bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024–03–24
forty papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. When the microbiome shapes the host: immune evolution implications for infectious disease.
  2. Host-derived protease promotes aggregation of Staphylococcus aureus by cleaving the surface protein SasG.
  3. Group 3 innate lymphoid cells: A trained Gutkeeper.
  4. Good girl goes bad: Understanding how gut commensals cause disease.
  5. Early life imprinting of intestinal immune tolerance and tissue homeostasis.
  6. Corrigendum: Inflammatory response against Staphylococcus aureus via intracellular sensing of nucleic acids in keratinocytes.
  7. Differentiation of keratinocytes or exposure to type 2 cytokines diminishes S. aureus internalization.
  8. A synthetic antibiotic overcomes antimicrobial resistance.
  9. The role of proteinaceous toxins secreted by Staphylococcus aureus in interbacterial competition.
  10. Macrophage Pyroptosis Induced by Candida Albicans.
  11. Physiologic disruption and metabolic reprogramming in infection and sepsis.
  12. Regulation of immune signal integration and memory by inflammation-induced chromosome conformation.
  13. A new lexicon in the age of microbiome research.
  14. A host-microbiota interactome reveals extensive transkingdom connectivity.
  15. Cell-Corpse Clearance after Lung Damage: The Essential Role of MerTK-mediated Alveolar Macrophage Efferocytosis.
  16. Exploration of gut microbiome and inflammation: A review on key signalling pathways.
  17. ROS signaling in innate immunity via oxidative protein modifications.
  18. Evidence for antigen presentation by human neutrophils.
  19. A map of signaling responses in the human airway epithelium.
  20. New insights into Gasdermin D pore formation.
  21. Astrocyte cells in the brain have immune memory.
  22. Staphylococcus aureus colonisation and strategies for decolonisation.
  23. Modulation of myeloid-derived suppressor cell functions by oral inflammatory diseases and important oral pathogens.
  24. Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation.
  25. Sculpting the microbiome.
  26. Distribution of Staphylococcus aureus carriage among healthcare workers in a Japanese convalescent and rehabilitation hospital.
  27. PPARγ Attenuates Cellular Senescence of Alveolar Macrophages in Asthma- COPD Overlap.
  28. Evolutionary dynamics of the accessory genomes of Staphylococcus aureus.
  29. Inflammasome diversity: exploring novel frontiers in the innate immune response.
  30. Human mesenchymal stromal cells inhibit Mycobacterium avium replication in clinically relevant models of lung infection.
  31. Tricarboxylic acid cycle metabolites: new players in macrophage.
  32. Sialic acid in the regulation of blood cell production, differentiation and turnover.
  33. Roles for integrin α3β1 in regulating the ability of epithelial cells to modulate the microenvironment during normal and pathological tissue remodeling.
  34. Novel air-liquid interface culture model to investigate stiffness-dependent behaviors of alveolar epithelial cells.
  35. Dual RNA sequencing of Helicobacter pylori and host cell transcriptomes reveals ontologically distinct host-pathogen interaction.
  36. A Spatial Multi-Modal Dissection of Host-Microbiome Interactions within the Colitis Tissue Microenvironment.
  37. Major alteration of Lung Microbiome and the Host Reaction in critically ill COVID-19 Patients with high viral load.
  38. Pyroptosis and polarization of macrophages in septic acute lung injury induced by lipopolysaccharide in mice.
  39. Loss of the scavenger receptor MARCO results in uncontrolled vomocytosis of fungi from macrophages.
  40. Streptococcus pneumoniae extracellular vesicles aggravate alveolar epithelial barrier disruption via autophagic degradation of OCLN (occludin).
  1. Philos Trans R Soc Lond B Biol Sci. 2024 May 06. 379(1901): 20230061
    When the microbiome shapes the host: immune evolution implications for infectious disease.
    Mark A Hanson.
      The microbiome includes both 'mutualist' and 'pathogen' microbes, regulated by the same innate immune architecture. A major question has therefore been: how do hosts prevent pathogenic infections while maintaining beneficial microbes? One idea suggests hosts can selectively activate innate immunity upon pathogenic infection, but not mutualist colonization. Another idea posits that hosts can selectively attack pathogens, but not mutualists. Here I review evolutionary principles of microbe recognition and immune activation, and reflect on newly observed immune effector-microbe specificity perhaps supporting the latter idea. Recent work in Drosophila has found a surprising importance for single antimicrobial peptides in combatting specific ecologically relevant microbes. The developing picture suggests these effectors have evolved for this purpose. Other defence responses like reactive oxygen species bursts can also be uniquely effective against specific microbes. Signals in other model systems including nematodes, Hydra, oysters, and mammals, suggest that effector-microbe specificity may be a fundamental principle of host-pathogen interactions. I propose this effector-microbe specificity stems from weaknesses of the microbes themselves: if microbes have intrinsic weaknesses, hosts can evolve effectors that exploit those weaknesses. I define this host-microbe relationship as 'the Achilles principle of immune evolution'. Incorporating this view helps interpret why some host-microbe interactions develop in a coevolutionary framework (e.g. Red Queen dynamics), or as a one-sided evolutionary response. This clarification should be valuable to better understand the principles behind host susceptibilities to infectious diseases. This article is part of the theme issue 'Sculpting the microbiome: how host factors determine and respond to microbial colonization'.
    Keywords:  antimicrobial peptide; host defence peptide; host–microbe interactions; host–pathogen; microbiota; reactive oxygen species
    DOI:  https://doi.org/10.1098/rstb.2023.0061
  2. mBio. 2024 Mar 21. e0348323
    Host-derived protease promotes aggregation of Staphylococcus aureus by cleaving the surface protein SasG.
    Heidi A Crosby, Klara Keim, Jakub M Kwiecinski, Christophe J Langouët-Astrié, Kaori Oshima, Wells B LaRivière, Eric P Schmidt, Alexander R Horswill.
      Staphylococcus aureus is one of the leading causes of hospital-acquired infections, many of which begin following attachment and accumulation on indwelling medical devices or diseased tissue. These infections are often linked to the establishment of biofilms, but another often overlooked key characteristic allowing S. aureus to establish persistent infection is the formation of planktonic aggregates. Such aggregates are physiologically similar to biofilms and protect pathogens from innate immune clearance and increase antibiotic tolerance. The cell-wall-associated protein SasG has been implicated in biofilm formation via mechanisms of intercellular aggregation but the mechanism in the context of disease is largely unknown. We have previously shown that the expression of cell-wall-anchored proteins involved in biofilm formation is controlled by the ArlRS-MgrA regulatory cascade. In this work, we demonstrate that the ArlRS two-component system controls aggregation, by repressing the expression of sasG by activation of the global regulator MgrA. We also demonstrate that SasG must be proteolytically processed by a non-staphylococcal protease to induce aggregation and that strains expressing functional full-length sasG aggregate significantly upon proteolysis by a mucosal-derived host protease found in human saliva. We used fractionation and N-terminal sequencing to demonstrate that human trypsin within saliva cleaves within the A domain of SasG to expose the B domain and induce aggregation. Finally, we demonstrated that SasG is involved in virulence during mouse lung infection. Together, our data point to SasG, its processing by host proteases, and SasG-driven aggregation as important elements of S. aureus adaptation to the host environment.IMPORTANCEHere, we demonstrate that the Staphylococcus aureus surface protein SasG is important for cell-cell aggregation in the presence of host proteases. We show that the ArlRS two-component regulatory system controls SasG levels through the cytoplasmic regulator MgrA. We identified human trypsin as the dominant protease triggering SasG-dependent aggregation and demonstrated that SasG is important for S. aureus lung infection. The discovery that host proteases can induce S. aureus aggregation contributes to our understanding of how this pathogen establishes persistent infections. The observations in this study demonstrate the need to strengthen our knowledge of S. aureus surface adhesin function and processing, regulation of adhesin expression, and the mechanisms that promote biofilm formation to develop strategies for preventing chronic infections.
    Keywords:  MRSA; SasG; Staphylococcus aureus; aggregation; lung infection
    DOI:  https://doi.org/10.1128/mbio.03483-23
  3. Immunol Rev. 2024 Mar 16.
    Group 3 innate lymphoid cells: A trained Gutkeeper.
    Nicolas Serafini, James P Di Santo.
      Group 3 innate lymphoid cells (ILC3s) are tissue-resident immune lymphocytes that critically regulate intestinal homeostasis, organogenesis, and immunity. ILC3s possess the capacity to "sense" the inflammatory environment within tissues, especially in the context of pathogen challenges that imprints durable non-antigen-specific changes in ILC3 function. As such, ILC3s become a new actor in the emerging field of trained innate immunity. Here, we summarize recent discoveries regarding ILC3 responses to bacterial challenges and the role these encounters play in triggering trained innate immunity. We further discuss how signaling events throughout ILC3 ontogeny potentially control the development and function of trained ILC3s. Finally, we highlight the open questions surrounding ILC3 "training" the answers to which may reveal new insights into innate immunity. Understanding the fundamental concepts behind trained innate immunity could potentially lead to the development of new strategies for improving immunity-based modulation therapies for inflammation, infectious diseases, and cancer.
    Keywords:  ILC3; bacterial infection; innate immune memory; innate lymphoid cell; intestinal immunity; microbiota
    DOI:  https://doi.org/10.1111/imr.13322
  4. Microb Pathog. 2024 Mar 16. pii: S0882-4010(24)00084-6. [Epub ahead of print]190 106617
    Good girl goes bad: Understanding how gut commensals cause disease.
    Priyankar Dey.
      This review examines the complex connection between commensal microbiota and the development of opportunistic infections. Several underlying conditions, such as metabolic diseases and weakened immune systems, increase the vulnerability of patients to opportunistic infections. The increasing antibiotic resistance adds significant complexity to the management of infectious diseases. Although commensals have long been considered beneficial, recent research contradicts this notion by uncovering chronic illnesses linked to atypical pathogens or commensal bacteria. This review examines conditions in which commensal bacteria, which are usually beneficial, contribute to developing diseases. Commensals' support for opportunistic infections can be categorized based on factors such as colonization fitness, pathoadaptive mutation, and evasion of host immune response. Individuals with weakened immune systems are especially susceptible, highlighting the importance of mucosal host-microbiota interaction in promoting infection when conditions are inappropriate. Dysregulation of gut microbial homeostasis, immunological modulation, and microbial interactions are caused by several factors that contribute to the development of chronic illnesses. Knowledge about these mechanisms is essential for developing preventive measures, particularly for susceptible populations, and emphasizes the importance of maintaining a balanced gut microbiota in reducing the impact of opportunistic infections.
    Keywords:  Dysbiosis; Gut; Infection; Inflammation; Microbiota; Pathogen
    DOI:  https://doi.org/10.1016/j.micpath.2024.106617
  5. Immunol Rev. 2024 Mar 19.
    Early life imprinting of intestinal immune tolerance and tissue homeostasis.
    Yoselin A Paucar Iza, Chrysothemis C Brown.
      Besides its canonical role in protecting the host from pathogens, the immune system plays an arguably equally important role in maintaining tissue homeostasis. Within barrier tissues that interface with the external microenvironment, induction of immune tolerance to innocuous antigens, such as commensal, dietary, and environmental antigens, is key to establishing immune homeostasis. The early postnatal period represents a critical window of opportunity in which parallel development of the tissue, immune cells, and microbiota allows for reciprocal regulation that shapes the long-term immunological tone of the tissue and subsequent risk of immune-mediated diseases. During early infancy, the immune system appears to sacrifice pro-inflammatory functions, prioritizing the establishment of tissue tolerance. In this review, we discuss mechanisms underlying early life windows for intestinal tolerance with a focus on newly identified RORγt+ antigen-presenting cells-Thetis cells-and highlight the role of the intestinal microenvironment in shaping intestinal immune system development and tolerance.
    Keywords:  Thetis cells; early life; gut microbiota; immune tolerance
    DOI:  https://doi.org/10.1111/imr.13321
  6. Front Immunol. 2024 ;15 1330357
    Corrigendum: Inflammatory response against Staphylococcus aureus via intracellular sensing of nucleic acids in keratinocytes.
    Quang Vinh Ngo, Larissa Faass, Aline Sähr, Dagmar Hildebrand, Tatjana Eigenbrod, Klaus Heeg, Dennis Nurjadi.
      [This corrects the article DOI: 10.3389/fimmu.2022.828626.].
    Keywords:  Staphylococcus aureus; Staphylococcus epidermidis; bacterial RNA; host-pathogen interaction; keratinocyte; skin immune response
    DOI:  https://doi.org/10.3389/fimmu.2024.1330357
  7. mSphere. 2024 Mar 19. e0068523
    Differentiation of keratinocytes or exposure to type 2 cytokines diminishes S. aureus internalization.
    Alexis R Morgenstern, Liam F Peterson, Kimberly A Arnold, Matthew G Brewer.
      Staphylococcus aureus is a leading cause of skin and soft tissue infections. Colonization by this bacterium is increased in individuals with chronic cutaneous diseases such as atopic dermatitis, psoriasis, and bullous pemphigoid. The greater abundance of S. aureus on the skin of subjects with atopic dermatitis in particular has been linked to recurrent cutaneous infections. The primary cell type of the epidermal layer of the skin is the keratinocyte, and it is thought that S. aureus internalized in keratinocytes associates with an increased incidence of skin infections. This study addresses whether keratinocyte differentiation and/or inflammation, two important characteristics altered in cutaneous diseases, influence bacterial internalization. To do this, S. aureus internalization was measured in immortalized and primary keratinocytes that were differentiated using high Ca2+-containing media and/or exposed to cytokines characteristic of atopic dermatitis (IL-4 and IL-13) or psoriasis (IL-17A and IL-22) skin. Our results indicate that S. aureus internalization is uniquely decreased upon keratinocyte differentiation, since this was not observed with another skin-resident bacterium, S. epidermidis. Additionally, treatment with IL-4 + IL-13 diminished bacterial internalization. We interpret this decrease as a mechanism of keratinocyte-based bacterial killing since a similar number of bacterial genomes were detected in cytokine-treated cells, but less viable internalized S. aureus was recovered. Finally, of the receptors reported for S. aureus binding/internalizing into keratinocytes, expression of the α5 component of the α5β1 integrin was in greatest accordance with the number of internalized bacteria in the context of keratinocyte differentiation.IMPORTANCEIndividuals with chronic cutaneous diseases demonstrate heightened susceptibility for severe and recurrent infections from Staphylococcus aureus. What drives this altered susceptibility remains poorly understood. Previous publications have detected S. aureus as deep as the dermal layer of skin in subjects with atopic dermatitis, suggesting that the cutaneous environment of this disease enables deeper bacterial infiltration than occurs in healthy individuals. This observation indicates that S. aureus has greater opportunity to interact with multiple skin cell types in individuals with chronic inflammatory skin diseases. Identifying the characteristics of the skin that influence bacterial internalization, a common method to establish reservoirs and evade the immune response, is critical for our understanding of S. aureus pathogenesis. The significance of this research is the novel identification of epidermal characteristics that influence S. aureus internalization. With this knowledge, methods can be developed to identify patient populations at greater risk for cutaneous infections.
    Keywords:  S. aureus; bacterial invasion; inflammation; keratinocyte
    DOI:  https://doi.org/10.1128/msphere.00685-23
  8. Nat Biotechnol. 2024 Mar;42(3): 379
    A synthetic antibiotic overcomes antimicrobial resistance.
    Iris Marchal.
      
    DOI:  https://doi.org/10.1038/s41587-024-02185-4
  9. FEMS Microbes. 2024 ;5 xtae006
    The role of proteinaceous toxins secreted by Staphylococcus aureus in interbacterial competition.
    Stephen R Garrett, Tracy Palmer.
      Staphylococcus aureus is highly adapted to colonization of the mammalian host. In humans the primary site of colonization is the epithelium of the nasal cavity. A major barrier to colonization is the resident microbiota, which have mechanisms to exclude S. aureus. As such, S. aureus has evolved mechanisms to compete with other bacteria, one of which is through secretion of proteinaceous toxins. S. aureus strains collectively produce a number of well-characterized Class I, II, and IV bacteriocins as well as several bacteriocin-like substances, about which less is known. These bacteriocins have potent antibacterial activity against several Gram-positive organisms, with some also active against Gram-negative species. S. aureus bacteriocins characterized to date are sporadically produced, and often encoded on plasmids. More recently the type VII secretion system (T7SS) of S. aureus has also been shown to play a role in interbacterial competition. The T7SS is encoded by all S. aureus isolates and so may represent a more widespread mechanism of competition used by this species. T7SS antagonism is mediated by the secretion of large protein toxins, three of which have been characterized to date: a nuclease toxin, EsaD; a membrane depolarizing toxin, TspA; and a phospholipase toxin, TslA. Further study is required to decipher the role that these different types of secreted toxins play in interbacterial competition and colonization of the host.
    Keywords:  Staphylococcus aureus; T7SS; bacteriocin; competition; host colonization; interbacterial; toxin
    DOI:  https://doi.org/10.1093/femsmc/xtae006
  10. Pathog Dis. 2024 Mar 18. pii: ftae003. [Epub ahead of print]
    Macrophage Pyroptosis Induced by Candida Albicans.
    Feng-Yuan Zhang, Ni Lian, Min Li.
      Candida albicans (C. albicans) is a prevalent opportunistic pathogen that causes mucocutaneous and systemic infections, particularly in immunocompromised individuals. Macrophages play a crucial role in eliminating C. albicans in local and bloodstream contexts, while also regulating antifungal immune responses. However, C. albicans can induce macrophage lysis through pyroptosis, a type of regulated cell death. This process can enable C. albicans to escape from immune cells and trigger the release of IL-1β and IL-18, which can impact both the host and the pathogen. Nevertheless, the mechanisms by which C. albicans triggers pyroptosis in macrophages and the key factors involved in this process remain unclear. In this review, we will explore various factors that may influence or trigger pyroptosis in macrophages induced by C. albicans, such as hypha, ergosterol, cell wall remodeling, and other virulence factors. We will also examine the possible immune response following macrophage pyroptosis.
    Keywords:   Candida albicans ; IL-18; IL-1β; NLRP3; macrophage; pyroptosis
    DOI:  https://doi.org/10.1093/femspd/ftae003
  11. Cell Metab. 2024 Mar 13. pii: S1550-4131(24)00058-5. [Epub ahead of print]
    Physiologic disruption and metabolic reprogramming in infection and sepsis.
    Katharina Willmann, Luis F Moita.
      Effective responses against severe systemic infection require coordination between two complementary defense strategies that minimize the negative impact of infection on the host: resistance, aimed at pathogen elimination, and disease tolerance, which limits tissue damage and preserves organ function. Resistance and disease tolerance mostly rely on divergent metabolic programs that may not operate simultaneously in time and space. Due to evolutionary reasons, the host initially prioritizes the elimination of the pathogen, leading to dominant resistance mechanisms at the potential expense of disease tolerance, which can contribute to organ failure. Here, we summarize our current understanding of the role of physiological perturbations resulting from infection in immune response dynamics and the metabolic program requirements associated with resistance and disease tolerance mechanisms. We then discuss how insight into the interplay of these mechanisms could inform future research aimed at improving sepsis outcomes and the potential for therapeutic interventions.
    Keywords:  disease tolerance; immunometabolism; infection; metabolic reprogramming; physiologic disruption; resistance; sepsis; surveillance immunity; therapy
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.013
  12. bioRxiv. 2024 Mar 04. pii: 2024.02.29.582872. [Epub ahead of print]
    Regulation of immune signal integration and memory by inflammation-induced chromosome conformation.
    Bence Daniel, Andy Y Chen, Katalin Sandor, Wenxi Zhang, Zhuang Miao, Caleb A Lareau, Kathryn E Yost, Howard Y Chang, Ansuman T Satpathy.
      3-dimensional (3D) genome conformation is central to gene expression regulation, yet our understanding of its contribution to rapid transcriptional responses, signal integration, and memory in immune cells is limited. Here, we study the molecular regulation of the inflammatory response in primary macrophages using integrated transcriptomic, epigenomic, and chromosome conformation data, including base pair-resolution Micro-Capture C. We demonstrate that interleukin-4 (IL-4) primes the inflammatory response in macrophages by stably rewiring 3D genome conformation, juxtaposing endotoxin-, interferon-gamma-, and dexamethasone-responsive enhancers in close proximity to their cognate gene promoters. CRISPR-based perturbations of enhancer-promoter contacts or CCCTC-binding factor (CTCF) boundary elements demonstrated that IL-4-driven conformation changes are indispensable for enhanced and synergistic endotoxin-induced transcriptional responses, as well as transcriptional memory following stimulus removal. Moreover, transcriptional memory mediated by changes in chromosome conformation often occurred in the absence of changes in chromatin accessibility or histone modifications. Collectively, these findings demonstrate that rapid and memory transcriptional responses to immunological stimuli are encoded in the 3D genome.
    DOI:  https://doi.org/10.1101/2024.02.29.582872
  13. Philos Trans R Soc Lond B Biol Sci. 2024 May 06. 379(1901): 20230060
    A new lexicon in the age of microbiome research.
    Thomas C G Bosch, Martin J Blaser, Edward Ruby, Margaret McFall-Ngai.
      At a rapid pace, biologists are learning the many ways in which resident microbes influence, and sometimes even control, their hosts to shape both health and disease. Understanding the biochemistry behind these interactions promises to reveal completely novel and targeted ways of counteracting disease processes. However, in our protocols and publications, we continue to describe these new results using a language that originated in a completely different context. This language developed when microbial interactions with hosts were perceived to be primarily pathogenic, as threats that had to be vanquished. Biomedicine had one dominating thought: winning this war against microorganisms. Today, we know that beyond their defensive roles, host tissues, especially epithelia, are vital to ensuring association with the normal microbiota, the communities of microbes that persistently live with the host. Thus, we need to adopt a language that better encompasses the newly appreciated importance of host-microbiota associations. We also need a language that frames the onset and progression of pathogenic conditions within the context of the normal microbiota. Such a reimagined lexicon should make it clear, from the very nature of its words, that microorganisms are primarily vital to our health, and only more rarely the cause of disease. This article is part of the theme issue 'Sculpting the microbiome: how host factors determine and respond to microbial colonization'.
    Keywords:  antimicrobial peptides; commensal; immunity; microbe-associated molecular patterns; pathogen; symbiosis
    DOI:  https://doi.org/10.1098/rstb.2023.0060
  14. Nature. 2024 Mar 20.
    A host-microbiota interactome reveals extensive transkingdom connectivity.
    Nicole D Sonnert, Connor E Rosen, Andrew R Ghazi, Eric A Franzosa, Brianna Duncan-Lowey, Jaime A González-Hernández, John D Huck, Yi Yang, Yile Dai, Tyler A Rice, Mytien T Nguyen, Deguang Song, Yiyun Cao, Anjelica L Martin, Agata A Bielecka, Suzanne Fischer, Changhui Guan, Julia Oh, Curtis Huttenhower, Aaron M Ring, Noah W Palm.
      The myriad microorganisms that live in close association with humans have diverse effects on physiology, yet the molecular bases for these impacts remain mostly unknown1-3. Classical pathogens often invade host tissues and modulate immune responses through interactions with human extracellular and secreted proteins (the 'exoproteome'). Commensal microorganisms may also facilitate niche colonization and shape host biology by engaging host exoproteins; however, direct exoproteome-microbiota interactions remain largely unexplored. Here we developed and validated a novel technology, BASEHIT, that enables proteome-scale assessment of human exoproteome-microbiome interactions. Using BASEHIT, we interrogated more than 1.7 million potential interactions between 519 human-associated bacterial strains from diverse phylogenies and tissues of origin and 3,324 human exoproteins. The resulting interactome revealed an extensive network of transkingdom connectivity consisting of thousands of previously undescribed host-microorganism interactions involving 383 strains and 651 host proteins. Specific binding patterns within this network implied underlying biological logic; for example, conspecific strains exhibited shared exoprotein-binding patterns, and individual tissue isolates uniquely bound tissue-specific exoproteins. Furthermore, we observed dozens of unique and often strain-specific interactions with potential roles in niche colonization, tissue remodelling and immunomodulation, and found that strains with differing host interaction profiles had divergent interactions with host cells in vitro and effects on the host immune system in vivo. Overall, these studies expose a previously unexplored landscape of molecular-level host-microbiota interactions that may underlie causal effects of indigenous microorganisms on human health and disease.
    DOI:  https://doi.org/10.1038/s41586-024-07162-0
  15. Am J Respir Cell Mol Biol. 2024 Mar 19.
    Cell-Corpse Clearance after Lung Damage: The Essential Role of MerTK-mediated Alveolar Macrophage Efferocytosis.
    Angela Haczku.
      
    Keywords:  alveolar macrophages, MerTK, efferocytosis
    DOI:  https://doi.org/10.1165/rcmb.2024-0108ED
  16. Cell Signal. 2024 Mar 16. pii: S0898-6568(24)00108-6. [Epub ahead of print]118 111140
    Exploration of gut microbiome and inflammation: A review on key signalling pathways.
    Manisha Nigam, Kanchan Devi, Henrique D M Coutinho, Abhay Prakash Mishra.
      The gut microbiome, a crucial component of the human system, is a diverse collection of microbes that belong to the gut of human beings as well as other animals. These microbial communities continue to coexist harmoniously with their host organisms and perform various functions that affect the host's general health. Each person's gut microbiota has a unique makeup. The gut microbiota is well acknowledged to have a part in the local as well as systemic inflammation that underlies a number of inflammatory disorders (e.g., atherosclerosis, diabetes mellitus, obesity, and inflammatory bowel disease).The gut microbiota's metabolic products, such as short-chain fatty acids (butyrate, propionate, and acetate) inhibit inflammation by preventing immune system cells like macrophages and neutrophils from producing pro-inflammatory factors, which are triggered by the structural elements of bacteria (like lipopolysaccharide). The review's primary goal is to provide comprehensive and compiled data regarding the contribution of gut microbiota to inflammation and the associated signalling pathways.
    Keywords:  Gut microbiome; Inflammation; Signalling pathways
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111140
  17. Front Immunol. 2024 ;15 1359600
    ROS signaling in innate immunity via oxidative protein modifications.
    Renuka Ramalingam Manoharan, Ankush Prasad, Pavel Pospíšil, Julia Kzhyshkowska.
      The innate immune response represents the first-line of defense against invading pathogens. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been implicated in various aspects of innate immune function, which involves respiratory bursts and inflammasome activation. These reactive species widely distributed within the cellular environment are short-lived intermediates that play a vital role in cellular signaling and proliferation and are likely to depend on their subcellular site of formation. NADPH oxidase complex of phagocytes is known to generate superoxide anion radical (O2 •-) that functions as a precursor for antimicrobial hydrogen peroxide (H2O2) production, and H2O2 is utilized by myeloperoxidase (MPO) to generate hypochlorous acid (HOCl) that mediates pathogen killing. H2O2 modulates the expression of redox-responsive transcriptional factors, namely NF-kB, NRF2, and HIF-1, thereby mediating redox-based epigenetic modification. Survival and function of immune cells are under redox control and depend on intracellular and extracellular levels of ROS/RNS. The current review focuses on redox factors involved in the activation of immune response and the role of ROS in oxidative modification of proteins in macrophage polarization and neutrophil function.
    Keywords:  inflammation; innate immune response; macrophage; neutrophils; oxidative stress; protein oxidation; reactive oxygen species
    DOI:  https://doi.org/10.3389/fimmu.2024.1359600
  18. Blood. 2024 Mar 18. pii: blood.2023023444. [Epub ahead of print]
    Evidence for antigen presentation by human neutrophils.
    Angus Moffat, Emily Gwyer Findlay.
      Neutrophils are the first migrating responders to sterile and infectious inflammation, and act in a powerful but non-specific fashion to kill a wide variety of pathogens. It is now clear that they can also act in a highly discriminating fashion; this is particularly evident in their interactions with other cells of the immune system. It is clear that neutrophils are present during the adaptive immune response, interacting with T cells in complex ways which differ between tissue types and disease state. One of the ways in which this interaction is mediated is by neutrophil expression of HLA molecules and presentation of antigen to T cells. In mice, this is well established to occur with both CD4+ and CD8+ T cells. However, the evidence is less strong with human cells. Here, we assembled available evidence for human neutrophil antigen presentation. We find that the human cells are clearly able to up-regulate HLA-DR and co-stimulatory molecules; are able to process protein antigen into fragments recognised by T cells; are able to enter lymph node T cell zones; and, in vitro, are able to present antigen to memory T cells, inducing proliferation and cytokine production. However, many questions remain, particularly concerning whether the cell-cell interactions can last for sufficient time to trigger naïve T cells. These experiments are now critical as we unravel the complex interactions between these cells and their importance for the development of human immunity.
    DOI:  https://doi.org/10.1182/blood.2023023444
  19. Cell Syst. 2024 Mar 18. pii: S2405-4712(24)00059-0. [Epub ahead of print]
    A map of signaling responses in the human airway epithelium.
    Katherine B McCauley, Kalki Kukreja, Alfredo E Tovar Walker, Aron B Jaffe, Allon M Klein.
      Receptor-mediated signaling plays a central role in tissue regeneration, and it is dysregulated in disease. Here, we build a signaling-response map for a model regenerative human tissue: the airway epithelium. We analyzed the effect of 17 receptor-mediated signaling pathways on organotypic cultures to determine changes in abundance and phenotype of epithelial cell types. This map recapitulates the gamut of known airway epithelial signaling responses to these pathways. It defines convergent states induced by multiple ligands and diverse, ligand-specific responses in basal cell and secretory cell metaplasia. We show that loss of canonical differentiation induced by multiple pathways is associated with cell-cycle arrest, but that arrest is not sufficient to block differentiation. Using the signaling-response map, we show that a TGFB1-mediated response underlies specific aberrant cells found in multiple lung diseases and identify interferon responses in COVID-19 patient samples. Thus, we offer a framework enabling systematic evaluation of tissue signaling responses. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  canalization; cell differentiation; epithelial stem cells; extracellular signaling; regeneration; respiratory disease; single-cell genomics; systems biology of disease
    DOI:  https://doi.org/10.1016/j.cels.2024.02.005
  20. Biochem Soc Trans. 2024 Mar 18. pii: BST20230549. [Epub ahead of print]
    New insights into Gasdermin D pore formation.
    Shirin Kappelhoff, Eleonora G Margheritis, Katia Cosentino.
      Gasdermin D (GSDMD) is a pore-forming protein that perforates the plasma membrane (PM) during pyroptosis, a pro-inflammatory form of cell death, to induce the unconventional secretion of inflammatory cytokines and, ultimately, cell lysis. GSDMD is activated by protease-mediated cleavage of its active N-terminal domain from the autoinhibitory C-terminal domain. Inflammatory caspase-1, -4/5 are the main activators of GSDMD via either the canonical or non-canonical pathways of inflammasome activation, but under certain stimuli, caspase-8 and other proteases can also activate GSDMD. Activated GSDMD can oligomerize and assemble into various nanostructures of different sizes and shapes that perforate cellular membranes, suggesting plasticity in pore formation. Although the exact mechanism of pore formation has not yet been deciphered, cysteine residues are emerging as crucial modulators of the oligomerization process. GSDMD pores and thus the outcome of pyroptosis can be modulated by various regulatory mechanisms. These include availability of activated GSDMD at the PM, control of the number of GSDMD pores by PM repair mechanisms, modulation of the lipid environment and post-translational modifications. Here, we review the latest findings on the mechanisms that induce GSDMD to form membrane pores and how they can be tightly regulated for cell content release and cell fate modulation.
    Keywords:  gasdermins; membrane environment; pore assembly; pyroptosis; regulated cell death; regulation of gasdermin pores
    DOI:  https://doi.org/10.1042/BST20230549
  21. Nature. 2024 Mar 20.
    Astrocyte cells in the brain have immune memory.
    Michael V Sofroniew.
      
    Keywords:  Immunology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-00676-7
  22. Lancet Microbe. 2024 Mar 19. pii: S2666-5247(24)00040-5. [Epub ahead of print]
    Staphylococcus aureus colonisation and strategies for decolonisation.
    Pipat Piewngam, Michael Otto.
      Staphylococcus aureus is a leading cause of death by infectious diseases worldwide. Treatment of S aureus infections is difficult due to widespread antibiotic resistance, necessitating alternative approaches and measures for prevention of infection. Because S aureus infections commonly arise from asymptomatic colonisation, decolonisation is considered a key approach for their prevention. Current decolonisation procedures include antibiotic-based and antiseptic-based eradication of S aureus from the nose and skin. However, despite the widespread implementation and partial success of such measures, S aureus infection rates remain worrisome, and resistance to decolonisation agents is on the rise. In this Review we outline the epidemiology and mechanisms of S aureus colonisation, describe how colonisation underlies infection, and discuss current and novel approaches for S aureus decolonisation, with a focus on the latest findings on probiotic strategies and the intestinal S aureus colonisation site.
    DOI:  https://doi.org/10.1016/S2666-5247(24)00040-5
  23. Front Immunol. 2024 ;15 1349067
    Modulation of myeloid-derived suppressor cell functions by oral inflammatory diseases and important oral pathogens.
    Fernando García-Arévalo, Ana Gabriela Leija-Montoya, Javier González-Ramírez, Mario Isiordia-Espinoza, Idanya Serafín-Higuera, Dulce Martha Fuchen-Ramos, J Gustavo Vazquez-Jimenez, Nicolas Serafín-Higuera.
      The oral cavity presents a diverse microbiota in a dynamic balance with the host. Disruption of the microbial community can promote dysregulation of local immune response which could generate oral diseases. Additionally, alterations in host immune system can result in inflammatory disorders. Different microorganisms have been associated with establishment and progression of the oral diseases. Oral cavity pathogens/diseases can modulate components of the inflammatory response. Myeloid-derived suppressor cells (MDSCs) own immunoregulatory functions and have been involved in different inflammatory conditions such as infectious processes, autoimmune diseases, and cancer. The aim of this review is to provide a comprehensive overview of generation, phenotypes, and biological functions of the MDSCs in oral inflammatory diseases. Also, it is addressed the biological aspects of MDSCs in presence of major oral pathogens. MDSCs have been mainly analyzed in periodontal disease and Sjögren's syndrome and could be involved in the outcome of these diseases. Studies including the participation of MDSCs in other important oral diseases are very scarce. Major oral bacterial and fungal pathogens can modulate expansion, subpopulations, recruitment, metabolism, immunosuppressive activity and osteoclastogenic potential of MDSCs. Moreover, MDSC plasticity is exhibited in presence of oral inflammatory diseases/oral pathogens and appears to be relevant in the disease progression and potentially useful in the searching of possible treatments. Further analyses of MDSCs in oral cavity context could allow to understand the contribution of these cells in the fine-tuned balance between host immune system and microorganism of the oral biofilm, as well as their involvement in the development of oral diseases when this balance is altered.
    Keywords:  inflammation; myeloid-derived suppressor cells (MDSCs); oral bacteria and fungi; oral diseases; oral pathogens
    DOI:  https://doi.org/10.3389/fimmu.2024.1349067
  24. Elife. 2024 Mar 21. pii: RP91157. [Epub ahead of print]12
    Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation.
    Volker Winstel, Evan R Abt, Thuc M Le, Caius G Radu.
      Host-directed therapy (HDT) is an emerging approach to overcome antimicrobial resistance in pathogenic microorganisms. Specifically, HDT targets host-encoded factors required for pathogen replication and survival without interfering with microbial growth or metabolism, thereby eliminating the risk of resistance development. By applying HDT and a drug repurposing approach, we demonstrate that (R)-DI-87, a clinical-stage anticancer drug and potent inhibitor of mammalian deoxycytidine kinase (dCK), mitigates Staphylococcus aureus abscess formation in organ tissues upon invasive bloodstream infection. Mechanistically, (R)-DI-87 shields phagocytes from staphylococcal death-effector deoxyribonucleosides that target dCK and the mammalian purine salvage pathway-apoptosis axis. In this manner, (R)-DI-87-mediated protection of immune cells amplifies macrophage infiltration into deep-seated abscesses, a phenomenon coupled with enhanced pathogen control, ameliorated immunopathology, and reduced disease severity. Thus, pharmaceutical blockade of dCK represents an advanced anti-infective intervention strategy against which staphylococci cannot develop resistance and may help to fight fatal infectious diseases in hospitalized patients.
    Keywords:  Staphylococcus aureus; apoptosis; infectious disease; macrophages; microbiology
    DOI:  https://doi.org/10.7554/eLife.91157
  25. Philos Trans R Soc Lond B Biol Sci. 2024 May 06. 379(1901): 20230057
    Sculpting the microbiome.
    Mark A Hanson, Hannah E Westlake, Catherine S Schrankel.
      
    Keywords:  development; gut; host–microbe; immunity; microbiome; microbiota
    DOI:  https://doi.org/10.1098/rstb.2023.0057
  26. J Microorg Control. 2024 ;29(1): 33-37
    Distribution of Staphylococcus aureus carriage among healthcare workers in a Japanese convalescent and rehabilitation hospital.
    Akiko Kanayama Katsuse, Izumo Kanesaka, Misato Enomoto, Satoko Tanikawa, Hiroshi Takahashi, Miyuki Nagano, Intetsu Kobayashi.
      Earlobes, nasal cavities, and fingers of 145 healthcare workers in convalescent and rehabilitation hospital (60 nurses and 85 rehabilitation healthcare workers) were sampled. Of the 3 sites sampled, Staphylococcus aureus was detected in one or more sites in 25 nurses and 27 rehabilitation workers. S. aureus was detected in all 3 sites in 2 (8.0%) nurses and 2 (7.4%) rehabilitation workers, and the S. aureus isolates in each case showed related PFGE pattern. S. aureus was detected in both the fingers and nasal cavities of 5 (18.5%) of the rehabilitation healthcare workers; in all 5 cases, the PFGE patterns of the S. aureus isolates from each site belonged to same cluster based on PFGE. Of the 2 cases in which methicillinresistant S. aureus (MRSA) was recovered from earlobes, fingers, and nasal cavities, in both cases, MRSA isolates from the 3 sites were the same clone according to PFGE analysis and SCCmec type IV. As S. aureus was detected in pierced earlobes of nurses, hand hygiene must be practiced after touching pierced earlobes and before patient contact. The same S. aureus clone in the nasal cavity and earlobes indicates that the route of transmission is through the fingers.
    Keywords:  MRSA; Staphylococcus aureus; convalescent and rehabilitation hospital; earlobe
    DOI:  https://doi.org/10.4265/jmc.29.1_33
  27. Res Sq. 2024 Mar 05. pii: rs.3.rs-4009724. [Epub ahead of print]
    PPARγ Attenuates Cellular Senescence of Alveolar Macrophages in Asthma- COPD Overlap.
    Rongjun Wan, Prakhyath Srika, Shaobing Xie, Qiong Chen, Chengping Hu, Mei Wan, Yuanyaun Li, Peisong Gao.
      Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) represents a complex condition characterized by shared clinical and pathophysiological features of asthma and COPD in older individuals. However, the pathophysiology of ACO remains unexplored. We aimed to identify the major inflammatory cells in ACO, examine senescence within these cells, and elucidate the genes responsible for regulating senescence. Bioinformatic analyses were performed to investigate major cell types and cellular senescence signatures in a public single-cell RNA sequencing (scRNA-Seq) dataset derived from the lung tissues of patients with ACO. Similar analyses were carried out in an independent cohort study Immune Mechanisms Severe Asthma (IMSA), which included bulk RNA-Seq and CyTOF data from bronchoalveolar lavage fluid (BALF) samples. The analysis of the scRNA-Seq data revealed that monocytes/ macrophages were the predominant cell type in the lung tissues of ACO patients, constituting more than 50% of the cells analyzed. Lung monocytes/macrophages from patients with ACO exhibited a lower prevalence of senescence as defined by lower enrichment scores of SenMayo and expression levels of cellular senescence markers. Intriguingly, analysis of the IMSA dataset showed similar results in patients with severe asthma. They also exhibited a lower prevalence of senescence, particularly in airway CD206 + macrophages, along with increased cytokine expression (e.g., IL-4, IL-13 , and IL-22 ). Further exploration identified alveolar macrophages as a major subtype of monocytes/macrophages driving cellular senescence in ACO. Differentially expressed genes related to oxidation-reduction, cytokines, and growth factors were implicated in regulating senescence in alveolar macrophages. PPARγ (Peroxisome Proliferator-Activated Receptor Gamma) emerged as one of the predominant regulators modulating the senescent signature of alveolar macrophages in ACO. Collectively, the findings suggest that senescence in macrophages, particularly alveolar macrophages, plays a crucial role in the pathophysiology of ACO. Furthermore, PPARγ may represent a potential therapeutic target for interventions aimed at modulating senescence-associated processes in ACO.
    DOI:  https://doi.org/10.21203/rs.3.rs-4009724/v1
  28. mSphere. 2024 Mar 19. e0075123
    Evolutionary dynamics of the accessory genomes of Staphylococcus aureus.
    Kathryn R Piper, Odion O Ikhimiukor, Stephanie S R Souza, Teddy Garcia-Aroca, Cheryl P Andam.
      Staphylococcus aureus is a ubiquitous commensal and opportunistic bacterial pathogen that can cause a wide gamut of infections, which are exacerbated by the presence of multidrug-resistant and methicillin-resistant S. aureus. S. aureus is genetically heterogeneous and consists of numerous distinct lineages. Using 558 complete genomes of S. aureus, we aim to determine how the accessory genome content among phylogenetic lineages of S. aureus is structured and has evolved. Bayesian hierarchical clustering identified 10 sequence clusters, of which seven contained major sequence types (ST 1, 5, 8, 30, 59, 239, and 398). The seven sequence clusters differed in their accessory gene content, including genes associated with antimicrobial resistance and virulence. Focusing on the two largest clusters, BAPS8 and BAPS10, and each consisting mostly of ST5 and ST8, respectively, we found that the structure and connected components in the co-occurrence networks of accessory genomes varied between them. These differences are explained, in part, by the variation in the rates at which the two sequence clusters gained and lost accessory genes, with the highest rate of gene accumulation occurring recently in their evolutionary histories. We also identified a divergent group within BAPS10 that has experienced high gene gain and loss early in its history. Together, our results show highly variable and dynamic accessory genomes in S. aureus that are structured by the history of the specific lineages that carry them.IMPORTANCEStaphylococcus aureus is an opportunistic, multi-host pathogen that can cause a variety of benign and life-threatening infections. Our results revealed considerable differences in the structure and evolution of the accessory genomes of major lineages within S. aureus. Such genomic variation within a species can have important implications on disease epidemiology, pathogenesis of infection, and interactions with the vertebrate host. Our findings provide important insights into the underlying genetic basis for the success of S. aureus as a highly adaptable and resistant pathogen, which will inform current efforts to control and treat staphylococcal diseases.
    Keywords:  Staphylococcus aureus; accessory genome; antimicrobial resistance; evolution; pan-genome
    DOI:  https://doi.org/10.1128/msphere.00751-23
  29. Trends Immunol. 2024 Mar 21. pii: S1471-4906(24)00029-2. [Epub ahead of print]
    Inflammasome diversity: exploring novel frontiers in the innate immune response.
    Gyeongju Yu, Young Ki Choi, SangJoon Lee.
      Pathogens elicit complex mammalian immune responses by activating multiple sensors within inflammasomes, which recognize diverse pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). This simultaneous activation induces the formation of protein complexes referred to as multiple inflammasomes, that orchestrate a spectrum of programmed cell death pathways, including pyroptosis, apoptosis, and necroptosis. This concept is crucial for comprehending the complexity of the innate immune system's response to diverse pathogens and its implications for various diseases. Novel contributions here include emphasizing simultaneous sensor activation by pathogens, proposing the existence of multiple inflammasome complexes, and advocating for further exploration of their structural basis. Understanding these mechanisms may offer insights into disease pathogenesis, paving the way for potential therapeutic interventions targeting inflammasome-mediated immune responses.
    Keywords:  apoptosis; cytokines; immune response; infection; inflammation; innate immunity; multiple inflammasome sensors; necroptosis; pathogen; pyroptosis
    DOI:  https://doi.org/10.1016/j.it.2024.02.004
  30. Thorax. 2024 Mar 20. pii: thorax-2023-220819. [Epub ahead of print]
    Human mesenchymal stromal cells inhibit Mycobacterium avium replication in clinically relevant models of lung infection.
    Timothy D Shaw, Anna D Krasnodembskaya, Gunnar N Schroeder, Declan F Doherty, Johnatas Dutra Silva, Shikha M Tandel, Yue Su, David Butler, Rebecca J Ingram, Cecilia M O'Kane.
       INTRODUCTION: Novel therapeutic strategies are urgently needed for Mycobacterium avium complex pulmonary disease (MAC-PD). Human mesenchymal stromal cells (MSCs) can directly inhibit MAC growth, but their effect on intracellular bacilli is unknown. We investigated the ability of human MSCs to reduce bacterial replication and inflammation in MAC-infected macrophages and in a murine model of MAC-PD.
    METHODS: Human monocyte-derived macrophages (MDMs) were infected with M. avium Chester strain and treated with human bone marrow-derived MSCs. Intracellular and extracellular colony-forming units (CFUs) were counted at 72 hours. Six-week-old female balb/c mice were infected by nebulisation of M. avium Chester. Mice were treated with 1×106 intravenous human MSCs or saline control at 21 and 28 days post-infection. Lungs, liver and spleen were harvested 42 days post-infection for bacterial counts. Cytokines were quantified by ELISA.
    RESULTS: MSCs reduced intracellular bacteria in MDMs over 72 hours (median 35% reduction, p=0.027). MSC treatment increased extracellular concentrations of prostaglandin E2 (PGE2) (median 10.1-fold rise, p=0.002) and reduced tumour necrosis factor-α (median 28% reduction, p=0.025). Blocking MSC PGE2 production by cyclo-oxygenase-2 (COX-2) inhibition with celecoxib abrogated the antimicrobial effect, while this was restored by adding exogenous PGE2. MSC-treated mice had lower pulmonary CFUs (median 18% reduction, p=0.012), but no significant change in spleen or liver CFUs compared with controls.
    CONCLUSION: MSCs can modulate inflammation and reduce intracellular M. avium growth in human macrophages via COX-2/PGE2 signalling and inhibit pulmonary bacterial replication in a murine model of chronic MAC-PD.
    Keywords:  Atypical Mycobacterial Infection; Innate Immunity; Macrophage Biology; Opportunist lung infections; Respiratory Infection
    DOI:  https://doi.org/10.1136/thorax-2023-220819
  31. Inflamm Res. 2024 Mar 18.
    Tricarboxylic acid cycle metabolites: new players in macrophage.
    Ying Yang, Bing-Bing Cui, Jian Li, Jiao-Jiao Shan, Jun Xu, Cheng-Yong Zhang, Xiao-Tong Wei, Ri-Ran Zhu, Jing-Yi Wang.
      Metabolic remodeling is a key feature of macrophage activation and polarization. Recent studies have demonstrated the role of tricarboxylic acid (TCA) cycle metabolites in the innate immune system. In the current review, we summarize recent advances in the metabolic reprogramming of the TCA cycle during macrophage activation and polarization and address the effects of these metabolites in modulating macrophage function. Deciphering the crosstalk between the TCA cycle and the immune response might provide novel potential targets for the intervention of immune reactions and favor the development of new strategies for the treatment of infection, inflammation, and cancer.
    Keywords:  Citrate; Fumarate; Macrophage; Succinate; Tricarboxylic acid cycle metabolites; α-Ketoglutarate
    DOI:  https://doi.org/10.1007/s00011-024-01853-0
  32. Immunology. 2024 Mar 19.
    Sialic acid in the regulation of blood cell production, differentiation and turnover.
    Eric Edward Irons, Sajina Gc, Joseph T Y Lau.
      Sialic acid is a unique sugar moiety that resides in the distal and most accessible position of the glycans on mammalian cell surface and extracellular glycoproteins and glycolipids. The potential for sialic acid to obscure underlying structures has long been postulated, but the means by which such structural changes directly affect biological processes continues to be elucidated. Here, we appraise the growing body of literature detailing the importance of sialic acid for the generation, differentiation, function and death of haematopoietic cells. We conclude that sialylation is a critical post-translational modification utilized in haematopoiesis to meet the dynamic needs of the organism by enforcing rapid changes in availability of lineage-specific cell types. Though long thought to be generated only cell-autonomously within the intracellular ER-Golgi secretory apparatus, emerging data also demonstrate previously unexpected diversity in the mechanisms of sialylation. Emphasis is afforded to the mechanism of extrinsic sialylation, whereby extracellular enzymes remodel cell surface and extracellular glycans, supported by charged sugar donor molecules from activated platelets.
    Keywords:  bone marrow; cell death; extrinsic sialylation; galactose; galectin; haematopoiesis; lectins; sialic acid; sialyltransferase; siglec
    DOI:  https://doi.org/10.1111/imm.13780
  33. Am J Physiol Cell Physiol. 2024 Mar 18.
    Roles for integrin α3β1 in regulating the ability of epithelial cells to modulate the microenvironment during normal and pathological tissue remodeling.
    Rakshitha Pandulal Miskin, C Michael DiPersio.
      Integrin receptors for the extracellular matrix activate intracellular signaling pathways that are critical for tissue development, homeostasis, and regeneration/repair, and their loss or dysregulation contributes to many developmental defects and tissue pathologies. This review will focus on tissue remodeling roles for integrin α3β1, a receptor for laminins found in the basement membranes that underlie epithelial cell layers. As a paradigm, we will discuss literature that supports a role for α3β1 in promoting ability of epidermal keratinocytes to modify their tissue microenvironment during skin development, wound healing or tumorigenesis. Preclinical and clinical studies have shown that this role depends largely on ability of α3β1 to govern the keratinocyte's repertoire of secreted proteins, or the "secretome", including (1) matrix proteins and proteases involved in matrix remodeling and (2) paracrine-acting growth factors/cytokines that stimulate other cells with important tissue remodeling functions (e.g., endothelial cells, fibroblasts, inflammatory cells). Moreover, α3β1 signaling controls gene expression that helps epithelial cells carry out these functions, including genes that encode secreted matrix proteins, proteases, growth factors, or cytokines. We will review what is known about α3β1-dependent gene regulation through both transcription and post-transcriptional mRNA stability. Regarding the latter, we will discuss examples of α3β1-dependent alternative splicing or alternative polyadenylation that prevents inclusion of cis-acting mRNA sequences that would otherwise target the transcript for degradation via nonsense-mediated decay or destabilizing AU-rich elements in the 3'-UTR. Finally, we will discuss prospects and anticipated challenges of exploiting α3β1 as a clinical target for the treatment of cancer or wound healing.
    Keywords:  gene regulation; integrin α3β1; secretome; tissue microenvironment; wound healing
    DOI:  https://doi.org/10.1152/ajpcell.00128.2024
  34. Biochem Biophys Res Commun. 2024 Mar 15. pii: S0006-291X(24)00327-9. [Epub ahead of print]708 149791
    Novel air-liquid interface culture model to investigate stiffness-dependent behaviors of alveolar epithelial cells.
    Yuto Takahashi, Satoru Ito, Jungfeng Wang, Jeonghyun Kim, Takeo Matsumoto, Eijiro Maeda.
      Pulmonary alveoli are functional units in gas exchange in the lung, and their dysfunctions in lung diseases such as interstitial pneumonia are accompanied by fibrotic changes in structure, elevating the stiffness of extracellular matrix components. The present study aimed to test the hypothesis that such changes in alveoli stiffness induce functional alteration of epithelial cell functions, exacerbating lung diseases. For this, we have developed a novel method of culturing alveolar epithelial cells on polyacrylamide gel with different elastic modulus at an air-liquid interface. It was demonstrated that A549 cells on soft gels, mimicking the modulus of a healthy lung, upregulated mRNA expression and protein synthesis of surfactant protein C (SFTPC). By contrast, the cells on stiff gels, mimicking the modulus of the fibrotic lung, exhibited upregulation of SFTPC gene expression but not at the protein level. Cell morphology, as well as cell nucleus volume, were also different between the two types of gels.
    Keywords:  (Up to 6); Air-liquid interface; Alveolar epithelial cells; Gel-ALI; Matrix stiffness; Polyacrylamide gel; Pulmonary fibrosis
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149791
  35. mSystems. 2024 Mar 22. e0020624
    Dual RNA sequencing of Helicobacter pylori and host cell transcriptomes reveals ontologically distinct host-pathogen interaction.
    Wei Hu, Zhi Yong Zhai, Zhao Yu Huang, Ze Min Chen, Ping Zhou, Xia Xi Li, Gen Hua Yang, Chong Ju Bao, Li Juan You, Xiao Bing Cui, Gui Li Xia, Mei Ping Ou Yang, Lin Zhang, William Ka Kei Wu, Long Fei Li, Yu Xuan Zhang, Zhan Gang Xiao, Wei Gong.
      Helicobacter pylori is a highly successful pathogen that poses a substantial threat to human health. However, the dynamic interaction between H. pylori and the human gastric epithelium has not been fully investigated. In this study, using dual RNA sequencing technology, we characterized a cytotoxin-associated gene A (cagA)-modulated bacterial adaption strategy by enhancing the expression of ATP-binding cassette transporter-related genes, metQ and HP_0888, upon coculturing with human gastric epithelial cells. We observed a general repression of electron transport-associated genes by cagA, leading to the activation of oxidative phosphorylation. Temporal profiling of host mRNA signatures revealed the downregulation of multiple splicing regulators due to bacterial infection, resulting in aberrant pre-mRNA splicing of functional genes involved in the cell cycle process in response to H. pylori infection. Moreover, we demonstrated a protective effect of gastric H. pylori colonization against chronic dextran sulfate sodium (DSS)-induced colitis. Mechanistically, we identified a cluster of propionic and butyric acid-producing bacteria, Muribaculaceae, selectively enriched in the colons of H. pylori-pre-colonized mice, which may contribute to the restoration of intestinal barrier function damaged by DSS treatment. Collectively, this study presents the first dual-transcriptome analysis of H. pylori during its dynamic interaction with gastric epithelial cells and provides new insights into strategies through which H. pylori promotes infection and pathogenesis in the human gastric epithelium.
    IMPORTANCE: Simultaneous profiling of the dynamic interaction between Helicobacter pylori and the human gastric epithelium represents a novel strategy for identifying regulatory responses that drive pathogenesis. This study presents the first dual-transcriptome analysis of H. pylori when cocultured with gastric epithelial cells, revealing a bacterial adaptation strategy and a general repression of electron transportation-associated genes, both of which were modulated by cytotoxin-associated gene A (cagA). Temporal profiling of host mRNA signatures dissected the aberrant pre-mRNA splicing of functional genes involved in the cell cycle process in response to H. pylori infection. We demonstrated a protective effect of gastric H. pylori colonization against chronic DSS-induced colitis through both in vitro and in vivo experiments. These findings significantly enhance our understanding of how H. pylori promotes infection and pathogenesis in the human gastric epithelium and provide evidence to identify targets for antimicrobial therapies.
    Keywords:  ATP-binding cassette transporter; Helicobacter pylori; alternative splicing; cytotoxin-associated genes A; dual RNA sequencing; inflammatory bowel disease; oxidative phosphorylation
    DOI:  https://doi.org/10.1128/msystems.00206-24
  36. bioRxiv. 2024 Mar 06. pii: 2024.03.04.583400. [Epub ahead of print]
    A Spatial Multi-Modal Dissection of Host-Microbiome Interactions within the Colitis Tissue Microenvironment.
    Bokai Zhu, Yunhao Bai, Yao Yu Yeo, Xiaowei Lu, Xavier Rovira-Clavé, Han Chen, Jason Yeung, Georg K Gerber, Mike Angelo, Alex K Shalek, Garry P Nolan, Sizun Jiang.
      The intricate and dynamic interactions between the host immune system and its microbiome constituents undergo dynamic shifts in response to perturbations to the intestinal tissue environment. Our ability to study these events on the systems level is significantly limited by in situ approaches capable of generating simultaneous insights from both host and microbial communities. Here, we introduce Micro biome Cart ography (MicroCart), a framework for simultaneous in situ probing of host features and its microbiome across multiple spatial modalities. We demonstrate MicroCart by comprehensively investigating the alterations in both gut host and microbiome components in a murine model of colitis by coupling MicroCart with spatial proteomics, transcriptomics, and glycomics platforms. Our findings reveal a global but systematic transformation in tissue immune responses, encompassing tissue-level remodeling in response to host immune and epithelial cell state perturbations, and bacterial population shifts, localized inflammatory responses, and metabolic process alterations during colitis. MicroCart enables a deep investigation of the intricate interplay between the host tissue and its microbiome with spatial multiomics.
    DOI:  https://doi.org/10.1101/2024.03.04.583400
  37. Res Sq. 2024 Mar 08. pii: rs.3.rs-3952944. [Epub ahead of print]
    Major alteration of Lung Microbiome and the Host Reaction in critically ill COVID-19 Patients with high viral load.
    Ingrid G Bustos, Rosana Wiscovitch-Russo, Harinder Singh, Benjamín L Sievers, Michele Matsuoka, Marcelo Freire, Gene S Tan, Mónica P Cala, Jose L Guerrero, Ignacio Martin-Loeches, Norberto Gonzalez-Juarbe, Luis Felipe Reyes.
      Background Patients with COVID-19 under invasive mechanical ventilation are at higher risk of developing ventilator-associated pneumonia (VAP), associated with increased healthcare costs, and unfavorable prognosis. The underlying mechanisms of this phenomenon have not been thoroughly dissected. Therefore, this study attempted to bridge this gap by performing a lung microbiota analysis and evaluating the host immune responses that could drive the development of VAP. Materials and methods In this prospective cohort study, mechanically ventilated patients with confirmed SARS-CoV-2 infection were enrolled. Nasal swabs (NS), endotracheal aspirates (ETA), and blood samples were collected initially within 12 hours of intubation and again at 72 hours post-intubation. Plasma samples underwent cytokine and metabolomic analyses, while NS and ETA samples were sequenced for lung microbiome examination. The cohort was categorized based on the development of VAP. Data analysis was conducted using RStudio version 4.3.1. Results In a study of 36 COVID-19 patients on mechanical ventilation, significant differences were found in the nasal and pulmonary microbiome, notably in Staphylococcus and Enterobacteriaceae , linked to VAP. Patients with VAP showed a higher SARS-CoV-2 viral load, elevated neutralizing antibodies, and reduced inflammatory cytokines, including IFN-δ, IL-1β, IL-12p70, IL-18, IL-6, TNF-α, and CCL4. Metabolomic analysis revealed changes in 22 metabolites in non-VAP patients and 27 in VAP patients, highlighting D-Maltose-Lactose, Histidinyl-Glycine, and various phosphatidylcholines, indicating a metabolic predisposition to VAP. Conclusions This study reveals a critical link between respiratory microbiome alterations and ventilator-associated pneumonia in COVID-19 patients, with elevated SARS-CoV-2 levels and metabolic changes, providing novel insights into the underlying mechanisms of VAP with potential management and prevention implications.
    DOI:  https://doi.org/10.21203/rs.3.rs-3952944/v1
  38. Immun Inflamm Dis. 2024 Mar;12(3): e1197
    Pyroptosis and polarization of macrophages in septic acute lung injury induced by lipopolysaccharide in mice.
    Sijiang Zhou, Xia Yang, Kanglin Mo, Zong Ning.
       BACKGROUND: Pyroptosis and polarization are significant contributors to the onset and development of many diseases. At present, the relationship between pyroptosis and polarization in acute lung injury (ALI) caused by sepsis remains unclear.
    METHODS: The ALI model for sepsis was created in mice and categorized into the blank control, lipopolysaccharide (LPS) group, LPS + low-dose Belnacasan group, LPS + high-dose Belnacasan group, LPS + low-dose Wedelolactone group, LPS + high-dose Wedelolactone group, and positive control group. The wet-dry specific gravity was evaluated to compare pulmonary edema. Hematoxylin-eosin, Masson, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining techniques were conducted to observe and contrast the pathological changes in lung tissue. ELISA was utilized to identify M1 and M2 macrophages and correlated inflammatory factors. Immunohistochemical staining and flow cytometry were employed to identify markers of M1 and M2 macrophages in lung tissue. Propidium iodide staining, together with flow cytometry, was utilized to observe the degree and positive rate of pyroptosis of alveolar macrophages. Western blot analysis was conducted to detect the expression levels of Caspase 1, Caspase 11, GSDMD, and IL-18 in the lung tissues of each group. The real-time quantitative polymerase chain reaction method was used to ascertain relative expression levels of NLRP3, Caspase 1, Caspase 11, GSDMD, IL-18, iNOS, and Arg-1 in lung tissues of all groups.
    RESULTS: In mice with sepsis-induced ALI, both classical and nonclassical pathways of pyroptosis are observed. Inhibiting pyroptosis has been found to ameliorate lung injury, pulmonary edema, and inflammation induced by LPS. Notably, the expression of NLRP3, Caspase 1, Caspase 11, GSDMD, IL-1β, IL-18, TGF-β, CD86, CD206, iNOS, and Arg-1 were all altered in this process. Additionally, alveolar macrophages were polarized along with pyroptosis in mice with ALI caused by sepsis.
    CONCLUSION: Pyroptosis of alveolar macrophages in the context of ALI in mice infected with sepsis has been linked to the polarization of alveolar macrophages toward type M1.
    Keywords:  acute lung injury; alveolar macrophage; polarization; pyroptosis; sepsis
    DOI:  https://doi.org/10.1002/iid3.1197
  39. Eur J Immunol. 2024 Mar 17. e2350771
    Loss of the scavenger receptor MARCO results in uncontrolled vomocytosis of fungi from macrophages.
    Chinaemerem U Onyishi, Yusun Jeon, Gyorgy Fejer, Subhankar Mukhopadhyay, Siamon Gordon, Robin C May.
      Vomocytosis, also known as nonlytic exocytosis, is a process whereby fully phagocytosed microbes are expelled from phagocytes without discernible damage to either the phagocyte or microbe. Although this phenomenon was first described in the opportunistic fungal pathogen Cryptococcus neoformans in 2006, to date, mechanistic studies have been hampered by an inability to reliably stimulate or inhibit vomocytosis. Here we present the fortuitous discovery that macrophages lacking the scavenger receptor MAcrophage Receptor with COllagenous domain (MARCO), exhibit near-total vomocytosis of internalised cryptococci within a few hours of infection. Marco-/- macrophages also showed elevated vomocytosis of a yeast-locked C. albicans strain, suggesting this to be a broadly relevant observation. We go on to show that MARCO's role in modulating vomocytosis is independent of its role as a phagocytic receptor, suggesting that this protein may play an important and hitherto unrecognised role in modulating macrophage behaviour.
    Keywords:  Cryptococcus; Fungal pathogen; Innate immunity; MARCO; Macrophage; Vomocytosis
    DOI:  https://doi.org/10.1002/eji.202350771
  40. Autophagy. 2024 Mar 18.
    Streptococcus pneumoniae extracellular vesicles aggravate alveolar epithelial barrier disruption via autophagic degradation of OCLN (occludin).
    Luqing Cui, Ruicheng Yang, Dong Huo, Liang Li, Xinyi Qu, Jundan Wang, Xinyi Wang, Hulin Liu, Huanchun Chen, Xiangru Wang.
      Streptococcus pneumoniae (S. pneumoniae) represents a major human bacterial pathogen leading to high morbidity and mortality in children and the elderly. Recent research emphasizes the role of extracellular vesicles (EVs) in bacterial pathogenicity. However, the contribution of S. pneumoniae EVs (pEVs) to host-microbe interactions has remained unclear. Here, we observed that S. pneumoniae infections in mice led to severe lung injuries and alveolar epithelial barrier (AEB) dysfunction. Infections of S. pneumoniae reduced the protein expression of tight junction protein OCLN (occludin) and activated macroautophagy/autophagy in lung tissues of mice and A549 cells. Mechanically, S. pneumoniae induced autophagosomal degradation of OCLN leading to AEB impairment in the A549 monolayer. S. pneumoniae released the pEVs that could be internalized by alveolar epithelial cells. Through proteomics, we profiled the cargo proteins inside pEVs and found that these pEVs contained many virulence factors, among which we identified a eukaryotic-like serine-threonine kinase protein StkP. The internalized StkP could induce the phosphorylation of BECN1 (beclin 1) at Ser93 and Ser96 sites, initiating autophagy and resulting in autophagy-dependent OCLN degradation and AEB dysfunction. Finally, the deletion of stkP in S. pneumoniae completely protected infected mice from death, significantly alleviated OCLN degradation in vivo, and largely abolished the AEB disruption caused by pEVs in vitro. Overall, our results suggested that pEVs played a crucial role in the spread of S. pneumoniae virulence factors. The cargo protein StkP in pEVs could communicate with host target proteins and even hijack the BECN1 autophagy initiation pathway, contributing to AEB disruption and bacterial pathogenicity.
    Keywords:  Alveolar epithelial barrier; Ocln/Occludin; StkP; autophagy; pevs; s. pneumoniae
    DOI:  https://doi.org/10.1080/15548627.2024.2330043
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