bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024‒04‒14
35 papers selected by
Chun-Chi Chang, University Hospital Zurich

  1. J Invest Dermatol. 2024 Apr 09. pii: S0022-202X(24)00277-X. [Epub ahead of print]
      The skin microbiome can both trigger beneficial immune stimulation and pose a potential infection threat. Previous studies have shown that colonization of mouse skin with the model human skin commensal Staphylococcus epidermidis is protective against subsequent excisional wound or pathogen challenge. However, less is known about concurrent skin damage and exposure to commensal microbes, despite growing interest in interventional probiotic therapy. Here, we address this open question by applying commensal skin bacteria at a high dose to abraded skin. While depletion of the skin microbiome via antibiotics delayed repair from damage, probiotic-like application of commensals-- including the mouse commensal Staphylococcus xylosus, three distinct isolates of S. epidermidis, and all other tested human skin commensals-- also significantly delayed barrier repair. Increased inflammation was observed within four hours of S. epidermidis exposure and persisted through day four, at which point the skin displayed a chronic wound-like inflammatory state with increased neutrophil infiltration, increased fibroblast activity, and decreased monocyte differentiation. Transcriptomic analysis suggested that the prolonged upregulation of early canonical proliferative pathways inhibited the progression of barrier repair. These results highlight the nuanced role of members of the skin microbiome in modulating barrier integrity and indicate the need for caution in their development as probiotics.
    Keywords:  epidermidis; microbiome; neutrophil; staphylococcus; wound
  2. Immunity. 2024 Apr 09. pii: S1074-7613(24)00133-X. [Epub ahead of print]57(4): 674-699
      Nucleotide-binding oligomerization domain (NOD)-like receptors, also known as nucleotide-binding leucine-rich repeat receptors (NLRs), are a family of cytosolic pattern recognition receptors that detect a wide variety of pathogenic and sterile triggers. Activation of specific NLRs initiates pro- or anti-inflammatory signaling cascades and the formation of inflammasomes-multi-protein complexes that induce caspase-1 activation to drive inflammatory cytokine maturation and lytic cell death, pyroptosis. Certain NLRs and inflammasomes act as integral components of larger cell death complexes-PANoptosomes-driving another form of lytic cell death, PANoptosis. Here, we review the current understanding of the evolution, structure, and function of NLRs in health and disease. We discuss the concept of NLR networks and their roles in driving cell death and immunity. An improved mechanistic understanding of NLRs may provide therapeutic strategies applicable across infectious and inflammatory diseases and in cancer.
    Keywords:  DAMP; IL-18; IL-1β; NF-κB; NLR; NLR network; PAMP; PANoptosis; PANoptosome; RIPK; apoptosis; caspase-1; gasdermin; inflammasome; inflammatory cell death; innate immune cell death; interferon; necroptosis; pattern recognition receptor; pyroptosis
  3. Sci Rep. 2024 04 10. 14(1): 8379
      Macrophage responses to activation are fluid and dynamic in their ability to respond appropriately to challenges, a role integral to host defence. While bacteria can influence macrophage differentiation and polarization into pro-inflammatory and alternatively activated phenotypes through direct interactions, many questions surround indirect communication mechanisms mediated through secretomes derived from gut bacteria, such as lactobacilli. We examined effects of secretome-mediated conditioning on THP-1 human monocytes, focusing on the ability of the Lacticaseibacillus rhamnosus R0011 secretome (LrS) to drive macrophage differentiation and polarization and prime immune responses to subsequent challenge with lipopolysaccharide (LPS). Genome-wide transcriptional profiling revealed increased M2-associated gene transcription in response to LrS conditioning in THP-1 cells. Cytokine and chemokine profiling confirmed these results, indicating increased M2-associated chemokine and cytokine production (IL-1Ra, IL-10). These cells had increased cell-surface marker expression of CD11b, CD86, and CX3CR1, coupled with reduced expression of the M1 macrophage-associated marker CD64. Mitochondrial substrate utilization assays indicated diminished reliance on glycolytic substrates, coupled with increased utilization of citric acid cycle intermediates, characteristics of functional M2 activity. LPS challenge of LrS-conditioned THP-1s revealed heightened responsiveness, indicative of innate immune priming. Resting stage THP-1 macrophages co-conditioned with LrS and retinoic acid also displayed an immunoregulatory phenotype with expression of CD83, CD11c and CD103 and production of regulatory cytokines. Secretome-mediated conditioning of macrophages into an immunoregulatory phenotype is an uncharacterized and potentially important route through which lactic acid bacteria and the gut microbiota may train and shape innate immunity at the gut-mucosal interface.
  4. Blood. 2024 Apr 11. pii: blood.2024024330. [Epub ahead of print]
      Inflammatory responses must be tightly coordinated with the activation of emergency myelopoiesis to produce potent myeloid cells that fight infection without causing excessive host damage. Here, we show that GM-CSF programs myeloid committed progenitors to produce trained macrophages (increased cytokine response), but programs the upstream non-committed LKS+ progenitors to produce tolerized macrophages (decreased cytokine response). In myeloid progenitors, GM-CSF strongly activates STAT5, ERK and Akt-mTOR signaling pathways, which are essential to establish a training program, whereas in LKS+ progenitors GM-CSF induces NF-κB translocation to the nucleus to establish a tolerization program. These differences arise from higher GM-CSF receptor expression in myeloid progenitors compared to LKS+ cells. We demonstrate that β-catenin regulation of NF-κB nuclear translocation is central in this process. Glycogen synthase kinase 3 (GSK3) inactivation by strong ERK and PI3K-Akt signaling increases cytoplasmic β-catenin levels to block NF-κB nuclear translocation in myeloid progenitors. In contrast, when ERK and PI3K-Akt signaling are weak, active GSK3 causes a decrease in β-catenin, allowing NF-κB nuclear translocation in LKS+ progenitors. Finally, GM-CSF-induced LKS+ tolerization takes place in several murine models of trained immunity and in human CD34+ CD38- progenitors. Our study reveals that in addition to activating myelopoiesis, GM-CSF also programs early and immediate myeloid progenitors to produce opposing immune memory phenotypes. We propose that the inflammatory response from immediate myeloid progenitors may be balanced by the tolerized phenotype of early progenitors, thus providing a mechanism for appropriate resolution of inflammation and protection against a prolonged cytokine storm.
  5. Int J Mol Sci. 2024 Apr 05. pii: 4051. [Epub ahead of print]25(7):
      Bacterial and viral respiratory tract infections are the most common infectious diseases, leading to worldwide morbidity and mortality. In the past 10 years, the importance of lung microbiota emerged in the context of pulmonary diseases, although the mechanisms by which it impacts the intestinal environment have not yet been fully identified. On the contrary, gut microbial dysbiosis is associated with disease etiology or/and development in the lung. In this review, we present an overview of the lung microbiome modifications occurring during respiratory infections, namely, reduced community diversity and increased microbial burden, and of the downstream consequences on host-pathogen interaction, inflammatory signals, and cytokines production, in turn affecting the disease progression and outcome. Particularly, we focus on the role of the gut-lung bidirectional communication in shaping inflammation and immunity in this context, resuming both animal and human studies. Moreover, we discuss the challenges and possibilities related to novel microbial-based (probiotics and dietary supplementation) and microbial-targeted therapies (antibacterial monoclonal antibodies and bacteriophages), aimed to remodel the composition of resident microbial communities and restore health. Finally, we propose an outlook of some relevant questions in the field to be answered with future research, which may have translational relevance for the prevention and control of respiratory infections.
    Keywords:  bacteria; dysbiosis; gut–lung axis; host–microbe interactions; microbial therapies; microbiota; mucosal immunity; virus
  6. PLoS Pathog. 2024 Apr 11. 20(4): e1012137
      Interleukin-1 (IL-1) signaling is essential for controlling virulent Mycobacterium tuberculosis (Mtb) infection since antagonism of this pathway leads to exacerbated pathology and increased susceptibility. In contrast, the triggering of type I interferon (IFN) signaling is associated with the progression of tuberculosis (TB) disease and linked with negative regulation of IL-1 signaling. However, mice lacking IL-1 signaling can control Mtb infection if infected with an Mtb strain carrying the rifampin-resistance conferring mutation H445Y in its RNA polymerase β subunit (rpoB-H445Y Mtb). The mechanisms that govern protection in the absence of IL-1 signaling during rpoB-H445Y Mtb infection are unknown. In this study, we show that in the absence of IL-1 signaling, type I IFN signaling controls rpoB-H445Y Mtb replication, lung pathology, and excessive myeloid cell infiltration. Additionally, type I IFN is produced predominantly by monocytes and recruited macrophages and acts on LysM-expressing cells to drive protection through nitric oxide (NO) production to restrict intracellular rpoB-H445Y Mtb. These findings reveal an unexpected protective role for type I IFN signaling in compensating for deficiencies in IL-1 pathways during rpoB-H445Y Mtb infection.
  7. Expert Rev Anti Infect Ther. 2024 Apr 12. 1-17
      INTRODUCTION: The microbiome is known to have a substantial impact on human health and disease. However, the impacts of the microbiome on immune system development, susceptibility to infectious diseases, and vaccine-elicited immune responses are emerging areas of interest.AREAS COVERED: In this review, we provide an overview of development of the microbiome during childhood. We highlight available data suggesting that the microbiome is critical to maturation of the immune system and modifies susceptibility to a variety of infections during childhood and adolescence, including respiratory tract infections, Clostridioides difficile infection, and sexually transmitted infections. We discuss currently available and investigational therapeutics that have the potential to modify the microbiome to prevent or treat infections among children. Finally, we review the accumulating evidence that the gut microbiome influences vaccine-elicited immune responses among children.
    EXPERT OPINION: Recent advances in sequencing technologies have led to an explosion of studies associating the human microbiome with the risk and severity of infectious diseases. As our knowledge of the extent to which the microbiome influences childhood infections continues to grow, microbiome-based diagnostics and therapeutics will increasingly be incorporated into clinical practice to improve the prevention, diagnosis, and treatment of infectious diseases among children.
    Keywords:  Colonization resistance; gastrointestinal microbiota; host-microbe interactions; metagenomic sequencing; pediatric infectious diseases; respiratory microbiota
  8. Immunity. 2024 Apr 09. pii: S1074-7613(24)00123-7. [Epub ahead of print]57(4): 700-717
      C-type lectin receptors (CLRs) expressed by myeloid cells constitute a versatile family of receptors that play a key role in innate immune recognition. Myeloid CLRs exhibit a remarkable ability to recognize an extensive array of ligands, from carbohydrates and beyond, and encompass pattern-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and markers of altered self. These receptors, classified into distinct subgroups, play pivotal roles in immune recognition and modulation of immune responses. Their intricate signaling pathways orchestrate a spectrum of cellular responses, influencing processes such as phagocytosis, cytokine production, and antigen presentation. Beyond their contributions to host defense in viral, bacterial, fungal, and parasitic infections, myeloid CLRs have been implicated in non-infectious diseases such as cancer, allergies, and autoimmunity. A nuanced understanding of myeloid CLR interactions with endogenous and microbial triggers is starting to uncover the context-dependent nature of their roles in innate immunity, with implications for therapeutic intervention.
    Keywords:  C-type lectin receptors; innate immunity; myeloid cells
  9. Immunity. 2024 Apr 09. pii: S1074-7613(24)00122-5. [Epub ahead of print]57(4): 649-673
      Toll-like receptors (TLRs) are an evolutionarily conserved family in the innate immune system and are the first line of host defense against microbial pathogens by recognizing pathogen-associated molecular patterns (PAMPs). TLRs, categorized into cell surface and endosomal subfamilies, recognize diverse PAMPs, and structural elucidation of TLRs and PAMP complexes has revealed their intricate mechanisms. TLRs activate common and specific signaling pathways to shape immune responses. Recent studies have shown the importance of post-transcriptional regulation in TLR-mediated inflammatory responses. Despite their protective functions, aberrant responses of TLRs contribute to inflammatory and autoimmune disorders. Understanding the delicate balance between TLR activation and regulatory mechanisms is crucial for deciphering their dual role in immune defense and disease pathogenesis. This review provides an overview of recent insights into the history of TLR discovery, elucidation of TLR ligands and signaling pathways, and their relevance to various diseases.
    Keywords:  PAMPs; PRRs; Toll-like receptors; inflammation; innate immunity
  10. Commun Biol. 2024 Apr 08. 7(1): 425
      Treatment of pneumococcal infections is limited by antibiotic resistance and exacerbation of disease by bacterial lysis releasing pneumolysin toxin and other inflammatory factors. We identified a previously uncharacterized peptide in the Klebsiella pneumoniae secretome, which enters Streptococcus pneumoniae via its AmiA-AliA/AliB permease. Subsequent downregulation of genes for amino acid biosynthesis and peptide uptake was associated with reduction of pneumococcal growth in defined medium and human cerebrospinal fluid, irregular cell shape, decreased chain length and decreased genetic transformation. The bacteriostatic effect was specific to S. pneumoniae and Streptococcus pseudopneumoniae with no effect on Streptococcus mitis, Haemophilus influenzae, Staphylococcus aureus or K. pneumoniae. Peptide sequence and length were crucial to growth suppression. The peptide reduced pneumococcal adherence to primary human airway epithelial cell cultures and colonization of rat nasopharynx, without toxicity. We identified a peptide with potential as a therapeutic for pneumococcal diseases suppressing growth of multiple clinical isolates, including antibiotic resistant strains, while avoiding bacterial lysis and dysbiosis.
  11. Immunity. 2024 Apr 09. pii: S1074-7613(24)00135-3. [Epub ahead of print]57(4): 632-648
      One of the most significant conceptual advances in immunology in recent history is the recognition that signals from the innate immune system are required for induction of adaptive immune responses. Two breakthroughs were critical in establishing this paradigm: the identification of dendritic cells (DCs) as the cellular link between innate and adaptive immunity and the discovery of pattern recognition receptors (PRRs) as a molecular link that controls innate immune activation as well as DC function. Here, we recount the key events leading to these discoveries and discuss our current understanding of how PRRs shape adaptive immune responses, both indirectly through control of DC function and directly through control of lymphocyte function. In this context, we provide a conceptual framework for how variation in the signals generated by PRR activation, in DCs or other cell types, can influence T cell differentiation and shape the ensuing adaptive immune response.
  12. mBio. 2024 Apr 09. e0011924
      Gonorrhea, caused by the bacterium Neisseria gonorrhoeae (Gc), is characterized by neutrophilic influx to infection sites. Gc has developed mechanisms to resist killing by neutrophils that include modifications to its surface lipooligosaccharide (LOS). One such LOS modification is sialylation: Gc sialylates its terminal LOS sugars with cytidine-5'-monophosphate-N-acetylneuraminic acid, which is scavenged from the host using LOS sialyltransferase (Lst) since Gc cannot make its sialic acid. Sialylation enables sensitive strains of Gc to resist complement-mediated killing in a serum-dependent manner. However, little is known about the contribution of sialylation to complement-independent, direct Gc-neutrophil interactions. In the absence of complement, we found sialylated Gc expressing opacity-associated (Opa) proteins decreased the oxidative burst and granule exocytosis from primary human neutrophils. In addition, sialylated Opa+ Gc survived better than vehicle treated or Δlst Gc when challenged with neutrophils. However, Gc sialylation did not significantly affect Opa-dependent association with or internalization of Gc by neutrophils. Previous studies have implicated sialic acid-binding immunoglobulin-type lectins (Siglecs) in modulating neutrophil interactions with sialylated Gc. Blocking neutrophil Siglecs with antibodies that bind to their extracellular domains eliminated the ability of sialylated Opa+ Gc to suppress the oxidative burst and resist neutrophil killing. These findings highlight a new role for sialylation in Gc evasion of human innate immunity, with implications for the development of vaccines and therapeutics for gonorrhea.IMPORTANCE: Neisseria gonorrhoeae, the bacterium that causes gonorrhea, is an urgent global health concern due to increasing infection rates, widespread antibiotic resistance, and its ability to thwart protective immune responses. The mechanisms by which Gc subverts protective immune responses remain poorly characterized. One way N. gonorrhoeae evades human immunity is by adding sialic acid that is scavenged from the host onto its lipooligosaccharide, using the sialyltransferase Lst. Here, we found that sialylation enhances N. gonorrhoeae survival from neutrophil assault and inhibits neutrophil activation, independently of the complement system. Our results implicate bacterial binding of sialic acid-binding lectins (Siglecs) on the neutrophil surface, which dampens neutrophil antimicrobial responses. This work identifies a new role for sialylation in protecting N. gonorrhoeae from cellular innate immunity, which can be targeted to enhance the human immune response in gonorrhea.
    Keywords:  Neisseria gonorrhoeae; degranulation; gonorrhea; infection; lipooligosaccharide; neutrophils; reactive oxygen species; sialylation
  13. Exp Cell Res. 2024 Apr 10. pii: S0014-4827(24)00120-4. [Epub ahead of print] 114029
      Aberrant expression of airway epithelial E-cadherin is a key feature of asthma, yet the underlying mechanisms are largely unknown. Ferroptosis is a novel form of regulated cell death involved in asthma pathogenesis. This study was aimed to evaluate the role of ferroptosis and to investigate whether ferroptosis mediates E-cadherin disruption in mixed granulocyte asthma (MGA). Two murine models of MGA were established using toluene diisocyanate (TDI) or ovalbumin with Complete Freund's Adjuvant (OVA/CFA). Specific antagonists of ferroptosis, including Liproxstatin-1 (Lip-1) and Ferrostatin-1 (Fer-1) were given to the mice. The allergen-exposed mice displayed markedly shrunk mitochondria in the airway epithelia, with decreased volume and denser staining accompanied by down-regulated GPX4 as well as up-regulated FTH1 and malondialdehyde, which are markers of ferroptosis. Decreased pulmonary expression of E-cadherin was also observed, with profound loss of membrane E-cadherin in the airway epithelia, as well as increased secretion of sE-cadherin. Treatment with Lip-1 not only showed potent protective effects against the allergen-induced airway hyperresponsiveness and inflammatory responses, but also rescued airway epithelial E-cadherin expression and inhibited the release of sE-cadherin. Taken together, our data demonstrated that ferroptosis mediates airway epithelial E-cadherin dysfunction in MGA.
    Keywords:  Airway epithelial cells; E-cadherin; Ferroptosis; Mixed granulocyte asthma
  14. Front Immunol. 2024 ;15 1363938
      Arginine and tryptophan are pivotal in orchestrating cytokine-driven macrophage polarization and immune activation. Specifically, interferon-gamma (IFN-γ) stimulates inducible nitric oxide synthase (iNOS) expression), leading to the conversion of arginine into citrulline and nitric oxide (NO), while Interleukin-4 (IL4) promotes arginase activation, shifting arginine metabolism toward ornithine. Concomitantly, IFN-γ triggers indoleamine 2,3-dioxygenase 1 (IDO1) and Interleukin-4 induced 1 (IL4i1), resulting in the conversion of tryptophan into kynurenine and indole-3-pyruvic acid. These metabolic pathways are tightly regulated by NAD+-dependent sirtuin proteins, with Sirt2 and Sirt5 playing integral roles. In this review, we present novel insights that augment our understanding of the metabolic pathways of arginine and tryptophan following Mycobacterium tuberculosis infection, particularly their relevance in macrophage responses. Additionally, we discuss arginine methylation and demethylation and the role of Sirt2 and Sirt5 in regulating tryptophan metabolism and arginine metabolism, potentially driving macrophage polarization.
    Keywords:  Sirt2; Sirt5; arginine metabolism; macrophages; tryptophan metabolism; tuberculosis
  15. Nat Commun. 2024 Apr 08. 15(1): 3009
      The composition of the microbial community in the intestine may influence the functions of distant organs such as the brain, lung, and skin. These microbes can promote disease or have beneficial functions, leading to the hypothesis that microbes in the gut explain the co-occurrence of intestinal and skin diseases. Here, we show that the reverse can occur, and that skin directly alters the gut microbiome. Disruption of the dermis by skin wounding or the digestion of dermal hyaluronan results in increased expression in the colon of the host defense genes Reg3 and Muc2, and skin wounding changes the composition and behavior of intestinal bacteria. Enhanced expression Reg3 and Muc2 is induced in vitro by exposure to hyaluronan released by these skin interventions. The change in the colon microbiome after skin wounding is functionally important as these bacteria penetrate the intestinal epithelium and enhance colitis from dextran sodium sulfate (DSS) as seen by the ability to rescue skin associated DSS colitis with oral antibiotics, in germ-free mice, and fecal microbiome transplantation to unwounded mice from mice with skin wounds. These observations provide direct evidence of a skin-gut axis by demonstrating that damage to the skin disrupts homeostasis in intestinal host defense and alters the gut microbiome.
  16. Signal Transduct Target Ther. 2024 Apr 08. 9(1): 87
      The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player in pyroptosis. This recently characterized class of pore-forming effector proteins is pivotal in orchestrating processes such as membrane permeabilization, pyroptosis, and the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants and infections. GSDMs have been implicated in a range of diseases including, but not limited to, sepsis, viral infections, and cancer, either through involvement in pyroptosis or independently of this process. The regulation of GSDM-mediated pyroptosis is gaining recognition as a promising therapeutic strategy for the treatment of various diseases. Current strategies for inhibiting GSDMD primarily involve binding to GSDMD, blocking GSDMD cleavage or inhibiting GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In this review, we delve into the cutting-edge understanding of the interplay between GSDMs and pyroptosis, elucidate the activation mechanisms of GSDMs, explore their associations with a range of diseases, and discuss recent advancements and potential strategies for developing GSDMD inhibitors.
  17. Nature. 2024 Apr 10.
      Gasdermin D (GSDMD) is the common effector for cytokine secretion and pyroptosis downstream of inflammasome activation and was previously shown to form large transmembrane pores upon cleavage by inflammatory caspases to generate the GSDMD N-terminal domain (GSDMD-NT)1-10. Here we report that GSDMD Cys191 is S-palmitoylated and palmitoylation is required for pore formation. S-palmitoylation, which does not affect GSDMD cleavage, is augmented by mitochondria-generated reactive oxygen species (ROS). Surprisingly, cleavage-deficient D275A GSDMD is also palmitoylated after inflammasome stimulation or treatment with ROS activators, and causes pyroptosis, although less efficiently than palmitoylated GSDMD-NT. Palmitoylated, but not unpalmitoylated, full-length GSDMD induces liposome leakage, and forms a pore similar in structure to GSDMD-NT pores shown by cryogenic electron microscopy. zDHHC5 and zDHHC9 are the major palmitoyltransferases that mediate GSDMD palmitoylation, and their expression is upregulated by inflammasome activation and ROS. The other human gasdermins are also palmitoylated in their N-termini. These data challenge the concept that cleavage is the only trigger for GSDMD activation. They suggest that reversible palmitoylation is a checkpoint for pore formation by both GSDMD-NT and intact GSDMD that serves as a general switch for the activation of this pore-forming family.
  18. Eur J Immunol. 2024 Apr 08. e2350955
      Type I interferons (IFN-Is) are key in fighting viral infections, but also serve major roles beyond antiviral immunity. Crucial is the tight regulation of IFN-I responses, while excessive levels are harmful to the cells. In essence, immune responses are generated by single cells making their own decisions, which are based on the signals they perceive. Additionally, immune cells must anticipate the future state of their environment, thereby weighing the costs and benefits of each possible outcome, in the presence of other potentially competitive decision makers (i.e., IFN-I producing cells). A rather new cellular communication mechanism called quorum sensing describes the effect of cell density on cellular secretory behaviors, which fits well with matching the right amount of IFN-Is produced to fight an infection. More competitive decision makers must contribute relatively less and vice versa. Intrigued by this concept, we assessed the effects of immune quorum sensing in pDCs, specialized immune cells known for their ability to mass produce IFN-Is. Using conventional microwell assays and droplet-based microfluidics assays, we were able the characterize the effect of quorum sensing in human primary immune cells in vitro. These insights open new avenues to manipulate IFN-I response dynamics in pathological conditions affected by aberrant IFN-I signaling.
    Keywords:  Droplet‐based microfluidics; Heterogeneity; Plasmacytoid dendritic cells; Quorum sensing; Type I interferon
  19. Sci Transl Med. 2024 Apr 10. 16(742): eado1449
      A study from Long et al. shows that many pathogens that cause surgical site infections during spine surgery come from the patient's own microbiome, suggesting a paradigm shift in the understanding of surgical site infections that questions the effectiveness of current enhanced sterility and antibiotic protocols.
  20. Lancet Microbe. 2024 Apr 09. pii: S2666-5247(24)00049-1. [Epub ahead of print]
      The incidence of antibiotic-resistant bacterial infections is increasing, and development of new antibiotics has been deprioritised by the pharmaceutical industry. Interdisciplinary research approaches, based on the ecological principles of bacterial fitness, competition, and transmission, could open new avenues to combat antibiotic-resistant infections. Many facultative bacterial pathogens use human mucosal surfaces as their major reservoirs and induce infectious diseases to aid their lateral transmission to new host organisms under some pathological states of the microbiome and host. Beneficial bacterial commensals can outcompete specific pathogens, thereby lowering the capacity of the pathogens to spread and cause serious infections. Despite the clinical relevance, however, the understanding of commensal-pathogen interactions in their natural habitats remains poor. In this Personal View, we highlight directions to intensify research on the interactions between bacterial pathogens and commensals in the context of human microbiomes and host biology that can lead to the development of innovative and sustainable ways of preventing and treating infectious diseases.
  21. Cell Rep. 2024 Apr 06. pii: S2211-1247(24)00395-4. [Epub ahead of print]43(4): 114067
      Mitochondrial dysfunction critically contributes to many major human diseases. The impact of specific gut microbial metabolites on mitochondrial functions of animals and the underlying mechanisms remain to be uncovered. Here, we report a profound role of bacterial peptidoglycan muropeptides in promoting mitochondrial functions in multiple mammalian models. Muropeptide addition to human intestinal epithelial cells (IECs) leads to increased oxidative respiration and ATP production and decreased oxidative stress. Strikingly, muropeptide treatment recovers mitochondrial structure and functions and inhibits several pathological phenotypes of fibroblast cells derived from patients with mitochondrial disease. In mice, muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. Muropeptides directly bind to ATP synthase, stabilize the complex, and promote its enzymatic activity in vitro, supporting the hypothesis that muropeptides promote mitochondria homeostasis at least in part by acting as ATP synthase agonists. This study reveals a potential treatment for human mitochondrial diseases.
    Keywords:  ATP synthase; CP: Cell biology; CP: Metabolism; Leigh syndrome; PGN; ROS; antibiotic-induced microbiome depletion; electron transfer chain; energy metabolism; intestinal epithelial cells; intestinal homeostasis; mitochondrial diseases; oxidative phosphorylation; oxidative stress; peptidoglycan
  22. Sci Immunol. 2024 Apr 12. 9(94): eadd1967
      Resident tissue macrophages (RTMs) encompass a highly diverse set of cells abundantly present in every tissue and organ. RTMs are recognized as central players in innate immune responses, and more recently their importance beyond host defense has started to be highlighted. Despite sharing a universal name and several canonical markers, RTMs perform remarkably specialized activities tailored to sustain critical homeostatic functions of the organs they reside in. These cells can mediate neuronal communication, participate in metabolic pathways, and secrete growth factors. In this Review, we summarize how the division of labor among different RTM subsets helps support tissue homeostasis. We discuss how the local microenvironment influences the development of RTMs, the molecular processes they support, and how dysregulation of RTMs can lead to disease. Last, we highlight both the similarities and tissue-specific distinctions of key RTM subsets, aiming to coalesce recent classifications and perspectives into a unified view.
  23. Ageing Res Rev. 2024 Apr 07. pii: S1568-1637(24)00114-4. [Epub ahead of print]97 102296
      Fibroblasts are abundant stromal cells which not only control the integrity of extracellular matrix (ECM) but also act as immune regulators. It is known that the structural cells within tissues can establish an organ-specific immunity expressing many immune-related genes and closely interact with immune cells. In fact, fibroblasts can modify their immune properties to display both pro-inflammatory and immunosuppressive activities in a context-dependent manner. After acute insults, fibroblasts promote tissue inflammation although they concurrently recruit immunosuppressive cells to enhance the resolution of inflammation. In chronic pathological states, tissue fibroblasts, especially senescent fibroblasts, can display many pro-inflammatory and immunosuppressive properties and stimulate the activities of different immunosuppressive cells. In return, immunosuppressive cells, such as M2 macrophages and myeloid-derived suppressor cells (MDSC), evoke an excessive conversion of fibroblasts into myofibroblasts, thus aggravating the severity of tissue fibrosis. Single-cell transcriptome studies on fibroblasts isolated from aged tissues have confirmed that tissue fibroblasts express many genes coding for cytokines, chemokines, and complement factors, whereas they lose some fibrogenic properties. The versatile immune properties of fibroblasts and their close cooperation with immune cells indicate that tissue fibroblasts have a crucial role in the aging process and age-related diseases.
    Keywords:  Cellular senescence; Fibroaging; Fibrosis; Immunosenescence; Inflammaging
  24. Eur J Immunol. 2024 Apr 05. e2350643
      We implicate a phenotype of trained immunity in bone-marrow-derived macrophages in the onset and progression of type 1 diabetes in nonobese diabetic mice. Treatment with FhHDM-1 reversed immune training, reducing histone methylation and glycolysis, and decreasing proinflammatory cytokine production to the same level as macrophages from nondiabetic immune-competent BALB/c mice.
    Keywords:  FhHDM‐1; Helminth therapy; Macrophage; Trained immunity; Type 1 diabetes
  25. Thorax. 2024 Apr 10. pii: thorax-2024-221551. [Epub ahead of print]
    Keywords:  Airway Epithelium
  26. Life Sci. 2024 Apr 06. pii: S0024-3205(24)00202-9. [Epub ahead of print]345 122612
      Gut microbiota is a complex microbial community with the ability of maintaining intestinal health. Intestinal homeostasis largely depends on the mucosal immune system to defense external pathogens and promote tissue repair. In recent years, growing evidence revealed the importance of gut microbiota in shaping intestinal mucosal immunity. Therefore, according to the existing findings, this review first provided an overview of intestinal mucosal immune system before summarizing the regulatory roles of gut microbiota in intestinal innate and adaptive immunity. Specifically, this review delved into the gut microbial interactions with the cells such as intestinal epithelial cells (IECs), macrophages, dendritic cells (DCs), neutrophils, and innate lymphoid cells (ILCs) in innate immunity, and T and B lymphocytes in adaptive immunity. Furthermore, this review discussed the main effects of gut microbiota dysbiosis in intestinal diseases and offered future research prospects. The review highlighted the key regulatory roles of gut microbiota in intestinal mucosal immunity via various host-microbe interactions, providing valuable references for the development of microbial therapy in intestinal diseases.
    Keywords:  Gut microbiota; Intestinal adaptive immunity; Intestinal diseases; Intestinal innate immunity; Intestinal mucosal immune system
  27. Immunity. 2024 Apr 09. pii: S1074-7613(24)00129-8. [Epub ahead of print]57(4): 815-831
      The sensory nervous system possesses the ability to integrate exogenous threats and endogenous signals to mediate downstream effector functions. Sensory neurons have been shown to activate or suppress host defense and immunity against pathogens, depending on the tissue and disease state. Through this lens, pro- and anti-inflammatory neuroimmune effector functions can be interpreted as evolutionary adaptations by host or pathogen. Here, we discuss recent and impactful examples of neuroimmune circuitry that regulate tissue homeostasis, autoinflammation, and host defense. Apparently paradoxical or conflicting reports in the literature also highlight the complexity of neuroimmune interactions that may depend on tissue- and microbe-specific cues. These findings expand our understanding of the nuanced mechanisms and the greater context of sensory neurons in innate immunity.
    Keywords:  barrier immunity; host defense; innate immunity; neuroimmune; neurons; sensory
  28. Arch Biochem Biophys. 2024 Apr 06. pii: S0003-9861(24)00103-6. [Epub ahead of print] 109984
      BACKGROUND: Allergen specific immunotherapy (AIT) has been widely used in allergy clinics. The therapeutic effects of it are to be improved. Macrophages occupy the largest proportion of airway immune cells. The aim of this study is to measure the effects of nasal instillation AIT (nAIT) on airway allergy by regulating macrophage functions.METHODS: An airway allergy mouse model was established with the ovalbumin-alum protocol. nAIT was conducted for mice with airway allergy through nasal instillation. The effects of nAIT were compared with subcutaneous injection AIT (SCIT) and sublingual AIT (SLIT).
    RESULTS: Mice with airway allergy showed the airway allergic response, including lung inflammation, airway hyper responsiveness, serum specific IgE, increase in the amounts of eosinophil peroxidase, mouse mast cell protease-1, and Th2 cytokines in bronchoalveolar lavage fluid. nAIT had a much better therapeutic effect on the airway allergic response than SCIT and SLIT. Mechanistically, we observed better absorption of allergen in macrophages, better production of IL-10 by macrophages, and better immune suppressive functions in macrophages in mice received nAIT than SCIT and SLIT.
    CONCLUSIONS: The nAIT has a much better therapeutic effect on suppressing the airway allergic response, in which macrophages play a critical role.
    Keywords:  Airway allergy; Immune regulation; Immunotherapy; Macrophage; Mucosal immunology
  29. Int J Mol Sci. 2024 Apr 05. pii: 4054. [Epub ahead of print]25(7):
      Chronic sinusitis with nasal polyps (CRSwNP) is one of the most common chronic inflammatory diseases, and involves tissue remodeling. One of the key mechanisms of tissue remodeling is the epithelial-mesenchymal transition (EMT), which also represents one of the pathophysiological processes of CRS observed in CRSwNP tissues. To date, many transcription factors and forms of extracellular stimulation have been found to regulate the EMT process. However, it is not known whether gangliosides, which are the central molecules of plasma membranes, involved in regulating signal transmission pathways, are involved in the EMT process. Therefore, we aimed to determine the role of gangliosides in the EMT process. First, we confirmed that N-cadherin, which is a known mesenchymal marker, and ganglioside GD3 were specifically expressed in CRSwNP_NP tissues. Subsequently, we investigated whether the administration of TNF-α to human nasal epithelial cells (hNECs) resulted in the upregulation of ganglioside GD3 and its synthesizing enzyme, ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialytransferase 1 (ST8Sia1), and the consequently promoted inflammatory processes. Additionally, the expression of N-cadherin, Zinc finger protein SNAI2 (SLUG), and matrix metallopeptidase 9 (MMP-9) were elevated, but that of E-cadherin, which is known to be epithelial, was reduced. Moreover, the inhibition of ganglioside GD3 expression by the siRNA or exogenous treatment of neuraminidase 3 (NEU 3) led to the suppression of inflammation and EMT. These results suggest that gangliosides may play an important role in prevention and therapy for inflammation and EMT.
    Keywords:  chronic sinusitis with nasal polyps (CRSwNP); epithelial-to-mesenchymal transition (EMT); ganglioside GD3; inflammation
  30. Math Med Biol. 2024 Apr 11. pii: dqae004. [Epub ahead of print]
      Macrophages play a wide range of roles in resolving the inflammatory damage that underlies many medical conditions, and have the ability to adopt different phenotypes in response to different environmental stimuli. Categorising macrophage phenotypes exactly is a difficult task, and there is disparity in the literature around the optimal nomenclature to describe these phenotypes; however, what is clear is that macrophages can exhibit both pro- and anti-inflammatory behaviours dependent upon their phenotype, rendering mathematical models of the inflammatory response potentially sensitive to their description of the macrophage populations that they incorporate. Many previous models of inflammation include a single macrophage population with both pro- and anti-inflammatory functions. Here, we build upon these existing models to include explicit descriptions of distinct macrophage phenotypes and examine the extent to which this influences the inflammatory dynamics that the models emit. We analyse our models via numerical simulation in Matlab and dynamical systems analysis in XPPAUT, and show that models that account for distinct macrophage phenotypes separately can offer more realistic steady state solutions than precursor models do (better capturing the anti-inflammatory activity of tissue resident macrophages), as well as oscillatory dynamics not previously observed. Finally, we reflect on the conclusions of our analysis in the context of the ongoing hunt for potential new therapies for inflammatory conditions, highlighting manipulation of macrophage polarisation states as a potential therapeutic target.
    Keywords:  XPPAUT; bifurcation analysis; inflammation; macrophage
  31. J Exp Med. 2024 Jun 03. pii: e20240389. [Epub ahead of print]221(6):
      Environmental airborne antigens are central to the development of allergic asthma, but the cellular processes that trigger disease remain incompletely understood. In this report, Schmitt et al. ( identify TNF-like protein 1A (TL1A) as an epithelial alarmin constitutively expressed by a subset of lung epithelial cells, which is released in response to airborne microbial challenge and synergizes with IL-33 to drive allergic disease.
  32. Visc Med. 2024 Apr;40(2): 82-91
      Background: Clostridioides difficile (C. difficile) is a spore-forming bacterial species that ubiquitously exists in the environment. Colonization by C. difficile is highly prevalent in infants, while fewer than 5% of adults are asymptomatic carriers. Disruption of the microbiome, such as through antibiotic treatment, triggers the germination of bacterial spores into numerous vegetative cells. These cells then produce enterotoxins that result in watery diarrhea and colonic inflammation. If left untreated, C. difficile infection (CDI) can lead to pseudomembranous colitis with the potentially life-threatening complication of toxic megacolon.Summary: Over the past few decades, the incidence, morbidity, and mortality associated with CDIs have increased. They have emerged as the primary cause of nosocomial gastrointestinal infections in industrialized countries, posing a significant burden on healthcare systems. Despite antibiotics often being the cause of CDIs, they remain the standard treatment. However, a considerable number of patients treated with antibiotics will experience recurrent CDI (rCDI). Microbiota-based therapies targeting the core issue of CDI - antibiotic-induced dysbiosis - hold promise for rCDI treatment. While data for probiotics are insufficient, numerous studies have highlighted the effectiveness of fecal microbiota transplantation (FMT) as a safe and viable therapeutic option for rCDI. This approach is now endorsed by multiple guidelines. Nonetheless, regulatory prerequisites, such as comprehensive stool donor screening, restrict the widespread adoption of FMT beyond specialized centers. Recently, the US Food and Drug Administration has approved two commercial microbiota-based therapeutics to prevent CDI recurrence. These therapeutics are available by prescription in the USA. RBX2660 (REBYOTA™) comprises a diverse consortium of live microbes derived from human stool and is administered via enema. On the other hand, SER-109 (VOWST™) is an orally administered spore-based medication. In this review, we discuss the potential of microbiota-based treatments for rCDI against the background of medico-legal challenges associated with classical FMT.
    Key Messages: FMT has emerged as a highly effective cure for rCDI. Nonetheless, regulatory prerequisites and laborious preparation procedures impede its widespread use. The establishment of ready-to-use microbiota-based therapeutics in clinical practice is necessary. In the USA, the recent approval of the first two commercial medications, including a spore-based oral preparation, marks a significant step forward.
    Keywords:  Clostridioides difficile; Fecal microbiota transplantation; Intestinal microbiota; Microbiome; Probiotics
  33. Immunity. 2024 Apr 09. pii: S1074-7613(24)00130-4. [Epub ahead of print]57(4): 832-834
      IL-23 activates pathogenic Th17 cells to drive inflammatory disease at barrier surfaces. Kim et al. now identify oral epithelial cells as the critical producers of IL-23 in human and mouse periodontitis, linking microbial dysbiosis to non-hematopoietic regulation of IL-17-associated inflammation.
  34. Nat Commun. 2024 Apr 09. 15(1): 3064
      The gastroesophageal squamocolumnar junction (GE-SCJ) is a critical tissue interface between the esophagus and stomach, with significant relevance in the pathophysiology of gastrointestinal diseases. Despite this, the molecular mechanisms underlying GE-SCJ development remain unclear. Using single-cell transcriptomics, organoids, and spatial analysis, we examine the cellular heterogeneity and spatiotemporal dynamics of GE-SCJ development from embryonic to adult mice. We identify distinct transcriptional states and signaling pathways in the epithelial and mesenchymal compartments of the esophagus and stomach during development. Fibroblast-epithelial interactions are mediated by various signaling pathways, including WNT, BMP, TGF-β, FGF, EGF, and PDGF. Our results suggest that fibroblasts predominantly send FGF and TGF-β signals to the epithelia, while epithelial cells mainly send PDGF and EGF signals to fibroblasts. We observe differences in the ligands and receptors involved in cell-cell communication between the esophagus and stomach. Our findings provide insights into the molecular mechanisms underlying GE-SCJ development and fibroblast-epithelial crosstalk involved, paving the way to elucidate mechanisms during adaptive metaplasia development and carcinogenesis.