dec 11. pii: 2043. [Epub ahead of print]13(24):

The Cellular and Transcriptomic Early Innate Immune Response to BCG Vaccination in Mice.

Liya G Kondratyeva, Olga A Rakitina, Victor V Pleshkan, Alexey I Kuzmich, Irina A Linge, Sofia A Kondratieva, Eugene V Snezhkov, Irina V Alekseenko, Eugene D Sverdlov.

  It is established that BCG vaccination results in the development of both a specific immune response to mycobacterial infections and a nonspecific (heterologous) immune response, designated as trained immunity (TRIM), to other pathogens. We hypothesized that local BCG immunization may induce an early immune response in bone marrow and spleen innate immunity cells. The early transcriptomic response of various populations of innate immune cells, including monocytes, neutrophils, and natural killer (NK) cells, to BCG vaccination was examined. To this end, C57Bl/6J mice were subcutaneously immunized with 106 CFU of BCG. Three days following BCG administration, the three cell populations were collected from the control and BCG-vaccinated groups using FACS. All cell populations obtained were utilized for the preparation and sequencing of RNA-seq libraries. The analysis of FACS data revealed an increase in the proportion of splenic NK cells and monocytes 3 days post-vaccination. Transcriptomic analysis revealed the deregulation of genes associated with the regulation of immune response (according to Gene Ontology terms) in NK cells, monocytes, and unsorted bone marrow cells. Two NK cell-specific immune ligands (Tnfsf14 and S100a8) and two bone marrow-specific immune receptors (C5ar1 and Csf2rb) were identified among differentially expressed genes. No alterations were identified in neutrophils in either their percentage or at the transcriptomic level. Thus, in this study, we demonstrated that BCG vaccination provides an early increase in the proportion of murine bone marrow and spleen immune cell populations, as well as transcriptomic alterations in monocytes, NK cells, and non-sorted bone marrow cells. This early innate immune response may be beneficial for enhancing TRIM.

Keywords:  BCG; RNA-seq; innate immunity; trained immunity; transcriptome; vaccination

DOI:  https://doi.org/10.3390/cells13242043
Cells. 2024 Dec 31. pii: 33. [Epub ahead of print]14(1):

CCL4 Affects Eosinophil Survival via the Shedding of the MUC1 N-Terminal Domain in Airway Inflammation.

Yoshiki Kobayashi, Chu Hong Hanh, Naoto Yagi, Nhi Kieu Thi Le, Yasutaka Yun, Akihiro Shimamura, Kenta Fukui, Akitoshi Mitani, Kensuke Suzuki, Akira Kanda, Hiroshi Iwai.

  Eosinophilic chronic rhinosinusitis (ECRS), a CRS with nasal polyps (CRSwNP), is characterized by eosinophilic infiltration with type 2 inflammation and is highly associated with bronchial asthma. Intractable ECRS with poorly controlled asthma is recognized as a difficult-to-treat eosinophilic airway inflammation. Although eosinophils are activated and coincubation with airway epithelial cells prolongs their survival, the interaction mechanism between eosinophils and epithelial cells is unclear. This study examined the effect of eosinophils on mucin glycoprotein 1 (MUC1), a member of membrane-bound mucin, in the airway epithelial cells, to elucidate the mechanisms of the eosinophil-airway epithelial cell interaction. Nasal polyp samples from patients with CRSwNP and BEAS-2B airway epithelial cells, coincubated with purified eosinophils, were stained with two MUC1 antibodies. To confirm the involvement of CCL4, an anti-CCL4 neutralizing antibody or recombinant CCL4 was used as needed. The immunofluorescence results revealed a negative correlation between the expression of full-length MUC1 and eosinophil count in nasal polyps. In BEAS-2B coincubated with eosinophils, full-length MUC1, but not the C-terminal domain, was reduced, and eosinophil survival was prolonged, which was concomitant with CCL4 increase, whereas the anti-CCL4 neutralizing antibody decreased these reactions. The survival of eosinophils that contacted recombinant MUC1 without the N-terminal domain was prolonged, and recombinant CCL4 increased the expression of metalloproteases. Increased CCL4 induces the contact between eosinophils and airway epithelial cells by shedding the MUC1 N-terminal domain and enhances eosinophil survival in eosinophilic airway inflammation. This novel mechanism may be a therapeutic target for difficult-to-treat eosinophilic airway inflammation.

Keywords:  CCL4; airway epithelial cell; bronchial asthma; chronic rhinosinusitis with nasal polyps; eosinophilic chronic rhinosinusitis; mucin glycoprotein 1

DOI:  https://doi.org/10.3390/cells14010033
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024 Aug 28. pii: 1672-7347(2024)08-1309-07. [Epub ahead of print]49(8): 1309-1315

Ferroptosis and tumor immunity.

Qian Tao, Nian Liu, Jing Chen, Jie Wu, Jie Li, Xiang Chen, Cong Peng.

  Ferroptosis is a unique form of cell death driven by iron-dependent lipid peroxidation, with regulatory mechanisms involving metabolic dysregulation and imbalance in redox systems. Ferroptosis is closely related to various immune cells in the tumor immune microenvironment, including both anti-tumor and pro-tumor immune cells, and it demonstrates significant potential in tumor immunotherapy. A systematic review of the regulatory mechanisms of ferroptosis and its relationship with immune cells can provide deeper insights into its application prospects in tumor immunotherapy.

Keywords:  ferroptosis; immune cells; tumor immunotherapy

DOI:  https://doi.org/10.11817/j.issn.1672-7347.2024.240389
Cell Host Microbe. 2025 Jan 08. pii: S1931-3128(24)00479-7. [Epub ahead of print]33(1): 6-8

Commensal fungi, a force to be reckoned with.

Dingjiacheng Jia, Shujie Chen.

Fungal symbionts play a key role in maintaining host homeostasis. In a recent issue of Nature, Liao et al. show that Kazachstania pintolopesii, a symbiotic fungus in mice, is shielded from the host immune system during homeostasis but induces type 2 immunity during mucus fluctuations.

DOI: https://doi.org/10.1016/j.chom.2024.12.012
Am J Respir Cell Mol Biol. 2025 Jan 06.

Iron Regulatory Protein 2 (IRP2) Deficiency Is Protective Against Resistive Breathing-induced Pulmonary Inflammation.

Dimitrios Toumpanakis, Vyronia Vassilakopoulou, Wen Gu, Eleftheria Mizi, Athanasia Chatzianastasiou, Vincent Richard, Christoph H Borchers, Yassene Mohammed, Carine Fillebeen, Theodoros Vassilakopoulos, Kostas Pantopoulos.

  Iron regulatory protein 2 (IRP2), a post-transcriptional regulator of cellular iron metabolism has been associated with susceptibility to chronic obstructive pulmonary disease (COPD). Resistive breathing (RB) is the hallmark of the pathophysiology of obstructive airway diseases, especially during exacerbations, where increased mechanical stress is imposed on the lung. We have previously shown that RB, through tracheal banding, mimicking severe airway obstruction, induces pulmonary inflammation and injury in previously healthy mice. To characterize the role of IRP2 in RB-induced lung injury, wild type and Irp2-/- mice were subjected to tracheal banding surgery. RB increased tissue elasticity and viscance in wild type but not in Irp2-/- mice, denoting that the latter were protected against lung injury. Moreover, Irp2-/- mice exhibited a lower score of lung inflammation. Additionally, only wild type but not Irp2-/- mice responded to RB by increasing bronchoalveolar lavage (BAL) cellularity due to higher macrophage count, which was accompanied by elevated BAL IL-1β and IL-6 levels. Lung proteomics and functional enrichment analysis revealed significant differences among wild type and Irp2-/- mice in RB-induced regulation of proteins involved in inflammatory and defense response pathways, but also of many proteins with unknown function. We conclude that IRP2 supports pro-inflammatory activities in the lungs, while its deficiency protects against RB-induced pulmonary inflammation via remodeling of the lung proteome.

Keywords:  COPD; IRP2; iron; resistive breathing; tracheal banding

DOI:  https://doi.org/10.1165/rcmb.2024-0286OC
iScience. 2024 Dec 20. 27(12): 111468

Heightened innate immune state induced by viral vector leads to enhanced response to challenge and prolongs malaria vaccine protection.

Komi Gbedande, Samad A Ibitokou, Mark Joseph D Endrino, George S Yap, Michael G Brown, Robin Stephens.

  Cytomegalovirus is a promising vaccine vector; however, mechanisms promoting CD4 T cell responses to challenge, by CMV as a vector, are unknown. The ability of MCMV to prolong immunity generated by short-lived malaria vaccine was tested. MCMV provided non-specific protection to challenge with Plasmodium and increased interleukin-12 (IL-12) and CD8α+ dendritic cell (DC) numbers through prolonged MCMV-dependent interferon gamma (IFN-γ) production. This late innate response to MCMV increased IL-12 upon challenge and increased the polyclonal CD4 effector T cell response to Plasmodium, protecting in an IL-12-dependent manner. Although Plasmodium-vaccine-induced protection decayed by d200, MCMV restored protection through IFN-γ. Mechanistically, protection depended on MCMV-induced-IFN-γ increasing CD8α+ DCs and IL-12p40. MCMV expressing a Plasmodium epitope increased parasite-specific CD4 effector and effector memory T cells persisting after malaria vaccination, both phenotypes reported to protect. Overall, enhanced innate cell status, a mechanism of heterologous protection by MCMV, led to a stronger T cell response to challenge.

Keywords:  Biological sciences; Immune response; Immunology; Microbiology; Natural sciences; Viral microbiology

DOI:  https://doi.org/10.1016/j.isci.2024.111468
Cytokine Growth Factor Rev. 2024 Dec 26. pii: S1359-6101(24)00103-5. [Epub ahead of print]

Granulocyte macrophage colony stimulating factor in virus-host interactions and its implication for immunotherapy.

Nasry Zane Bouzeineddine, Alecco Philippi, Katrina Gee, Sam Basta.

  Viruses have evolved to strategically exploit cellular signaling pathways to evade host immune defenses. GM-CSF signaling plays a pivotal role in regulating inflammation, activating myeloid cells, and enhancing the immune response to infections. Due to its central role in the immune system, viruses may target this pathway to further establish infection. This review focuses on key studies elucidating virus interactions with GM-CSF signaling proteins and summarizes findings on the impact of viral infections on GM-CSF production. Additionally, therapeutic strategies centered around GM-CSF are investigated, such as the potential benefits of administering GM-CSF versus inhibiting GM-CSF signaling to mitigate viral-induced aberrant inflammation. Understanding these virus-host interactions provides valuable insights that help further our understanding to develop future therapeutic approaches in modulating the immune response during viral infections.

Keywords:  GM-CSF; antiviral therapeutics; inflammation; innate immunity; macrophage; virus

DOI:  https://doi.org/10.1016/j.cytogfr.2024.12.002
Sci Signal. 2025 Jan 07. 18(868): eado8860

IRF1 cooperates with ISGF3 or GAF to form innate immune de novo enhancers in macrophages.

Carolina Chavez, Kelly Lin, Alexis Malveaux, Aleksandr Gorin, Stefanie Brizuela, Quen J Cheng, Alexander Hoffmann.

Macrophages exposed to immune stimuli reprogram their epigenomes to alter their subsequent functions. Exposure to bacterial lipopolysaccharide (LPS) causes widespread nucleosome remodeling and the formation of thousands of de novo enhancers. We dissected the regulatory logic by which the network of interferon regulatory factors (IRFs) induces the opening of chromatin and the formation of de novo enhancers. We found that LPS-activated IRF3 mediated de novo enhancer formation indirectly by activating the type I interferon (IFN)-induced ISGF3. However, ISGF3 was generally needed to collaborate with IRF1, particularly where chromatin was less accessible. At these locations, IRF1 was required for the initial opening of chromatin, with ISGF3 extending accessibility and promoting the deposition of H3K4me1, marking poised enhancers. Because IRF1 expression depends on the transcription factor NF-κB, which is activated in infected but not bystander cells, IRF-regulated enhancers required activation of both the IRF3 and NF-κB branches of the innate immune signaling network. However, type II IFN (IFN-γ), which is typically produced by T cells, may also induce IRF1 expression through the STAT1 homodimer GAF. We showed that, upon IFN-γ stimulation, IRF1 was also responsible for opening inaccessible chromatin sites that could then be exploited by GAF to form de novo enhancers. Together, our results reveal how combinatorial logic gates of IRF1-ISGF3 or IRF1-GAF restrict immune epigenomic memory formation to macrophages exposed to pathogens or IFN-γ-secreting T cells but not bystander macrophages exposed transiently to type I IFN.

DOI: https://doi.org/10.1126/scisignal.ado8860
Cell Rep. 2025 Jan 07. pii: S2211-1247(24)01523-7. [Epub ahead of print]44(1): 115172

Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine.

Juliana Escher Toller-Kawahisa, Paula Ramos Viacava, Eva Margareta Palsson-McDermott, Daniele Carvalho Nascimento, Mariana Patricia Cervantes-Silva, Shane Myles O'Carroll, Alessia Zotta, Luis Eduardo Alves Damasceno, Gabriel Azevedo Públio, Pedro Forti, João Paulo Mesquita Luiz, Bruno Marcel Silva de Melo, Timna Varela Martins, Vitor Marcel Faça, Annie Curtis, Thiago Mattar Cunha, Fernando de Queiroz Cunha, Luke Anthony John O'Neill, José Carlos Alves-Filho.

  Macrophages play a crucial role in immune responses and undergo metabolic reprogramming to fulfill their functions. The tetramerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) induces the production of the anti-inflammatory cytokine interleukin (IL)-10 in vivo, but the underlying mechanism remains elusive. Here, we report that PKM2 activation with the pharmacological agent TEPP-46 increases IL-10 production in LPS-activated macrophages by metabolic reprogramming, leading to the production and release of ATP from glycolysis. The effect of TEPP-46 is abolished in PKM2-deficient macrophages. Extracellular ATP is converted into adenosine by ectonucleotidases that activate adenosine receptor A2a (A2aR) to enhance IL-10 production. Interestingly, IL-10 production induced by PKM2 activation is associated with improved mitochondrial health. Our results identify adenosine derived from glycolytic ATP as a driver of IL-10 production, highlighting the role of tetrameric PKM2 in regulating glycolysis to promote IL-10 production.

Keywords:  CP: Immunology; CP: Metabolism; IL-10; PKM2; adenosine; macrophage; mitochondria dynamics

DOI:  https://doi.org/10.1016/j.celrep.2024.115172
Nat Rev Immunol. 2025 Jan 07.

Regulation of cGAS-STING signalling and its diversity of cellular outcomes.

Zhengyin Zhang, Conggang Zhang.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling pathway, which recognizes both pathogen DNA and host-derived DNA, has emerged as a crucial component of the innate immune system, having important roles in antimicrobial defence, inflammatory disease, ageing, autoimmunity and cancer. Recent work suggests that the regulation of cGAS-STING signalling is complex and sophisticated. In this Review, we describe recent insights from structural studies that have helped to elucidate the molecular mechanisms of the cGAS-STING signalling cascade and we discuss how the cGAS-STING pathway is regulated by both activating and inhibitory factors. Furthermore, we summarize the newly emerging understanding of crosstalk between cGAS-STING signalling and other signalling pathways and provide examples to highlight the wide variety of cellular processes in which cGAS-STING signalling is involved, including autophagy, metabolism, ageing, inflammation and tumorigenesis.

DOI: https://doi.org/10.1038/s41577-024-01112-7
STAR Protoc. 2025 Jan 07. pii: S2666-1667(24)00685-3. [Epub ahead of print]6(1): 103520

Protocol for generating and characterizing a nasal epithelial model using imaging with application for respiratory viruses.

Victor H K Lam, Aleena Ghafoor, Yazan Khan, Shirley Constable, Lane B Buchanan, David Zuanazzi, Reeya Parmar, Zeynep G Tepe, Leigh J Sowerby, Cindy M Liu, Ryan M Troyer, Jessica L Prodger.

  Air-liquid interface (ALI) culture can differentiate airway epithelial cells to recapitulate the respiratory tract in vitro. Here, we present a protocol for isolating and culturing nasal epithelial cells from turbinate tissues for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We describe steps to overcome challenges of imaging fragile cultures, detect the production of mucus, and quantify intracellular virus post-SARS-CoV-2 infection. We present data on the optimal duration of ALI maturation prior to experimentation and describe which steps can be altered to optimize testing of specific hypotheses.

Keywords:  cell culture; cell isolation; microbiology; microscopy

DOI:  https://doi.org/10.1016/j.xpro.2024.103520
Int J Mol Sci. 2024 Dec 13. pii: 13369. [Epub ahead of print]25(24):

Bovine Lactoferrin Enhances Toll-like Receptor 7 Response in Plasmacytoid Dendritic Cells and Modulates Cellular Immunity.

Takumi Yago, Asuka Tada, Shutaro Kubo, Hirotsugu Oda, Sadahiro Iwabuchi, Miyuki Tanaka, Shinichi Hashimoto.

  Plasmacytoid dendritic cells (pDCs) express Toll-like receptor 7 (TLR7) in the endosomes, recognize viral single-stranded RNA (ssRNA), and produce significant amounts of interferon (IFN)-α. Bovine lactoferrin (LF) enhances the response of IFN regulatory factors followed by the activation of IFN-sensitive response elements located in the promoter regions of the IFN-α gene and IFN-stimulated genes in the TLR7 reporter THP-1 cells in the presence of R-848, a TLR7 agonist. In ex vivo experiments using human peripheral blood mononuclear cells, LF enhances IFN-α levels in the supernatant in the presence of R-848. Additionally, it increases the expression of IFN-α, human leukocyte antigen (HLA)-DR, and CD86 in pDCs; HLA-DR and CD86 in myeloid dendritic cells; CD69 in CD56 dim natural killer and T killer cells; and IFN-γ in T helper type 1 and B cells in the presence of R-848. The inhibition of phagocytosis or neutralization of nucleolin, a receptor of LF, suppresses LF incorporation into pDCs. These results suggest that pDCs incorporate LF through phagocytosis or nucleolin-mediated endocytosis, and LF enhances TLR7 response in the endosome and subsequent IFN signaling pathway and activates innate and adaptive immune cells. We anticipate that LF modulates antiviral immunity against environmental ssRNA viruses and contributes to homeostasis.

Keywords:  bovine lactoferrin; immune cells; interferon; peripheral blood mononuclear cells; plasmacytoid dendritic cells; toll-like receptor 7

DOI:  https://doi.org/10.3390/ijms252413369
Foods. 2024 Dec 19. pii: 4118. [Epub ahead of print]13(24):

Effects of Lacticaseibacillus paracasei L9 on Oral Microbiota and Cariogenic Factors in Streptococcus mutans-Infected Mice.

Xinyao Pu, Bing Fang, Jianmin Wu, Zhi Zhao, Yue Liu, Jingyu Li, Haina Gao, Ran Wang, Ming Zhang.

  In the pathogenesis of dental caries, Streptococcus mutans (S. mutans) plays a central role. S. mutans can produce extracellular polysaccharides, which can help the bacteria form biofilms on the tooth surface, create a stable living environment, and hinder the removal of bacteria by natural defense substances in the oral cavity such as saliva. Meanwhile, the oral microbiota and dietary habits exert long-term influences on its development. This study, employing the BALB/c mouse model, explored the effects of L. paracasei L9 on dental caries. In the experiment, mice underwent the S. mutans inoculation and were subsequently treated with L. paracasei L9 or S. salivarius K12 for 28 consecutive days. The results showed that L. paracasei L9 significantly ameliorated early enamel caries, and both L. paracasei L9 and S. salivarius K12 cooperatively downregulated the expressions of critical cariogenic factors, effectively suppressing the initial adhesion of S. mutans and the formation of dental plaques. L. paracasei L9 reshaped the oral microbiota of caries-affected mice, selectively reducing pathogens abundances and augmenting abundances of probiotics such as Lactobacillaceae and Streptococcus salivarius. This study offers a strategic approach for the management of dental caries, highlighting the potential of these probiotics in the field of oral health.

Keywords:  Lacticaseibacillus paracasei; Streptococcus mutans; dental caries; oral health

DOI:  https://doi.org/10.3390/foods13244118
Nat Neurosci. 2025 Jan 06.

Monocyte-derived macrophages act as reinforcements when microglia fall short in Alzheimer's disease.

Miguel A Abellanas, Maitreyee Purnapatre, Chiara Burgaletto, Michal Schwartz.

The central nervous system (CNS) is endowed with its own resident innate immune cells, the microglia. They constitute approximately 10% of the total cells within the CNS parenchyma and act as 'sentinels', sensing and mitigating any deviation from homeostasis. Nevertheless, under severe acute or chronic neurological injury or disease, microglia are unable to contain the damage, and the reparative activity of monocyte-derived macrophages (MDMs) is required. The failure of the microglia under such conditions could be an outcome of their prolonged exposure to hostile stimuli, leading to their exhaustion or senescence. Here, we describe the conditions under which the microglia fall short, focusing mainly on the context of Alzheimer's disease, and shed light on the functions performed by MDMs. We discuss whether and how MDMs engage in cross-talk with the microglia, why their recruitment is often inadequate, and potential ways to augment their homing to the brain in a well-controlled manner.

DOI: https://doi.org/10.1038/s41593-024-01847-5
Nat Chem Biol. 2025 Jan 07.

Mechanisms of metabolism-coupled protein modifications.

Bingsen Zhang, Frank C Schroeder.

Intricate coupling between metabolism and protein post-translational modifications (PTMs) has emerged as a fundamental aspect of cellular regulation. Recent studies demonstrate that protein modifications can originate from diverse metabolites, and that their regulation is closely tied to the cellular metabolic state. Here we explore recently uncovered PTMs, including the concept of 'modification of a modification', as well as associated feedback and feedforward regulatory mechanisms, in which modified proteins impact not only related metabolic pathways but also other signaling cascades affecting physiology and diseases. The recently uncovered role of nucleus-localized metabolic enzymes for histone modifications additionally highlights the importance of cell-compartment-specific metabolic states. We further comment on the utility of untargeted metabolomics and proteomics for previously unrecognized PTMs and associated metabolic patterns. Together, these advances have uncovered a dynamic interplay between metabolism and PTMs, offering new perspectives for understanding metabolic regulation and developing targeted therapeutic strategies.

DOI: https://doi.org/10.1038/s41589-024-01805-z
Pharmaceutics. 2024 Dec 01. pii: 1539. [Epub ahead of print]16(12):

Targeted Antibacterial Endolysin to Treat Infected Wounds on 3D Full-Thickness Skin Model: XZ.700 Efficacy.

Marisa Meloni, Bob de Rooij, Ferdinand W Janssen, Francesca Rescigno, Bernadette Lombardi.

  Backgrounds/Objectives: Skin wound healing is a physiological process orchestrated by epithelial and mesenchymal cells able to restore tissue continuity by re-organizing themselves and the ECM. This research study aimed to develop an optimized in vitro experimental model of full-thickness skin, to address molecular and morphological modifications occurring in the re-epithelization and wound healing process. Methods: Wound healing starting events were investigated within an experimental window of 8 days at the molecular level by gene expression and immunofluorescence of key epidermal and dermal biomarkers. To mirror the behavior of infected wounds, the established wound healing model was then colonized with S. aureus, and the efficacy of a novel antibacterial agent, XZ.700, was investigated. Viable counts (CFU/tissue), IF, and ultrastructural analysis (SEM) were performed to evaluate S. aureus colonization inside and around the wound bed in an experimental window of 3 h of colonization and 24 h of treatment. Results: Endolysin showed an efficacy in counteracting bacterial growth and invasion within the wound bed, reducing the S. aureus load compared to its placebo, thanks to its selective antimicrobial activity interfering with biofilm formation. Conclusions: The preclinical in vitro infected wound model on FT-kin showed interesting applications to assess the repair efficacy of dermo-pharmaceutical and cosmetic formulations.

Keywords:  anti-microbial adhesion; anti-microbial effect; biofilm efficacy; injury model; re-epithelization process; wound healing

DOI:  https://doi.org/10.3390/pharmaceutics16121539
Commun Biol. 2025 Jan 07. 8(1): 20

NLRP3 promotes inflammatory signaling and IL-1β cleavage in acute lung injury caused by cell wall extract of Lactobacillus casei.

Lingui Gu, Jinjin Zhu, Qingbing Nie, Binghua Xie, Shuo Xue, Ailing Zhang, Qiangwei Li, Zhengzhong Zhang, Shupeng Li, Yusen Li, Qinquan Shi, Weiwei Shi, Lei Zhao, Shuzhen Liu, Xuanming Shi.

Gram-positive bacterial pneumonia is a significant cause of hospitalization and death. Shortage of a good experimental model and therapeutic targets hinders the cure of acute lung injury (ALI). This study has established a mouse model of ALI using Gram-positive bacteria Lactobacillus casie cell wall extracts (LCWE) and identified the key regulator NLRP3. We show that LCWE induces TNF, NF-κB signaling, and so on pathways. Similar to lipopolysaccharide (LPS), LCWE induces the infiltration of CD11b-positive cells and inflammation in lungs. LCWE also triggers inflammatory signaling through TLR2, different from LPS through TLR4. It suggests that cytokines amplify inflammation signaling relying on NLRP3 in LCWE-induced ALI. NLRP3 deletion disrupts inflammation, IL-1β cleavage, and the infiltration of neutrophils and macrophages in the injured lung. Our study highlights an animal ALI model for Gram-positive bacterial pneumonia and that NLRP3 is a key therapeutic target to prevent inflammation and lung damage in LCWE-induced ALI.

DOI: https://doi.org/10.1038/s42003-025-07462-9
J Interferon Cytokine Res. 2025 Jan 09.

The Ability of SOCS1 to Cross-Regulate GM-CSF Signaling is Dose Dependent.

Grace M Bidgood, Narelle Keating, Lizeth Meza Guzman, Kunlun Li, Evelyn Leong, Andrew Kueh, Jeffrey J Babon, Colin Hockings, Karen Doggett, Sandra E Nicholson.

  Suppressor of cytokine signaling (SOCS) 1 is a key negative regulator of interferon (IFN), interleukin (IL)12, and IL-2 family cytokine signaling through inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. To investigate the temporal induction of SOCS1 in response to cytokine in live cells and its selective regulation of signaling pathways, we generated a mouse expressing a Halo-tag-SOCS1 fusion protein (Halo-SOCS1) under control of the endogenous Socs1 promoter. Homozygous Halo-SOCS1 mice (Halo-Socs1KI/KI) were viable with minor T cell abnormalities, most likely due to enhanced Halo-SOCS1 expression in thymocytes compared with the untagged protein. IFNγ and IL-4 induced Halo-SOCS1 expression in macrophages derived from Halo-Socs1KI/KI mice, and a critical level of SOCS1 expression was required for inhibition of both IFNγ and granulocyte macrophage-colony stimulating factor (GM-CSF)-driven JAK-STAT signaling. In contrast, IFNγ priming to induce SOCS1 did not cross-regulate IL-4 signaling. This study indicates that while SOCS1 expression needs to exceed a critical threshold to inhibit IFNγ signaling, its selective regulation of cytokine signaling results from an as yet undetermined, level of regulatory control.

Keywords:  GM-CSF; JAK-STAT; SOCS1; interferon; signaling

DOI:  https://doi.org/10.1089/jir.2024.0140
Curr Opin Microbiol. 2025 Jan 08. pii: S1369-5274(24)00154-1. [Epub ahead of print]83 102578

Harnessing gut microbial communities to unravel microbiome functions.

Samir Giri, Handuo Shi, Athanasios Typas, Kerwyn Casey Huang.

The gut microbiome impacts human health in direct and indirect ways. While many associations have been discovered between specific microbiome compositions and diseases, establishing causality, understanding the underlying mechanisms, and developing successful microbiome-based therapies require novel experimental approaches. In this opinion, we discuss how in vitro cultivation of diverse communities enables systematic investigation of the individual and collective functions of gut microbes. Up to now, the field has relied mostly on simple, bottom-up assembled synthetic communities or more complex, undefined stool-derived communities. Although powerful for dissecting interactions and mapping causal effects, these communities suffer either from ignoring the complexity, diversity, coevolution, and dynamics of natural communities or from lack of control of community composition. These limitations can be overcome in the future by establishing personalized culture collections from stool samples of different donors and assembling personalized communities to investigate native interactions and ecological relationships in a controlled manner.

DOI: https://doi.org/10.1016/j.mib.2024.102578