bims-bac4me 2024-08-04 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024–08–04
28 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Macrophage plasticity: signaling pathways, tissue repair, and regeneration.
Investigating the pro-inflammatory differentiation of macrophages with bacterial ghosts in potential infection control.
Research progress on the relationship between phenotype and signaling pathways of pulmonary macrophages and asthma.
Interactions between toll-like receptors signaling pathway and gut microbiota in host homeostasis.
Defining PANoptosis: Biochemical and Mechanistic Evaluation of Innate Immune Cell Death Activation.
Never trust a single myeloid marker: Ly6G on repair-promoting lung macrophages.
Translational 3D-Cell Culture Model to Assess Hyperoxia Effects on Human Neonatal Airway Epithelial Cells.
CPT1A-IL-10-mediated macrophage metabolic and phenotypic alterations ameliorate acute lung injury.
cAMP signaling of Bordetella adenylate cyclase toxin blocks M-CSF triggered upregulation of iron acquisition receptors on differentiating CD14+ monocytes.
Trained immunity inducers in cancer immunotherapy.
Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.
Early life antibiotics have lasting effects on the lung epithelium.
Immunomodulation in diabetic wounds healing: The intersection of macrophage reprogramming and immunotherapeutic hydrogels.
Phenotypic Heterogeneity in Pathogens.
Commensal microbiome dysbiosis elicits interleukin-8 signaling to drive fibrotic skin disease.
Exploring the Multifaceted Therapeutic Potential of Probiotics: A Review of Current Insights and Applications.
Phenotypic heterogeneity follows a growth-viability tradeoff in response to amino acid identity.
The arginine and nitric oxide metabolic pathway regulate the gut colonization and expansion of Ruminococcous gnavus.
Innate immune mechanisms promote human response to Acinetobacter baumannii infection.
Functional and epigenetic changes in monocytes from adults immunized with an AS01-adjuvanted vaccine.
Ferroptosis is involved in Staphylococcus aureus-induced mastitis through autophagy activation by endoplasmic reticulum stress.
Immunological memory diversity in the human upper airway.
Beyond Antibiotics: Novel Approaches in the Treatment of Recurrent Clostridioides difficile Infection.
A multistage protein subunit vaccine as BCG-booster confers protection against Mycobacterium tuberculosis infection in murine models.
The World Needs a Staph Vaccine-New Research Could Bring It a Step Closer.
Turbinate-homing IgA-secreting cells originate in the nasal lymphoid tissues.
Host and environmental factors shape upper airway microbiota and respiratory health across the human lifespan.
Metabolic Regulation of Microbiota and Tissue Response.

MedComm (2020). 2024 Aug;5(8): e658

Macrophage plasticity: signaling pathways, tissue repair, and regeneration.

Lingfeng Yan, Jue Wang, Xin Cai, Yih-Cherng Liou, Han-Ming Shen, Jianlei Hao, Canhua Huang, Gaoxing Luo, Weifeng He.

  Macrophages are versatile immune cells with remarkable plasticity, enabling them to adapt to diverse tissue microenvironments and perform various functions. Traditionally categorized into classically activated (M1) and alternatively activated (M2) phenotypes, recent advances have revealed a spectrum of macrophage activation states that extend beyond this dichotomy. The complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications orchestrates macrophage polarization, allowing them to respond to various stimuli dynamically. Here, we provide a comprehensive overview of the signaling cascades governing macrophage plasticity, focusing on the roles of Toll-like receptors, signal transducer and activator of transcription proteins, nuclear receptors, and microRNAs. We also discuss the emerging concepts of macrophage metabolic reprogramming and trained immunity, contributing to their functional adaptability. Macrophage plasticity plays a pivotal role in tissue repair and regeneration, with macrophages coordinating inflammation, angiogenesis, and matrix remodeling to restore tissue homeostasis. By harnessing the potential of macrophage plasticity, novel therapeutic strategies targeting macrophage polarization could be developed for various diseases, including chronic wounds, fibrotic disorders, and inflammatory conditions. Ultimately, a deeper understanding of the molecular mechanisms underpinning macrophage plasticity will pave the way for innovative regenerative medicine and tissue engineering approaches.

Keywords:  epigenetic regulation; macrophages; plasticity; signaling pathways; tissue repair

DOI:  https://doi.org/10.1002/mco2.658
Arch Microbiol. 2024 Jul 27. 206(8): 361

Investigating the pro-inflammatory differentiation of macrophages with bacterial ghosts in potential infection control.

Aiswarya Pradeep, Asish Issac Mathew, Praveen Kumar Vemula, Sarita Ganapathy Bhat, Sreeja Narayanan.

  In the complex realm of bacterial infections, particularly those caused by Staphylococcus aureus (S. aureus), macrophages play a pivotal role in orchestrating the immune response. During the initial stages of infection, the monocytes give rise to macrophages with a pro-inflammatory (M1 type) behaviour, engulfing and neutralizing the invading pathogens. However, under the sustained influence of S. aureus infection, monocytes can undergo a transition into an anti-inflammatory M2 state (pro-infection) rather than the M1 state (anti-infection), thereby compromising effective infection control. Therefore, it is necessary to develop a strategy that would preserve the pro-inflammatory functions of macrophages, in a safe and controlled manner. For this, we focused on harnessing the potential of S. aureus-derived ghost cells (GCs) which are non-live empty envelopes of bacterial cells, but with the antigenic determinants intact. Through a unique Lugol's-iodine treatment, we generated GCs and characterization of these GCs using gel electrophoresis, FTIR, flow cytometry, TEM, and SEM confirmed their structural integrity. Following this, we assessed the extend of cellular association of the GCs with RAW267.4 macrophages, and observed an immediate interaction between the two, as evident from the flowcytometry and microscopy studies. We then performed macrophage polarisation on a human monocyte-macrophage model cell line, THP-1. Our findings revealed that GCs effectively activated macrophages, and promoted a pro-inflammatory polarisation with the expression of M1 differentiation markers (CD86, TNFα, IL-1β, IL-6, IL-12) evaluated through both qPCR and ELISA. Interestingly an intermediary expression of M2 markers viz., CD206 and IL-10 was also observed, but was overruled by the enhanced expression of M1 markers at a later time point. Overall, our study introduces a novel approach utilizing GCs to guide naïve macrophages towards M1 subtypes, thereby potentiating immune responses during microbial infections. This innovative strategy can modulate macrophage function, ultimately improving outcomes in S. aureus infections and beyond.

Keywords:   S. aureus ; Bacterial ghosts; Cytokines; Infection; Inflammation; Macrophages

DOI:  https://doi.org/10.1007/s00203-024-04089-y
J Asthma. 2024 Jul 29. 1-27

Research progress on the relationship between phenotype and signaling pathways of pulmonary macrophages and asthma.

Minghui Li, Zhuying Li.

  Asthma is a heterogeneous chronic inflammatory lung disease Lung tissue macrophages are important immune cells in respiratory tract. Lung macrophages are also heterogenous in that there are separate subsets and, depending on the environment, different effector functions. They have different phenotypes and biological functions in different disease environments. At present, the study on the different phenotypes and function analysis of macrophages in lung tissue is not perfect. Pulmonary macrophages undergo phenotypic changes during asthma. This review summarizes current literature and provides a detailed introduction to the role of macrophages as key inflammatory mediators in the pathogenesis of asthma, as well as existing knowledge gaps. In addition, we propose that regulatory macrophages may prevent the development of asthma by producing IL-10, and regulating the polarization of pulmonary macrophages may be a new direction for asthma treatment.

Keywords:  Inflammatory diseases; Pulmonary macrophages; asthma

DOI:  https://doi.org/10.1080/02770903.2024.2386634
Immun Inflamm Dis. 2024 Jul;12(7): e1356

Interactions between toll-like receptors signaling pathway and gut microbiota in host homeostasis.

Luping Chen, Linfang Zhang, Hua Hua, Li Liu, Yuejian Mao, Ruirui Wang.

   BACKGROUND: Toll-like receptors (TLRs) are a family of fundamental pattern recognition receptors in the innate immune system, constituting the first line of defense against endogenous and exogenous antigens. The gut microbiota, a collection of commensal microorganisms in the intestine, is a major source of exogenous antigens. The components and metabolites of the gut microbiota interact with specific TLRs to contribute to whole-body immune and metabolic homeostasis.
OBJECTIVE: This review aims to summarize the interaction between the gut microbiota and TLR signaling pathways and to enumerate the role of microbiota dysbiosis-induced TLR signaling pathways in obesity, inflammatory bowel disease (IBD), and colorectal cancer (CRC).
RESULTS: Through the recognition of TLRs, the microbiota facilitates the development of both the innate and adaptive immune systems, while the immune system monitors dynamic changes in the commensal bacteria to maintain the balance of the host-microorganism symbiosis. Dysbiosis of the gut microbiota can induce a cascade of inflammatory and metabolic responses mediated by TLR signaling pathways, potentially resulting in various metabolic and inflammatory diseases.
CONCLUSION: Understanding the crosstalk between TLRs and the gut microbiota contributes to potential therapeutic applications in related diseases, offering new avenues for treatment strategies in conditions like obesity, IBD, and CRC.

Keywords:  TLRs; colorectal cancer; gut microbiota; inflammatory bowel disease; obesity

DOI:  https://doi.org/10.1002/iid3.1356
Curr Protoc. 2024 Jul;4(7): e1112

Defining PANoptosis: Biochemical and Mechanistic Evaluation of Innate Immune Cell Death Activation.

Rebecca E Tweedell, Taylor Hibler, Thirumala-Devi Kanneganti.

  The innate immune system is the first line of host defense. Innate immune activation utilizes pattern recognition receptors to detect pathogens, pathogen-associated and damage-associated molecular patterns (PAMPs and DAMPs), and homeostatic alterations and drives inflammatory signaling pathways and regulated cell death. Cell death activation is critical to eliminate pathogens and aberrant or damaged cells, while excess activation can be linked to inflammation, tissue damage, and disease. Therefore, there is increasing interest in studying cell death mechanisms to understand the underlying biology and identify therapeutic strategies. However, there are significant technical challenges, as many cell death pathways share key molecules with each other, and genetic models where these cell death molecules are deleted remain the gold standard for evaluation. Furthermore, extensive crosstalk has been identified between the cell death pathways pyroptosis, apoptosis, necroptosis, and the more recently characterized PANoptosis, which is defined as a prominent, unique innate immune, lytic, and inflammatory cell death pathway initiated by innate immune sensors and driven by caspases and RIPKs through PANoptosomes. PANoptosomes are multi-protein complexes assembled by innate immune sensor(s) in response to pathogens, PAMPs, DAMPs, cytokines, and homeostatic changes that drive PANoptosis. In this article, we provide methods for molecularly defining distinct cell death pathways, including PANoptosis, using both genetic and chemical approaches through western blot, LDH assay, and microscopy readouts. This procedure allows for the assessment of cell death on the cell population and single-cell levels even without access to genetic models. Having this comprehensive workflow that is more accessible to all labs will improve our ability as a scientific community to accelerate discovery. Using these protocols will help identify new innate immune sensors that drive PANoptosis and define the molecular mechanisms and regulators involved to establish new targets for clinical translation. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Induction and quantification of cell death using live cell imaging Alternate Protocol 1: Quantification of cell death using LDH Alternate Protocol 2: Assessment of cell death complexes in single cells using immunofluorescence staining Basic Protocol 2: Analysis of cell death mechanisms by immunoblots (western blots).

Keywords:  MLKL; NLRs; PANoptosis; PANoptosome; apoptosis; caspase; gasdermin; inflammasome; necroptosis; pyroptosis; sensors

DOI:  https://doi.org/10.1002/cpz1.1112
Sci Immunol. 2024 Aug 02. 9(98): eadq7306

Never trust a single myeloid marker: Ly6G on repair-promoting lung macrophages.

Chrysante S Iliakis, Andreas Wack.

Short-lived repair-promoting macrophages are recruited to foci of lung damage during influenza infection-and they are Ly6G positive (see related Research Article by Ruscitti et al.).

DOI: https://doi.org/10.1126/sciimmunol.adq7306
J Vis Exp. 2024 Jul 12.

Translational 3D-Cell Culture Model to Assess Hyperoxia Effects on Human Neonatal Airway Epithelial Cells.

Cynthia M Carter, Maxwell M Mathias, Lora Bailey-Downs, Trent E Tipple, Peter F Vitiello, Matthew S Walters, Abhrajit Ganguly.

The preterm neonatal airway epithelium is constantly exposed to environmental stressors. One of these stressors in neonates with lung disease includes oxygen (O2) tension higher than the ambient atmosphere - termed hyperoxia (>21% O2). The effect of hyperoxia on the airway depends on various factors, including the developmental stage of the airway, the degree of hyperoxia, and the duration of exposure, with variable exposures potentially leading to unique phenotypes. While there has been extensive research on the effect of hyperoxia on neonatal lung alveolarization and airway hyperreactivity, little is known about the short and long-term underlying effect of hyperoxia on human neonatal airway epithelial cells. A major reason for this is the scarcity of an effective in vitro model to study human neonatal airway epithelial development and function. Here, we describe a method for isolating and expanding human neonatal tracheal airway epithelial cells (nTAECs) utilizing human neonatal tracheal aspirates and culturing these cells in air-liquid interface (ALI) culture. We demonstrate that nTAECs form a mature polarized cell-monolayer in ALI culture and undergo mucociliary differentiation. We also present a method for moderate hyperoxia exposure of the cell monolayer in ALI culture using a specialized incubator. Additionally, we describe an assay to measure cellular oxidative stress following hyperoxia exposure in ALI culture using fluorescent quantification, which confirms that moderate hyperoxia exposure induces cellular oxidative stress but does not cause significant cell membrane damage or apoptosis. This model can potentially be used to simulate clinically relevant hyperoxia exposure encountered by neonatal airways in the Neonatal Intensive Care Unit (NICU) and used to study the short and long-lasting effects of O2 on neonatal airway epithelial programming. Studies using this model could be utilized to explore ways to mitigate early-life oxidative injury to developing airways, which is implicated in the development of long-term airway diseases in former premature infants.

DOI: https://doi.org/10.3791/65913
Clin Transl Med. 2024 Aug;14(8): e1785

CPT1A-IL-10-mediated macrophage metabolic and phenotypic alterations ameliorate acute lung injury.

Muyun Wang, Di Wu, Ximing Liao, Haiyang Hu, Jing Gao, Linlin Meng, Feilong Wang, Wujian Xu, Shaoyong Gao, Jing Hua, Yuanyuan Wang, Qiang Li, Kun Wang, Wei Gao.

   BACKGROUND: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common acute respiratory failure due to diffuse pulmonary inflammation and oedema. Elaborate regulation of macrophage activation is essential for managing this inflammatory process and maintaining tissue homeostasis. In the past decades, metabolic reprogramming of macrophages has emerged as a predominant role in modulating their biology and function. Here, we observed reduced expression of carnitine palmitoyltransferase 1A (CPT1A), a key rate-limiting enzyme of fatty acid oxidation (FAO), in macrophages of lipopolysaccharide (LPS)-induced ALI mouse model. We assume that CPT1A and its regulated FAO is involved in the regulation of macrophage polarization, which could be positive regulated by interleukin-10 (IL-10).
METHODS: After nasal inhalation rIL-10 and/or LPS, wild type (WT), IL-10-/-, Cre-CPT1Afl/fl and Cre+CPT1Afl/fl mice were sacrificed to harvest bronchoalveolar lavage fluid, blood serum and lungs to examine cell infiltration, cytokine production, lung injury severity and IHC. Bone marrow-derived macrophages (BMDMs) were extracted from mice and stimulated by exogenous rIL-10 and/or LPS. The qRT-PCR, Seahorse XFe96 and FAO metabolite related kits were used to test the glycolysis and FAO level in BMDMs. Immunoblotting assay, confocal microscopy and fluorescence microplate were used to test macrophage polarization as well as mitochondrial structure and function damage.
RESULTS: In in vivo experiments, we found that mice lacking CPT1A or IL-10 produced an aggravate inflammatory response to LPS stimulation. However, the addition of rIL-10 could alleviate the pulmonary inflammation in mice effectively. IHC results showed that IL-10 expression in lung macrophage decreased dramatically in Cre+CPT1Afl/fl mice. The in vitro experiments showed Cre+CPT1Afl/fl and IL-10-/- BMDMs became more "glycolytic", but less "FAO" when subjected to external attacks. However, the supplementation of rIL-10 into macrophages showed reverse effect. CPT1A and IL-10 can drive the polarization of BMDM from M1 phenotype to M2 phenotype, and CPT1A-IL-10 axis is also involved in the process of maintaining mitochondrial homeostasis.
CONCLUSIONS: CPT1A modulated metabolic reprogramming and polarisation of macrophage under LPS stimulation. The protective effects of CPT1A may be partly attributed to the induction of IL-10/IL-10 receptor expression.

Keywords:  acute lung injury; carnitine palmitoyltransferase 1A; fatty acid oxidation; interleukin‐10; macrophage

DOI:  https://doi.org/10.1002/ctm2.1785
mSphere. 2024 Jul 30. e0040724

cAMP signaling of Bordetella adenylate cyclase toxin blocks M-CSF triggered upregulation of iron acquisition receptors on differentiating CD14+ monocytes.

Jawid Nazir Ahmad, Peter Sebo.

  Bordetella pertussis infects the upper airways of humans and disarms host defense by the potent immuno-subversive activities of its pertussis (PT) and adenylate cyclase (CyaA) toxins. CyaA action near-instantly ablates the bactericidal activities of sentinel CR3-expressing myeloid phagocytes by hijacking cellular signaling pathways through the unregulated production of cAMP. Moreover, CyaA-elicited cAMP signaling also inhibits the macrophage colony-stimulating factor (M-CSF)-induced differentiation of incoming inflammatory monocytes into bactericidal macrophages. We show that CyaA/cAMP signaling via protein kinase A (PKA) downregulates the M-CSF-elicited expression of monocyte receptors for transferrin (CD71) and hemoglobin-haptoglobin (CD163), as well as the expression of heme oxygenase-1 (HO-1) involved in iron liberation from internalized heme. The impact of CyaA action on CD71 and CD163 levels in differentiating monocytes is largely alleviated by the histone deacetylase inhibitor trichostatin A (TSA), indicating that CyaA/cAMP signaling triggers epigenetic silencing of genes for micronutrient acquisition receptors. These results suggest a new mechanism by which B. pertussis evades host sentinel phagocytes to achieve proliferation on airway mucosa.IMPORTANCETo establish a productive infection of the nasopharyngeal mucosa and proliferate to sufficiently high numbers that trigger rhinitis and aerosol-mediated transmission, the pertussis agent Bordetella pertussis deploys several immunosuppressive protein toxins that compromise the sentinel functions of mucosa patrolling phagocytes. We show that cAMP signaling elicited by very low concentrations (22 pM) of Bordetella adenylate cyclase toxin downregulates the iron acquisition systems of CD14+ monocytes. The resulting iron deprivation of iron, a key micronutrient, then represents an additional aspect of CyaA toxin action involved in the inhibition of differentiation of monocytes into the enlarged bactericidal macrophage cells. This corroborates the newly discovered paradigm of host defense evasion mechanisms employed by bacterial pathogens, where manipulation of cellular cAMP levels blocks monocyte to macrophage transition and replenishment of exhausted phagocytes, thereby contributing to the formation of a safe niche for pathogen proliferation and dissemination.

Keywords:  Bordetella pertussis; adenylate cyclase toxin; cyclic AMP; differentiation; iron acquisition; macrophages; monocytes

DOI:  https://doi.org/10.1128/msphere.00407-24
Front Immunol. 2024 ;15 1427443

Trained immunity inducers in cancer immunotherapy.

Yongjun Sui, Jay A Berzofsky.

  While most of the cancer immunotherapy strategies engage adaptive immunity, especially tumor-associated T cells, the small fraction of responding patients and types of cancers amenable, and the possibility of severe adverse effects limit its usage. More effective and general interventions are urgently needed. Recently, a de facto innate immune memory, termed 'trained immunity', has become a new research focal point, and promises to be a powerful tool for achieving long-term therapeutic benefits against cancers. Trained immunity-inducing agents such as BCG and fungal glucan have been shown to be able to avert the suppressive tumor microenvironment (TME), enhance T cell responses, and eventually lead to tumor regression. Here, we review the current understating of trained immunity induction and highlight the critical roles of emergency granulopoiesis, interferon γ and tissue-specific induction. Preclinical and clinical studies that have exploited trained immunity inducers for cancer immunotherapy are summarized, and repurposed trained immunity inducers from other fields are proposed. We also outline the challenges and opportunities for trained immunity in future cancer immunotherapies. We envisage that more effective cancer vaccines will combine the induction of trained immunity with T cell therapies.

Keywords:  T cell responses; cancer immunotherapy; interferon γ; trained immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1427443
Nat Commun. 2024 Jul 31. 15(1): 6438

Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.

Meiyue Wang, Heinrich Flaswinkel, Abhinav Joshi, Matteo Napoli, Sergi Masgrau-Alsina, Julia M Kamper, Antonia Henne, Alexander Heinz, Marleen Berouti, Niklas A Schmacke, Karsten Hiller, Elisabeth Kremmer, Benedikt Wefers, Wolfgang Wurst, Markus Sperandio, Jürgen Ruland, Thomas Fröhlich, Veit Hornung.

Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than PfklS775A/S775A after LPS treatment. In an in vivo inflammation model, PfklS775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis.

DOI: https://doi.org/10.1038/s41467-024-50104-7
Nat Rev Immunol. 2024 Jul 29.

Early life antibiotics have lasting effects on the lung epithelium.

Lucy Bird.

DOI: https://doi.org/10.1038/s41577-024-01072-y
J Tissue Eng. 2024 Jan-Dec;15:15 20417314241265202

Immunomodulation in diabetic wounds healing: The intersection of macrophage reprogramming and immunotherapeutic hydrogels.

Dan Sun, Qiang Chang, Feng Lu.

  Diabetic wound healing presents a significant clinical challenge due to the interplay of systemic metabolic disturbances and local inflammation, which hinder the healing process. Macrophages undergo a phenotypic shift from M1 to M2 during wound healing, a transition pivotal for effective tissue repair. However, in diabetic wounds, the microenvironment disrupts this phenotypic polarization, perpetuating inflammation, and impeding healing. Reprograming macrophages to restore their M2 phenotype offers a potential avenue for modulating the wound immune microenvironment and promoting healing. This review elucidates the mechanisms underlying impaired macrophage polarization toward the M2 phenotype in diabetic wounds and discusses novel strategies, including epigenetic and metabolic interventions, to promote macrophage conversion to M2. Hydrogels, with their hydrated 3D cross-linked structure, closely resemble the physiological extracellular matrix and offer advantageous properties such as biocompatibility, tunability, and versatility. These characteristics make hydrogels promising candidates for developing immunomodulatory materials aimed at addressing diabetic wounds. Understanding the role of hydrogels in immunotherapy, particularly in the context of macrophage reprograming, is essential for the development of advanced wound care solutions. This review also highlights recent advancements in immunotherapeutic hydrogels as a step toward precise and effective treatments for diabetic wounds.

Keywords:  Diabetic wound; healing; hydrogel; immunomodulation; macrophage reprograming

DOI:  https://doi.org/10.1177/20417314241265202
Annu Rev Genet. 2024 Jul 31.

Phenotypic Heterogeneity in Pathogens.

Jessica Sherry, E Hesper Rego.

Pathogen diversity within an infected organism has traditionally been explored through the lens of genetic heterogeneity. Hallmark studies have characterized how genetic diversity within pathogen subpopulations contributes to treatment escape and infectious disease progression. However, recent studies have begun to reveal the mechanisms by which phenotypic heterogeneity is established within genetically identical populations of invading pathogens. Furthermore, exciting new work highlights how these phenotypically heterogeneous subpopulations contribute to a pathogen population better equipped to handle the complex and fluctuating environment of a host organism. In this review, we focus on how bacterial pathogens, including Staphylococcus aureus, Salmonella typhimurium, Pseudomonas aeruginosa, and Mycobacterium tuberculosis, establish and maintain phenotypic heterogeneity, and we explore recent work demonstrating causative links between this heterogeneity and infection outcome.

DOI: https://doi.org/10.1146/annurev-genet-111523-102459
PNAS Nexus. 2024 Jul;3(7): pgae273

Commensal microbiome dysbiosis elicits interleukin-8 signaling to drive fibrotic skin disease.

Wenyu Zhang, Qili Peng, Xian Huang, Qing Huang, Zhiliang Zhang, Fuli Li, Naisheng Zheng, Binsheng Shi, Zhihong Fan, Tomasz Maj, Rui Chen.

  Wound healing is an intensely studied topic involved in many relevant pathophysiological processes, including fibrosis. Despite the large interest in fibrosis, the network that is related to commensal microbiota and skin fibrosis remains mysterious. Here, we pay attention to keloid, a classical yet intractable skin fibrotic disease to establish the association between commensal microbiota to scaring tissue. Our histological data reveal the presence of microbiota in the keloids. 16S rRNA sequencing characterizes microbial composition and divergence between the pathological and normal skin tissues. Moreover, the data show elevation of interleukin-8 (IL-8) in both the circulation and keloid tissue, which elicited the collagen accumulation and migratory program of dermal fibroblasts via CXCR1/2 receptor. Our research provides insights into the pathology of human fibrotic diseases, advocating commensal bacteria and IL-8 signaling as useful targets in future interventions of recurrent keloid disease.

Keywords:  IL-8; keloid; microbiota; skin fibrosis

DOI:  https://doi.org/10.1093/pnasnexus/pgae273
Probiotics Antimicrob Proteins. 2024 Jul 28.

Exploring the Multifaceted Therapeutic Potential of Probiotics: A Review of Current Insights and Applications.

Kashyapi Chakravarty, Smriti Gaur, Rohit Kumar, Niraj Kumar Jha, Piyush Kumar Gupta.

  The interplay between human health and the microbiome has gained extensive attention, with probiotics emerging as pivotal therapeutic agents due to their vast potential in treating various health issues. As significant modulators of the gut microbiota, probiotics are crucial in maintaining intestinal homeostasis and enhancing the synthesis of short-chain fatty acids. Despite extensive research over the past decades, there remains an urgent need for a comprehensive and detailed review that encapsulates probiotics' latest insights and applications. This review focusses on the multifaceted roles of probiotics in promoting health and preventing disease, highlighting the complex mechanisms through which these beneficial bacteria influence both gut flora and the human body at large. This paper also explores probiotics' neurological and gastrointestinal applications, focussing on their significant impact on the gut-brain axis and their therapeutic potential in a broad spectrum of pathological conditions. Current innovations in probiotic formulations, mainly focusing on integrating genomics and biotechnological advancements, have also been comprehensively discussed herein. This paper also critically examines the regulatory landscape that governs probiotic use, ensuring safety and efficacy in clinical and dietary settings. By presenting a comprehensive overview of recent studies and emerging trends, this review aims to illuminate probiotics' extensive therapeutic capabilities, leading to future research and clinical applications. However, besides extensive research, further advanced explorations into probiotic interactions and mechanisms will be essential for developing more targeted and effective therapeutic strategies, potentially revolutionizing health care practices for consumers.

Keywords:  Biotherapeutics; Gut microbiome; Postbiotics; Probiotics; Psychobiotics; Synbiotics

DOI:  https://doi.org/10.1007/s12602-024-10328-x
Nat Commun. 2024 Aug 02. 15(1): 6515

Phenotypic heterogeneity follows a growth-viability tradeoff in response to amino acid identity.

Kiyan Shabestary, Cinzia Klemm, Benedict Carling, James Marshall, Juline Savigny, Marko Storch, Rodrigo Ledesma-Amaro.

In their natural environments, microorganisms mainly operate at suboptimal growth conditions with fluctuations in nutrient abundance. The resulting cellular adaptation is subject to conflicting tasks: growth or survival maximisation. Here, we study this adaptation by systematically measuring the impact of a nitrogen downshift to 24 nitrogen sources on cellular metabolism at the single-cell level. Saccharomyces lineages grown in rich media and exposed to a nitrogen downshift gradually differentiate to form two subpopulations of different cell sizes where one favours growth while the other favours viability with an extended chronological lifespan. This differentiation is asymmetrical with daughter cells representing the new differentiated state with increased viability. We characterise the metabolic response of the subpopulations using RNA sequencing, metabolic biosensors and a transcription factor-tagged GFP library coupled to high-throughput microscopy, imaging more than 800,000 cells. We find that the subpopulation with increased viability is associated with a dormant quiescent state displaying differences in MAPK signalling. Depending on the identity of the nitrogen source present, differentiation into the quiescent state can be actively maintained, attenuated, or aborted. These results establish amino acids as important signalling molecules for the formation of genetically identical subpopulations, involved in chronological lifespan and growth rate determination.

DOI: https://doi.org/10.1038/s41467-024-50602-8
J Biol Chem. 2024 Jul 30. pii: S0021-9258(24)02115-X. [Epub ahead of print] 107614

The arginine and nitric oxide metabolic pathway regulate the gut colonization and expansion of Ruminococcous gnavus.

Juan A Flores, Jayson M Antonio, Panan Suntornsaratoon, Vik Meadows, Sheila Bandyopadhyay, Jiangmeng Han, Rajbir Singh, Iyshwarya Balasubramanian, Ravij Upadhyay, Yue Liu, Edward M Bonder, Pawel Kiela, Xiaoyang Su, Ronaldo Ferraris, Nan Gao.

   BACKGROUND: Ruminococcus gnavus is a mucolytic commensal bacterium whose increased gut colonization has been associated with chronic inflammatory and metabolic diseases in humans. Whether R. gnavus metabolites can modulate host intestinal physiology remains largely understudied.
METHODS: We performed untargeted metabolomic and bulk RNA sequencing analyses using R. gnavus mono-colonization in germ free mice. Based on transcriptome-metabolome correlations, we tested the impact of specific arginine metabolites on intestinal epithelial production of nitric oxide (NO) and examined the effect of NO on the growth of various strains of R. gnavus in vitro and in Nos2-deficient mice.
RESULTS: R. gnavus produces specific arginine, tryptophan and tyrosine metabolites, some of which are regulated by the environmental richness of sialic acid and mucin. R. gnavus colonization promotes expression of amino acid transporters and enzymes involved in metabolic flux of arginine and associated metabolites into NO. R. gnavus induced elevated levels of Nitric Oxide Synthase 2 (NOS2) while Nos2 ablation resulted in R. gnavus expansion in vivo. The growth of various R. gnavus strains can be inhibited by NO. Specific R. gnavus metabolites modulate intestinal epithelial cell NOS2 abundance and reduce epithelial barrier function at higher concentrations.
CONCLUSIONS: Intestinal colonization and interaction with R. gnavus are partially regulated by an arginine-NO metabolic pathway, whereby a balanced control by the gut epithelium may restrain R. gnavus growth in healthy individuals. Disruption in this arginine metabolic regulation will contribute to the expansion and blooming of R. gnavus.

Keywords:  R. gnavus; arginine; intestine; metabolite; nitric oxide

DOI:  https://doi.org/10.1016/j.jbc.2024.107614
Eur J Immunol. 2024 Jul 28. e2451170

Innate immune mechanisms promote human response to Acinetobacter baumannii infection.

Andrea Sabatini, Massimiliano Lucidi, Serena Ciolfi, Claudia Vuotto, Marco De Bardi, Paolo Visca, Luca Battistini, Daniela Visaggio, Elisabetta Volpe.

  Acinetobacter baumannii is an opportunistic Gram-negative bacterium representing one of the leading causes of ventilator-associated pneumonia. The development of pneumonia results from a complex interplay between pathogens and pulmonary innate mucosal immunity. Therefore, the knowledge of the host immune responses is pivotal for the development of effective therapeutics to treat A. baumannii infections. Previous studies were conducted using cell lines and animal models, but a comprehensive understanding of the interaction between A. baumannii and primary human immune cells is still lacking. To bridge this gap, we investigated the response of primary monocytes, macrophages, and dendritic cells to the A. baumannii-type strain and an epidemic clinical isolate. We found that all immune cells trigger different responses when interacting with A. baumannii. In particular, macrophages and monocytes mediate bacterial clearance, whereas monocytes and dendritic cells activate a late response through the production of cytokines, chemokines, and the expression of co-stimulatory molecules. The epidemic strain induces lower expression of interleukin-10 and CD80 compared with the type strain, potentially constituting two immune evasion strategies.

Keywords:  Acinetobacter baumannii; Dendritic cells; Innate immunity; Macrophages; Monocytes; Opportunistic infections

DOI:  https://doi.org/10.1002/eji.202451170
Sci Transl Med. 2024 Jul 31. 16(758): eadl3381

Functional and epigenetic changes in monocytes from adults immunized with an AS01-adjuvanted vaccine.

Viviane Bechtold, Kinga K Smolen, Wivine Burny, Simone P de Angelis, Simon Delandre, Ahmed Essaghir, Arnaud Marchant, Cheikh Ndour, Martin Taton, Robbert van der Most, Fabienne Willems, Arnaud M Didierlaurent.

The adjuvant AS01 plays a key role in the immunogenicity of several approved human vaccines with demonstrated high efficacy. Its adjuvant effect relies on activation of the innate immune system. However, specific effects of AS01-adjuvanted vaccines on innate cell function and epigenetic remodeling, as described for Bacille Calmette-Guérin (BCG) and influenza vaccines, are still unknown. We assessed the long-term functional and epigenetic changes in circulating monocytes and dendritic cells induced by a model vaccine containing hepatitis B surface antigen and AS01 in healthy adults (NCT01777295). The AS01-adjuvanted vaccine, but not an Alum-adjuvanted vaccine, increased the number of circulating monocytes and their expression of human leukocyte antigen (HLA)-DR, which correlated with the magnitude of the memory CD4+ T cell response. Single-cell analyses revealed epigenetic alterations in monocyte and dendritic cell subsets, affecting accessibility of transcription factors involved in cell functions including activator protein-1 (AP-1), GATA, C/EBP, and interferon regulatory factor. The functional changes were characterized by a reduced proinflammatory response to Toll-like receptor activation and an improved response to interferon-γ, a cytokine critical for the adjuvant's mode of action. Epigenetic changes were most evident shortly after the second vaccine dose in CD14+ monocytes, for which accessibility differences of some transcription factors could persist for up to 6 months postvaccination. Together, we show that reprogramming of monocyte subsets occurs after vaccination with an AS01-adjuvanted vaccine, an effect that may contribute to the impact of vaccination beyond antigen-specific protection.

DOI: https://doi.org/10.1126/scitranslmed.adl3381
Int Immunopharmacol. 2024 Jul 29. pii: S1567-5769(24)01339-0. [Epub ahead of print]140 112818

Ferroptosis is involved in Staphylococcus aureus-induced mastitis through autophagy activation by endoplasmic reticulum stress.

Lijuan Bao, Yihong Zhao, Shiyu Duan, Keyi Wu, Ruping Shan, Yi Liu, Yang Yang, Qiujie Chen, Changlong Song, Wenjia Li.

  Cell death caused by severe Staphylococcus aureus (S. aureus) infection is a fatal threat to humans and animals. However, whether ferroptosis, an iron-dependent form of cell death, is involved in S. aureus-induced cell death and its role in S. aureus-induced diseases are unclear. Using a mouse mastitis model and mammary epithelial cells (MMECs), we investigated the role of ferroptosis in the pathogenesis of S. aureus infection. The results revealed that S. aureus-induced ferroptosis in vivo and in vitro as demonstrated by dose-dependent increases in cell death; the level of malondialdehyde (MDA), the final product of lipid peroxidation; and dose-dependent decrease the production of the antioxidant glutathione (GSH). Treatment with typical inhibitors of ferroptosis, including ferrostatin-1 (Fer-1) and deferiprone (DFO), significantly inhibited S. aureus-induced death in MMECs. Mechanistically, treatment with S. aureus activated the protein kinase RNA-like ER kinase (PERK)-eukaryotic initiation factor 2, α subunit (eIF2α)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) pathway, which subsequently upregulated autophagy and promoted S. aureus-induced ferroptosis. The activation of autophagy degraded ferritin, resulting in iron dysregulation and ferroptosis. In addition, we found that excessive reactive oxygen species (ROS) production induced ferroptosis and activated endoplasmic reticulum (ER) stress, manifesting as elevated p-PERK-p-eIF2α-ATF4-CHOP pathway protein levels. Collectively, our findings indicate that ferroptosis is involved in S. aureus-induced mastitis via ER stress-mediated autophagy activation, implying a potential strategy for the prevention of S. aureus-associated diseases by targeting ferroptosis. In conclusion, the ROS-ER stress-autophagy axis is involved in regulating S. aureus-induced ferroptosis in MMECs. These findings not only provide a new potential mechanism for mastitis induced by S. aureus but also provide a basis for the treatment of other ferroptotic-related diseases.

Keywords:  Autophagy; ER stress; Ferroptosis; Mastitis; S. aureus

DOI:  https://doi.org/10.1016/j.intimp.2024.112818
Nature. 2024 Jul 31.

Immunological memory diversity in the human upper airway.

Sydney I Ramirez, Farhoud Faraji, L Benjamin Hills, Paul G Lopez, Benjamin Goodwin, Hannah D Stacey, Henry J Sutton, Kathryn M Hastie, Erica Ollmann Saphire, Hyun Jik Kim, Sara Mashoof, Carol H Yan, Adam S DeConde, Gina Levi, Shane Crotty.

The upper airway is an important site of infection, but immune memory in the human upper airway is poorly understood, with implications for COVID-19 and many other human diseases1-4. Here we demonstrate that nasal and nasopharyngeal swabs can be used to obtain insights into these challenging problems, and define distinct immune cell populations, including antigen-specific memory B cells and T cells, in two adjacent anatomical sites in the upper airway. Upper airway immune cell populations seemed stable over time in healthy adults undergoing monthly swabs for more than 1 year, and prominent tissue resident memory T (TRM) cell and B (BRM) cell populations were defined. Unexpectedly, germinal centre cells were identified consistently in many nasopharyngeal swabs. In subjects with SARS-CoV-2 breakthrough infections, local virus-specific BRM cells, plasma cells and germinal centre B cells were identified, with evidence of local priming and an enrichment of IgA+ memory B cells in upper airway compartments compared with blood. Local plasma cell populations were identified with transcriptional profiles of longevity. Local virus-specific memory CD4+ TRM cells and CD8+ TRM cells were identified, with diverse additional virus-specific T cells. Age-dependent upper airway immunological shifts were observed. These findings provide new understanding of immune memory at a principal mucosal barrier tissue in humans.

DOI: https://doi.org/10.1038/s41586-024-07748-8
ACG Case Rep J. 2024 Aug;11(8): e01333

Beyond Antibiotics: Novel Approaches in the Treatment of Recurrent Clostridioides difficile Infection.

Syed Murtaza Haider Zaidi, Ramsha Haider, Syeda Amna Batool Kazmi, Ali Husnain, Saniah Khan, Sabrina Merchant, Hamnah Tayyab, Fazl Rahim Wazeen, Ammad Javaid Chaudhary.



Keywords:  Clostridioides Difficile infection; fecal microbiota transplant; gut microbiome; oral microbiome therapy

DOI:  https://doi.org/10.14309/crj.0000000000001333
Int Immunopharmacol. 2024 Jul 27. pii: S1567-5769(24)01332-8. [Epub ahead of print]139 112811

A multistage protein subunit vaccine as BCG-booster confers protection against Mycobacterium tuberculosis infection in murine models.

Zhenyan Chen, Ying Zhang, Juan Wu, Jinchuan Xu, Zhidong Hu, Xiao-Yong Fan.

  The eradication of tuberculosis remains a global challenge. Despite being the only licensed vaccine, Bacillus Calmette-Guérin (BCG) confers limited protective efficacy in adults and individuals with latent tuberculosis infections (LTBI). There is an urgent need to develop novel vaccines that can enhance the protective effect of BCG. Protein subunit vaccines have garnered significant research interest due to their safety and plasticity. Based on previous studies, we selected three antigens associated with LTBI (Rv2028c, Rv2029c, Rv3126c) and fused them with an immunodominant antigen Ag85A, resulting in the construction of a multistage protein subunit vaccine named A986. We evaluated the protective effect of recombinant protein A986 adjuvanted with MPL/QS21 as a booster vaccine for BCG against Mycobacterium tuberculosis (Mtb) infection in mice. The A986 + MPL/QS21 induced the secretion of antigen-specific Th1 (IL-2+, IFN-γ+ and TNF-α+) and Th17 (IL-17A+) cytokines in CD4+ and CD8+ T cells within the lung and spleen of mice, while also increased the frequency of central memory and effector memory T cells. Additionally, it also induced the enhanced production of IgG antibodies. Compared to BCG alone, A986 + MPL/QS21 boosting significantly augmented the proliferation of antigen-specific multifunctional T cells and effectively reduced bacterial load in infected mice. Taken together, A986 + MPL/QS21 formulation induced robust antigen-specific immune responses and provided enhanced protection against Mtb infection as a booster of BCG vaccine.

Keywords:  BCG-booster; Latent infection; Multistage; Protein vaccine; Tuberculosis

DOI:  https://doi.org/10.1016/j.intimp.2024.112811
JAMA. 2024 Aug 02.

The World Needs a Staph Vaccine-New Research Could Bring It a Step Closer.

Donavyn Coffey.

DOI: https://doi.org/10.1001/jama.2024.1015
Nature. 2024 Jul 31.

Turbinate-homing IgA-secreting cells originate in the nasal lymphoid tissues.

Jingjing Liu, Liat Stoler-Barak, Hadas Hezroni-Bravyi, Adi Biram, Sacha Lebon, Natalia Davidzohn, Merav Kedmi, Muriel Chemla, David Pilzer, Marina Cohen, Ori Brenner, Moshe Biton, Ziv Shulman.

Nasal vaccination elicits a humoral immune response that provides protection from airborne pathogens1, yet the origins and specific immune niches of antigen-specific IgA-secreting cells in the upper airways are unclear2. Here we define nasal glandular acinar structures and the turbinates as immunological niches that recruit IgA-secreting plasma cells from the nasal-associated lymphoid tissues (NALTs)3. Using intact organ imaging, we demonstrate that nasal vaccination induces B cell expansion in the subepithelial dome of the NALT, followed by invasion into commensal-bacteria-driven chronic germinal centres in a T cell-dependent manner. Initiation of the germinal centre response in the NALT requires pre-expansion of antigen-specific T cells, which interact with cognate B cells in interfollicular regions. NALT ablation and blockade of PSGL-1, which mediates interactions with endothelial cell selectins, demonstrated that NALT-derived IgA-expressing B cells home to the turbinate region through the circulation, where they are positioned primarily around glandular acinar structures. CCL28 expression was increased in the turbinates in response to vaccination and promoted homing of IgA+ B cells to this site. Thus, in response to nasal vaccination, the glandular acini and turbinates provide immunological niches that host NALT-derived IgA-secreting cells. These cellular events could be manipulated in vaccine design or in the treatment of upper airway allergic responses.

DOI: https://doi.org/10.1038/s41586-024-07729-x
Cell. 2024 Jul 25. pii: S0092-8674(24)00768-2. [Epub ahead of print]

Host and environmental factors shape upper airway microbiota and respiratory health across the human lifespan.

Mari-Lee Odendaal, Wouter A A de Steenhuijsen Piters, Eelco Franz, Mei Ling J N Chu, James A Groot, Elske M van Logchem, Raiza Hasrat, Sjoerd Kuiling, Roan Pijnacker, Rob Mariman, Krzysztof Trzciński, Fiona R M van der Klis, Elisabeth A M Sanders, Lidwien A M Smit, Debby Bogaert, Thijs Bosch.

  Our understanding of the normal variation in the upper respiratory tract (URT) microbiota across the human lifespan and how these relate to host, environment, and health is limited. We studied the microbiota of 3,104 saliva (<10 year-olds)/oropharynx (≥10 year-olds) and 2,485 nasopharynx samples of 3,160 Dutch individuals 0-87 years of age, participating in a cross-sectional population-wide study (PIENTER-3) using 16S-rRNA sequencing. The microbiota composition was strongly related to age, especially in the nasopharynx, with maturation occurring throughout childhood and adolescence. Clear niche- and age-specific associations were found between the microbiota composition and host/environmental factors and health outcomes. Among others, social interaction, sex, and season were associated with the nasopharyngeal microbial community. By contrast, the oral microbiota was more related to antibiotics, tobacco, and alcohol use. We present an atlas of the URT microbiota across the lifespan in association with environment and health, establishing a baseline for future research.

Keywords:  16S-rRNA sequencing; environment; exposure; health outcomes; host; human lifespan; microbiome; microbiota; population-wide; upper respiratory tract

DOI:  https://doi.org/10.1016/j.cell.2024.07.008
Gastroenterol Clin North Am. 2024 Sep;pii: S0889-8553(24)00003-7. [Epub ahead of print]53(3): 399-412

Metabolic Regulation of Microbiota and Tissue Response.

Zhilu Xu, Manman Chen, Siew Chien Ng.

  The microbiota in our gut regulates the sophisticated metabolic system that the human body has, essentially converting food into energy and the building blocks for various bodily functions. In this review, we discuss the multifaceted impact of the microbiota on host nutritional status by producing short-chain fatty acids, influencing gut hormones and mediating bile acid metabolism, and the key role in maintaining intestinal barrier integrity and immune homeostasis. Understanding and leveraging the power of the gut microbiome holds tremendous potential for enhancing human health and preventing various diseases.

Keywords:  Bile acid; Gut immunity; Gut microbiome; Intestinal barrier; Short-chain fatty acids

DOI:  https://doi.org/10.1016/j.gtc.2024.01.003