bims-bac4me 2023-11-05 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2023–11–05
29 papers selected by
Chun-Chi Chang, University Hospital Zurich

Microbiome dysbiosis: a modifiable state and target to prevent Staphylococcus aureus infections and other diseases in neonates.
Streptococcal peptides and their roles in host-microbe interactions.
The intersection between bacterial metabolism and innate immunity.
The destruction of mucosal barriers, epithelial remodeling, and impaired mucociliary clearance: possible pathogenic mechanisms of Pseudomonas aeruginosa and Staphylococcus aureus in chronic rhinosinusitis.
Exploring intrinsic variability between cultured nasal and bronchial epithelia in cystic fibrosis.
Engineered probiotic Lactobacillus plantarum WCSF I for monitoring and treatment of Staphylococcus aureus infection.
Differential survival of Staphylococcal species in macrophages.
Informed interpretation of metagenomic data by StrainPhlAn enables strain retention analyses of the upper airway microbiome.
Innate immunity: the bacterial connection.
Neonatal Microbiome: Is it still Beneficial?
Effect of glucose on growth and co-culture of Staphylococcus aureus and Pseudomonas aeruginosa in artificial sputum medium.
Insights into the immunological links between dietary habits and asthma.
Tolerogenic dendritic cells and TLR4/IRAK4/NF-κB signaling pathway in allergic rhinitis.
The novel bacteriocin romsacin from Staphylococcus haemolyticus inhibits Gram-positive WHO priority pathogens.
Chemical shift assignments of the catalytic domain of Staphylococcus aureus LytM.
Glycoconjugate vaccines against antimicrobial resistant pathogens.
Increased epithelial mTORC1 activity in chronic rhinosinusitis with nasal polyps.
Wall Teichoic Acid Mediates Staphylococcus aureus Binding to Endothelial Cells via the Scavenger Receptor LOX-1.
Enterococcus faecalis suppresses Staphylococcus aureus-induced NETosis and promotes bacterial survival in polymicrobial infections.
Impaired gut microbiota-mediated short-chain fatty acid production precedes morbidity and mortality in people with HIV.
Editorial: The spatial-temporal dynamics of host-pathogen interaction during inflammatory disease.
An optimized cocktail of small molecule inhibitors promotes the maturation of dendritic cells in GM-CSF mouse bone marrow culture.
Mechanistic insights into the role of probiotics in modulating immune cells in ulcerative colitis.
Microbiota as key factors in inflammatory bowel disease.
Characteristics of the pulmonary microbiota in patients with mild and severe pulmonary infection.
GLUT3 regulates alternative macrophage signaling through a glucose transport-independent role.
Human Dendritic Cell Subset Isolation by Magnetic Bead Sorting: A Protocol to Efficiently Obtain Pure Populations.
Discovering unknown associations between prokaryotic receptors and their ligands.
Strategies adopted by Salmonella to survive in host: a review.

J Perinatol. 2023 Oct 30.

Microbiome dysbiosis: a modifiable state and target to prevent Staphylococcus aureus infections and other diseases in neonates.

Anushree Aneja, Julia Johnson, Erica C Prochaska, Aaron M Milstone.

Bacterial infections present a significant threat to neonates. Increasingly, studies demonstrate associations between human diseases and the microbiota, the communities of microorganisms on or in the body. A "healthy" microbiota with a great diversity and balance of microorganisms can resist harmful pathogens and protect against infections, whereas a microbiota suffering from dysbiosis, can predispose to pathogen colonization and subsequent infection. For decades, strategies such as bacterial interference, decolonization, prebiotics, and probiotics have been tested to reduce Staphylococcus aureus disease and other infections in neonates. More recently, microbiota transplant has emerged as a strategy to broadly correct dysbiosis, promote colonization resistance, and prevent infections. This paper discusses the benefits of a healthy neonate's microbiota, exposures that alter the microbiota, associations of dysbiosis and neonatal disease, strategies to prevent dysbiosis, such as microbiota transplantation, and presents a framework of microbiome manipulation to reduce Staphylococcus aureus (S. aureus) and other infections in neonates.

DOI: https://doi.org/10.1038/s41372-023-01810-5
Front Cell Infect Microbiol. 2023 ;13 1282622

Streptococcal peptides and their roles in host-microbe interactions.

Emily R Wahlenmayer, Daniel E Hammers.

  The genus Streptococcus encompasses many bacterial species that are associated with hosts, ranging from asymptomatic colonizers and commensals to pathogens with a significant global health burden. Streptococci produce numerous factors that enable them to occupy their host-associated niches, many of which alter their host environment to the benefit of the bacteria. The ability to manipulate host immune systems to either evade detection and clearance or induce a hyperinflammatory state influences whether bacteria are able to survive and persist in a given environment, while also influencing the propensity of the bacteria to cause disease. Several bacterial factors that contribute to this inter-species interaction have been identified. Recently, small peptides have become increasingly appreciated as factors that contribute to Streptococcal relationships with their hosts. Peptides are utilized by streptococci to modulate their host environment in several ways, including by directly interacting with host factors to disrupt immune system function and signaling to other bacteria to control the expression of genes that contribute to immune modulation. In this review, we discuss the many contributions of Streptococcal peptides in terms of their ability to contribute to pathogenesis and disruption of host immunity. This discussion will highlight the importance of continuing to elucidate the functions of these Streptococcal peptides and pursuing the identification of new peptides that contribute to modulation of host environments. Developing a greater understanding of how bacteria interact with their hosts has the potential to enable the development of techniques to inhibit these peptides as therapeutic approaches against Streptococcal infections.

Keywords:  Streptococcus; Streptolysin S; host-microbe interactions; inflammation; peptides; quorum sensing

DOI:  https://doi.org/10.3389/fcimb.2023.1282622
J Innate Immun. 2023 Oct 27.

The intersection between bacterial metabolism and innate immunity.

Ivan C Acosta, Francis Alonzo Iii.

BACKGROUND: The innate immune system is the first line of defense against microbial pathogens and is essential for maintaining good health. If pathogens breach innate barriers, the likelihood of infection is significantly increased. Many bacterial pathogens pose a threat to human health on account of their ability to evade innate immunity and survive in growth-restricted environments. These pathogens have evolved sophisticated strategies to obtain nutrients as well as manipulate innate immune responses, resulting in disease or chronic infection.
SUMMARY: The relationship between bacterial metabolism and innate immunity is complex. Although aspects of bacterial metabolism can be beneficial to the host, particularly those related to the microbiota and barrier integrity, others can be harmful. Several bacterial pathogens harness metabolism to evade immune responses and persist during infection. The study of these adaptive traits provides insight into the roles of microbial metabolism in pathogenesis that extend beyond energy balance. This review considers recent studies on bacterial metabolic pathways that promote infection by circumventing several facets of the innate immune system. We also discuss relationships between innate immunity and antibiotics and highlight future directions for research in this field.
KEY MESSAGES: Pathogenic bacteria have a remarkable capacity to harness metabolism to manipulate immune responses and promote pathogenesis. While we are beginning to understand the multifaceted and complex metabolic adaptations that occur during infection, there is still much to uncover with future research.

DOI: https://doi.org/10.1159/000534872
Cell Commun Signal. 2023 Oct 30. 21(1): 306

The destruction of mucosal barriers, epithelial remodeling, and impaired mucociliary clearance: possible pathogenic mechanisms of Pseudomonas aeruginosa and Staphylococcus aureus in chronic rhinosinusitis.

Zahra Chegini, Milad Noei, Jaber Hemmati, Mohammad Reza Arabestani, Aref Shariati.

  Chronic rhinosinusitis (CRS) is a pathological condition characterized by persistent inflammation in the upper respiratory tract and paranasal sinuses. The epithelium serves as the first line of defense against potential threats and protects the nasal mucosa. The fundamental mechanical barrier is formed by the cell-cell contact and mucociliary clearance (MCC) systems. The physical-mechanical barrier is comprised of many cellular structures, including adhesion junctions and tight junctions (TJs). To this end, different factors, such as the dysfunction of MCC, destruction of epithelial barriers, and tissue remodeling, are related to the onset and development of CRS. Recently published studies reported the critical role of different microorganisms, such as Staphylococcus aureus and Pseudomonas aeruginosa, in the induction of the mentioned factors. Bacteria could result in diminished ciliary stimulation capacity, and enhance the chance of CRS by reducing basal ciliary beat frequency. Additionally, bacterial exoproteins have been demonstrated to disrupt the epithelial barrier and induce downregulation of transmembrane proteins such as occludin, claudin, and tricellulin. Moreover, bacteria exert an influence on TJ proteins, leading to an increase in the permeability of polarized epithelial cells. Noteworthy, it is evident that the activation of TLR2 by staphylococcal enterotoxin can potentially undermine the structural integrity of TJs and the epithelial barrier through the induction of pro-inflammatory cytokines. The purpose of this article is an attempt to investigate the possible role of the most important microorganisms associated with CRS and their pathogenic mechanisms against mucosal surfaces and epithelial barriers in the paranasal sinuses. Video Abstract.

Keywords:  CRS; Epithelial remodeling; Mucociliary clearance; Mucosal barriers; Pseudomonas aeruginosa; Staphylococcus aureous

DOI:  https://doi.org/10.1186/s12964-023-01347-2
Sci Rep. 2023 Oct 30. 13(1): 18573

Exploring intrinsic variability between cultured nasal and bronchial epithelia in cystic fibrosis.

Lisa W Rodenburg, Mieke Metzemaekers, Isabelle S van der Windt, Shannon M A Smits, Loes A den Hertog-Oosterhoff, Evelien Kruisselbrink, Jesse E Brunsveld, Sabine Michel, Karin M de Winter-de Groot, Cornelis K van der Ent, Ralph Stadhouders, Jeffrey M Beekman, Gimano D Amatngalim.

The nasal and bronchial epithelium are unified parts of the respiratory tract that are affected in the monogenic disorder cystic fibrosis (CF). Recent studies have uncovered that nasal and bronchial tissues exhibit intrinsic variability, including differences in mucociliary cell composition and expression of unique transcriptional regulatory proteins which relate to germ layer origin. In the present study, we explored whether intrinsic differences between nasal and bronchial epithelial cells persist in cell cultures and affect epithelial cell functioning in CF. Comparison of air-liquid interface (ALI) differentiated epithelial cells from subjects with CF revealed distinct mucociliary differentiation states of nasal and bronchial cultures. Moreover, using RNA sequencing we identified cell type-specific signature transcription factors in differentiated nasal and bronchial epithelial cells, some of which were already poised for expression in basal progenitor cells as evidenced by ATAC sequencing. Analysis of differentiated nasal and bronchial epithelial 3D organoids revealed distinct capacities for fluid secretion, which was linked to differences in ciliated cell differentiation. In conclusion, we show that unique phenotypical and functional features of nasal and bronchial epithelial cells persist in cell culture models, which can be further used to investigate the effects of tissue-specific features on upper and lower respiratory disease development in CF.

DOI: https://doi.org/10.1038/s41598-023-45201-4
Microbiol Spectr. 2023 Nov 01. e0182923

Engineered probiotic Lactobacillus plantarum WCSF I for monitoring and treatment of Staphylococcus aureus infection.

Haoran Li, Minjun Jia, Qingsheng Qi, Qian Wang.

  Lactobacillus plantarum is one of the most thoroughly researched species of the genus Lactobacillus, which possesses the characteristics of easy genetic transformation, high-density growth, and high intestinal tract survival. L. plantarum has been proven to play a potential role as a probiotic delivery vector. Staphylococcus aureus is a common Gram-positive pathogenic bacterium. It uses an autoinducer peptide (AIP) produced by its Agr quorum-sensing (AgrQS) system to sense the population density. Using the quorum-sensing mechanism exclusive to S. aureus, we constructed an AgrQS system in L. plantarum WCSF induction and killing modules based on AIP sensing and regulation so that L. plantarum could effectively eliminate S. aureus when detecting exogenous AIP at nanomolar concentrations. By optimizing the expression strength of the two-component system AgrAC using different L. plantarum-derived promoters and replacing the core promoter of the AgrA-activating promoter, the activation strength of AgrQS increased from the initial 1.2-fold to 5.3-fold. By introducing the signal peptide N20-guided lysostaphin aureus protein, engineered L. plantarum was able to effectively control the release of lysostaphin aureus protein and inhibit the growth of S. aureus. For the first time, engineered L. plantarum can detect and treat S. aureus infection, laying the groundwork for the future development of engineered probiotics for the monitoring and therapy of intestinal pathogens.IMPORTANCEBacterial infection and the emergence of drug-resistant strains are major problems in clinical treatment. Staphylococcus aureus, which typically infects the skin and blood of animals, is also a potential intestinal pathogen that needs to be addressed by the emergence of a new treatment approach. Probiotic therapy is the most likely alternative to antibiotic therapy to solve the problem of bacterial drug resistance in clinical practice. In this study, the engineered Lactobacillus plantarum can not only sense the signal AIP to detect S. aureus but also kill S. aureus by secreting the lysostaphin enzyme. Our strategy employed an Agr quorum-sensing genetic circuit to simultaneously detect and treat pathogenic bacteria, which provided a theoretical possibility for solving practical clinical bacterial infection cases in the future.

Keywords:  Agr quorum-sensing system; Lactobacillus plantarum WCSF I; Staphylococcus aureus; biosensors; lysostaphin enzyme; self-inducing peptide

DOI:  https://doi.org/10.1128/spectrum.01829-23
Mol Microbiol. 2023 Oct 28.

Differential survival of Staphylococcal species in macrophages.

Janina Bayer, Janna Becker, Xiao Liu, Lisa Gritsch, Ellen Daiber, Natalya Korn, Filipp Oesterhelt, Martin Fraunholz, Alexander Weber, Christiane Wolz.

  Staphylococcus aureus is considered an extracellular pathogen, yet the bacterium is able to survive within and escape from host cells. An agr/sae mutant of strain USA300 is unable to escape from macrophages but can replicate and survive within. We questioned whether such "non-toxic" S. aureus resembles the less pathogenic coagulase-negative Staphylococcal (CoNS) species like S. epidermidis, S. carnosus, S. lugdunensis, S. capitis, S. warneri, or S. pettenkoferi. We show that the CoNS are more efficiently killed in macrophage-like THP-1 cells or in human primary macrophages. Mutations in katA, copL, the regulatory system graRS, or sigB did not impact bacterial survival in THP-1 cells. Deletion of the superoxide dismutases impaired S. aureus survival in primary macrophages but not in THP-1 cells. However, expression of the S. aureus-specific sodM in S. epidermidis was not sufficient to protect this species from being killed. Thus, at least in those cells, better bacterial survival of S. aureus could not be linked to higher protection from ROS. However, "non-toxic" S. aureus was found to be insensitive to pH, whereas most CoNS were protected when phagosomal acidification was inhibited. Thus, species differences are at least partially linked to differences in sensitivity to acidification.

Keywords:   Staphylococcus ; bacterial killing; macroage; pH; reactive oxygen species

DOI:  https://doi.org/10.1111/mmi.15184
mSystems. 2023 Nov 02. e0072423

Informed interpretation of metagenomic data by StrainPhlAn enables strain retention analyses of the upper airway microbiome.

Nadja Mostacci, Tsering Monika Wüthrich, Léa Siegwald, Silas Kieser, Ruth Steinberg, Olga Sakwinska, Philipp Latzin, Insa Korten, Markus Hilty.

  Shotgun metagenomic sequencing has the potential to provide bacterial strain-level resolution which is of key importance to tackle a host of clinical questions. While bioinformatic tools that achieve strain-level resolution are available, thorough benchmarking is needed to validate their use for less investigated and low biomass microbiomes like those from the upper respiratory tract. We analyzed a previously published data set of longitudinally collected nasopharyngeal samples from Bangladeshi infants (Microbiota and Health study) and a novel data set of oropharyngeal samples from Swiss children with cystic fibrosis. Data from bacterial cultures were used for benchmarking the parameters of StrainPhlAn 3, a bioinformatic tool designed for strain-level resolution. In addition, StrainPhlAn 3 results were compared with metagenomic assemblies derived from StrainGE and newly derived whole-genome sequencing data. After optimizing the analytical parameters, we compared StrainPhlAn 3 results to culture gold standard methods and achieved sensitivity values of 87% (Streptococcus pneumoniae), 80% (Moraxella catarrhalis), 75% (Haemophilus influenzae), and 57% (Staphylococcus aureus) for 420 nasopharyngeal and 75% (H. influenzae) and 46% (S. aureus) for 260 oropharyngeal samples. Comparing the phylogenetic tree of the core genome of 50 S. aureus isolates with a corresponding marker gene tree generated by StrainPhlAn 3 revealed a striking similarity in tree topology for all but three samples indicating adequate strain resolution. In conclusion, a comparison of StrainPhlAn 3 results to data from bacterial cultures revealed that strain-level tracking of the respiratory microbiome is feasible despite the high content of host DNA when parameters are carefully optimized to fit low biomass microbiomes.IMPORTANCEThe usage of 16S rRNA gene sequencing has become the state-of-the-art method for the characterization of the microbiota in health and respiratory disease. The method is reliable for low biomass samples due to prior amplification of the 16S rRNA gene but has limitations as species and certainly strain identification is not possible. However, the usage of metagenomic tools for the analyses of microbiome data from low biomass samples is not straight forward, and careful optimization is needed. In this work, we show that by validating StrainPhlAn 3 results with the data from bacterial cultures, the strain-level tracking of the respiratory microbiome is feasible despite the high content of host DNA being present when parameters are carefully optimized to fit low biomass microbiomes. This work further proposes that strain retention analyses are feasible, at least for more abundant species. This will help to better understand the longitudinal dynamics of the upper respiratory microbiome during health and disease.

Keywords:  bacterial culture; genome analysis; metagenomics; respiratory tract; strain resolution

DOI:  https://doi.org/10.1128/msystems.00724-23
Trends Immunol. 2023 Oct 31. pii: S1471-4906(23)00208-9. [Epub ahead of print]

Innate immunity: the bacterial connection.

François Rousset.

  Pathogens have fueled the diversification of intracellular defense strategies that collectively define cell-autonomous innate immunity. In bacteria, innate immunity is manifested by a broad arsenal of defense systems that provide protection against bacterial viruses, called phages. The complexity of the bacterial immune repertoire has only been realized recently and is now suggesting that innate immunity has commonalities across the tree of life: many components of eukaryotic innate immunity are found in bacteria where they protect against phages, including the cGAS-STING pathway, gasdermins, and viperins. Here, I summarize recent findings on the conservation of innate immune pathways between prokaryotes and eukaryotes and hypothesize that bacterial defense mechanisms can catalyze the discovery of novel molecular players of eukaryotic innate immunity.

Keywords:  ATP nucleosidase; CBASS; ISG15; NLR; SAMHD1; TIR; bacterial defense; cGAS-STING; cGLR; gasdermin; inflammasomme; innate immunity; phage; viperin

DOI:  https://doi.org/10.1016/j.it.2023.10.001
Endocr Metab Immune Disord Drug Targets. 2023 Oct 24.

Neonatal Microbiome: Is it still Beneficial?

Mohamed Shawky Elfarargy, Dalia Hamdy Elbadry, Ahmad Roshdy, Hany Elhady.

  The neonatal microbiome includes all the microorganisms living within or on the surface of the newborn, as well as their genes (i.e., bacteria, fungi, and viruses), which are composed mainly of bacteria. The majority of these microorganisms reside in the gastrointestinal tract (GIT), which is known as the gut microbiome. They include trillions of microbes, which exceed the total number of neonate cells. In this study, we have examined factors affecting neonatal microbiome colonization, various phyla of the microbiome in neonates, and their characteristics. In addition, we have discussed symbiosis and dysbiosis, precipitating diseases, breast milk's role in the neonatal gut microbiome, prebiotics, probiotics, postbiotics, and synbiotics, as well as the airway or respiratory microbiome, and the main role of the neonatal microbiome. We have also discussed neonatal mycobiome and neonatal virome, as well as the research done on the neonatal microbiome.

Keywords:  COVID-19; breast milk; dysbiosis; microbiome; mycobiome; neonate; probiotics; symbiosis; virome

DOI:  https://doi.org/10.2174/0118715303238665231010062701
Heliyon. 2023 Nov;9(11): e21469

Effect of glucose on growth and co-culture of Staphylococcus aureus and Pseudomonas aeruginosa in artificial sputum medium.

Stanislavs Vasiljevs, Arya Gupta, Deborah Baines.

  People with cystic fibrosis-related diabetes (CFRD) suffer from chronic infections with Staphylococcus aureus and/or Pseudomonas aeruginosa. In people with CFRD, the concentration of glucose in the airway surface liquid (ASL) was shown to be elevated from 0.4 to 4 mM. The effect of glucose on bacterial growth/interactions in ASL is not well understood and here we studied the relationship between these lung pathogens in artificial sputum medium (ASM), an environment similar to ASL in vivo. S. aureus exhibited more rapid adaptation to growth in ASM than P. aeruginosa. Supplementation of ASM with glucose significantly increased the growth of S. aureus (p < 0.01, n = 5) and P. aeruginosa (p < 0.001, n = 3). ASM conditioned by the presence of S. aureus promoted growth of P. aeruginosa with less lag time compared with non-conditioned ASM, or conditioned medium that had been heated to 121 °C. Stable co-culture of S. aureus and P. aeruginosa could be established in a 50:50 mix of ASM and S. aureus-conditioned supernatant. These data indicate that glucose, in a nutrient depleted environment, can promote the growth of S. aureus and P. aeruginosa. In addition, heat labile factors present in S. aureus pre-conditioned ASM promoted the growth of P. aeruginosa. We suggest that the use of ASM allows investigation of the effects of nutrients such as glucose on common lung pathogens. ASM could be further used to understand the relationship between S. aureus and P. aeruginosa in a co-culture scenario. Our model of stable co-culture could be extrapolated to include other common lung pathogens and could be used to better understand disease progression in vitro.

Keywords:  Artificial sputum medium; Co-culture; Glucose; Pseudomonas aeruginosa; Staphylococcus aureus

DOI:  https://doi.org/10.1016/j.heliyon.2023.e21469
Expert Rev Clin Immunol. 2023 Oct 28. 1-4

Insights into the immunological links between dietary habits and asthma.

Ahmad Z Al Meslamani.



Keywords:  Asthma; diet; immunity; immunometabolism; trained immunity

DOI:  https://doi.org/10.1080/1744666X.2023.2277864
Front Immunol. 2023 ;14 1276512

Tolerogenic dendritic cells and TLR4/IRAK4/NF-κB signaling pathway in allergic rhinitis.

Chenglin Kang, Xiaomei Li, Peng Liu, Yue Liu, Yuan Niu, Xianhai Zeng, Hailiang Zhao, Jiangqi Liu, Shuqi Qiu.

  Dendritic cells (DCs), central participants in the allergic immune response, can capture and present allergens leading to allergic inflammation in the immunopathogenesis of allergic rhinitis (AR). In addition to initiating antigen-specific immune responses, DCs induce tolerance and modulate immune homeostasis. As a special type of DCs, tolerogenic DCs (tolDCs) achieve immune tolerance mainly by suppressing effector T cell responses and inducing regulatory T cells (Tregs). TolDCs suppress allergic inflammation by modulating immune tolerance, thereby reducing symptoms of AR. Activation of the TLR4/IRAK4/NF-κB signaling pathway contributes to the release of inflammatory cytokines, and inhibitors of this signaling pathway induce the production of tolDCs to alleviate allergic inflammatory responses. This review focuses on the relationship between tolDCs and TLR4/IRAK4/NF-κB signaling pathway with AR.

Keywords:  TLR4/IRAK4/NF-κB signaling pathway; allergic rhinitis; immune response; immune tolerance; tolerogenic dendritic cells

DOI:  https://doi.org/10.3389/fimmu.2023.1276512
Microbiol Spectr. 2023 Oct 31. e0086923

The novel bacteriocin romsacin from Staphylococcus haemolyticus inhibits Gram-positive WHO priority pathogens.

Runa Wolden, Kirill V Ovchinnikov, Hermoine J Venter, Thomas F Oftedal, Dzung B Diep, Jorunn Pauline Cavanagh.

  Staphylococcus haemolyticus is an increasingly relevant nosocomial pathogen. The combination of multi-drug resistance and ability to form biofilms makes S. haemolyticus infections difficult to treat. Bacteriocins are ribosomally synthesized antimicrobial peptides produced by bacteria to inhibit growth of often closely related bacteria. Due to differences in the modes of action between bacteriocins and antibiotics, bacteriocins are normally equally potent against antibiotic-resistant and antibiotic-sensitive strains. To find bacteriocins able to inhibit S. haemolyticus and related species, clinical and commensal S. haemolyticus isolates (n = 174) were assayed for bacteriocin production. One commensal isolate produced an antimicrobial substance inhibiting S. haemolyticus and Staphylococcus aureus. The substance had physicochemical properties that are characteristic of bacteriocins. Purification, whole-genome sequencing, and mass spectrometry identified the antimicrobial as a novel two-peptide lantibiotic, hereafter named romsacin. The bacteriocin was active against a broad range of Gram-positive bacteria, such as the World Health Organization priority pathogens S. aureus [methicillin-resistant S. aureus (MRSA)] and Enterococcus faecium [vancomycin-resistant E. faecium (VRE)]. Importantly, the bacteriocin also eradicated S. haemolyticus, Staphylococcus epidermidis, MRSA, and VRE biofilms. IMPORTANCE Bacteria produce bacteriocins to inhibit growth of other bacterial species. We have studied the antimicrobial activity of a new bacteriocin produced by the skin bacterium S. haemolyticus. The bacteriocin is effective against several types of Gram-positive bacteria, including highly virulent and antibiotic-resistant strains such as Staphylococcus aureus and Enterococcus faecium. Effective antimicrobials are important for the treatment of infections and the success of major surgery and chemotherapy. Bacteriocins can be part of the solution to the global concern of antimicrobial resistance.

Keywords:  AMR; CoNS; Staphylococcus haemolyticus; WHO priority pathogens; antimicrobial resistance; bacteriocin; biofilm; lanthipeptides; lantibiotics; romsacin

DOI:  https://doi.org/10.1128/spectrum.00869-23
Biomol NMR Assign. 2023 Nov 02.

Chemical shift assignments of the catalytic domain of Staphylococcus aureus LytM.

Helena Tossavainen, Ilona Pitkänen, Lina Antenucci, Chandan Thapa, Perttu Permi.

  S. aureus resistance to antibiotics has increased rapidly. MRSA strains can simultaneously be resistant to many different classes of antibiotics, including the so-called "last-resort" drugs. Resistance complicates treatment, increases mortality and substantially increases the cost of treatment. The need for new drugs against (multi)resistant S. aureus is high. M23B family peptidoglycan hydrolases, enzymes that can kill S. aureus by cleaving glycine-glycine peptide bonds in S. aureus cell wall are attractive targets for drug development because of their binding specificity and lytic activity. M23B enzymes lysostaphin, LytU and LytM have closely similar catalytic domain structures. They however differ in their lytic activities, which can arise from non-conserved residues in the catalytic groove and surrounding loops or differences in dynamics. We report here the near complete 1H/13C/15N resonance assignment of the catalytic domain of LytM, residues 185-316. The chemical shift data allow comparative structural and functional studies between the enzymes and is essential for understanding how these hydrolases degrade the cell wall.

Keywords:  Antimicrobial resistance; LytM; Peptidoglycan hydrolase; Staphylococcus aureus

DOI:  https://doi.org/10.1007/s12104-023-10161-3
Expert Rev Vaccines. 2023 Oct 30.

Glycoconjugate vaccines against antimicrobial resistant pathogens.

Charlotte Sorieul, Marta Dolce, Maria Rosaria Romano, Jeroen Codée, Roberto Adamo.

   INTRODUCTION: Antimicrobial resistance (AMR) is responsible for the death of millions worldwide and stands as a major threat to our healthcare systems, which are heavily reliant on antibiotics to fight bacterial infections. The development of vaccines against the main pathogens involved is urgently required as prevention remains essential against the rise of AMR.
AREAS COVERED: A systematic research review was conducted on MEDLINE database focusing on the six AMR pathogens defined as ESPAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli), which are considered critical or high priority pathogens by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC). The analysis was interseacted with the terms carbohydrate, glycoconjugate, bioconjugate, glyconanoparticle and multiple presenting antigen system vaccines.
EXPERT OPINION: Glycoconjugate vaccines have been successful in preventing meningitis and pneumoniae, and there are high expectations that they will play a key role in fighting AMR. We herein discuss the recent technological, preclinical and clinical advances, as well as the challenges associated with the development of carbohydrate-based vaccines against leading AMR bacteria, with focus on the ESKAPE pathogens. The need of innovative clinical and regulatory approaches to tackle these targets is also highlighted.

Keywords:  A. baumannii; E. coli; E. faecalis; ESKAPE; K. pneumoniae; P. aeruginosa; S. aureus; antimicrobial resistance; glycoconjugate; infection; vaccine

DOI:  https://doi.org/10.1080/14760584.2023.2274955
bioRxiv. 2023 Oct 17. pii: 2023.10.13.562288. [Epub ahead of print]

Increased epithelial mTORC1 activity in chronic rhinosinusitis with nasal polyps.

George X Huang, Nils R Hallen, Minkyu Lee, Kelly Zheng, Xin Wang, Michael V Mandanas, Sarah Djeddi, Daniela Fernandez, Jonathan Hacker, Tessa Ryan, Regan W Bergmark, Neil Bhattacharyya, Stella Lee, Alice Z Maxfield, Rachel E Roditi, Kathleen M Buchheit, Tanya M Laidlaw, James E Gern, Teal S Hallstrand, Anuradha Ray, Sally E Wenzel, Joshua A Boyce, Maria Gutierrez-Arcelus, Nora A Barrett.

Background: The airway epithelium plays a central role in the pathogenesis of chronic respiratory diseases such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), but the mechanisms by which airway epithelial cells (EpCs) maintain inflammation are poorly understood.
Objective: We hypothesized that transcriptomic assessment of sorted airway EpCs across the spectrum of differentiation would allow us to define mechanisms by which EpCs perpetuate airway inflammation.
Methods: Ethmoid sinus EpCs from adult patients with CRS were sorted into 3 subsets, bulk RNA sequenced, and analyzed for differentially expressed genes and pathways. Single cell RNA-seq (scRNA-seq) datasets from eosinophilic and non-eosinophilic CRSwNP and bulk RNA-seq of EpCs from mild/moderate and severe asthma were assessed. Immunofluorescent staining and ex vivo functional analysis of sinus EpCs were used to validate our findings.
Results: Analysis within and across purified EpC subsets revealed an enrichment in glycolytic programming in CRSwNP vs CRSsNP. Correlation analysis identified mammalian target of rapamycin complex 1 (mTORC1) as a potential regulator of the glycolytic program and identified EpC expression of cytokines and wound healing genes as potential sequelae. mTORC1 activity was upregulated in CRSwNP, and ex vivo inhibition demonstrated that mTOR is critical for EpC generation of CXCL8, IL-33, and CXCL2. Across patient samples, the degree of glycolytic activity was associated with T2 inflammation in CRSwNP, and with both T2 and non-T2 inflammation in severe asthma.
Conclusions: Together, these findings highlight a metabolic axis required to support epithelial generation of cytokines critical to both chronic T2 and non-T2 inflammation in CRSwNP and asthma.
KEY MESSAGES: Epithelial mTORC1 activity is upregulated in CRSwNP.mTOR regulates EpC cytokine generation.Epithelial metabolic reprograming correlates with T2 inflammation in CRSwNP, and with both T2 and non-T2 inflammation in asthma.
CAPSULE SUMMARY: mTORC1 mediates EpC cytokine generation in CRSwNP.

DOI: https://doi.org/10.1101/2023.10.13.562288
ACS Infect Dis. 2023 Nov 01.

Wall Teichoic Acid Mediates Staphylococcus aureus Binding to Endothelial Cells via the Scavenger Receptor LOX-1.

Jessica Slavetinsky, Esther Lehmann, Christoph Slavetinsky, Lisa Gritsch, Rob van Dalen, Dorothee Kretschmer, Lisa Bleul, Christiane Wolz, Christopher Weidenmaier, Andreas Peschel.

  The success of Staphylococcus aureus as a major cause for endovascular infections depends on effective interactions with blood-vessel walls. We have previously shown that S. aureus uses its wall teichoic acid (WTA), a surface glycopolymer, to attach to endothelial cells. However, the endothelial WTA receptor remained unknown. We show here that the endothelial oxidized low-density lipoprotein receptor 1 (LOX-1) interacts with S. aureus WTA and permits effective binding of S. aureus to human endothelial cells. Purified LOX-1 bound to isolated S. aureus WTA. Ectopic LOX-1 expression led to increased binding of S. aureus wild type but not of a WTA-deficient mutant to a cell line, and LOX-1 blockage prevented S. aureus binding to endothelial cells. Moreover, WTA and LOX-1 expression levels correlated with the efficacy of the S. aureus-endothelial interaction. Thus, LOX-1 is an endothelial ligand for S. aureus, whose blockage may help to prevent or treat severe endovascular infections.

Keywords:  LOX-1; Staphylococcus aureus; bloodstream infections; scavenger receptor; sepsis; wall teichoic acid

DOI:  https://doi.org/10.1021/acsinfecdis.3c00252
FEMS Microbes. 2023 ;4 xtad019

Enterococcus faecalis suppresses Staphylococcus aureus-induced NETosis and promotes bacterial survival in polymicrobial infections.

Patrick Hsien-Neng Kao, Jun-Hong Ch'ng, Kelvin K L Chong, Claudia J Stocks, Siu Ling Wong, Kimberly A Kline.

  Enterococcus faecalis is an opportunistic pathogen that is frequently co-isolated with other microbes in wound infections. While E. faecalis can subvert the host immune response and promote the survival of other microbes via interbacterial synergy, little is known about the impact of E. faecalis-mediated immune suppression on co-infecting microbes. We hypothesized that E. faecalis can attenuate neutrophil-mediated responses in mixed-species infection to promote survival of the co-infecting species. We found that neutrophils control E. faecalis infection via phagocytosis, ROS production, and degranulation of azurophilic granules, but it does not trigger neutrophil extracellular trap formation (NETosis). However, E. faecalis attenuates Staphylococcus aureus-induced NETosis in polymicrobial infection by interfering with citrullination of histone, suggesting E. faecalis can actively suppress NETosis in neutrophils. Residual S. aureus-induced NETs that remain during co-infection do not impact E. faecalis, further suggesting that E. faecalis possess mechanisms to evade or survive NET-associated killing mechanisms. E. faecalis-driven reduction of NETosis corresponds with higher S. aureus survival, indicating that this immunomodulating effect could be a risk factor in promoting the virulence polymicrobial infection. These findings highlight the complexity of the immune response to polymicrobial infections and suggest that attenuated pathogen-specific immune responses contribute to pathogenesis in the mammalian host.

Keywords:  Enterococcus faecalis; Staphylococcus aureus; neutrophil extracellular traps; neutrophils; polymicrobial infection

DOI:  https://doi.org/10.1093/femsmc/xtad019
Cell Rep. 2023 Oct 30. pii: S2211-1247(23)01348-7. [Epub ahead of print] 113336

Impaired gut microbiota-mediated short-chain fatty acid production precedes morbidity and mortality in people with HIV.

Irini Sereti, Myrthe L Verburgh, Jacob Gifford, Alice Lo, Anders Boyd, Eveline Verheij, Aswin Verhoeven, Ferdinand W N M Wit, Maarten F Schim van der Loeff, Martin Giera, Neeltje A Kootstra, Peter Reiss, Ivan Vujkovic-Cvijin.

  Antiretroviral therapy (ART) has dramatically lengthened lifespan among people with HIV (PWH), but this population experiences heightened rates of inflammation-related comorbidities. HIV-associated inflammation is linked with an altered microbiome; whether such alterations precede inflammation-related comorbidities or occur as their consequence remains unknown. We find that ART-treated PWH exhibit depletion of gut-resident bacteria that produce short-chain fatty acids (SCFAs)-crucial microbial metabolites with anti-inflammatory properties. Prior reports establish that fecal SCFA concentrations are not depleted in PWH. We find that gut-microbiota-mediated SCFA production capacity is better reflected in serum than in feces and that PWH exhibit reduced serum SCFA, which associates with inflammatory markers. Leveraging stool and serum samples collected prior to comorbidity onset, we find that HIV-specific microbiome alterations precede morbidity and mortality in ART-treated PWH. Among these microbiome alterations, reduced microbiome-mediated conversion of lactate to propionate precedes mortality in PWH. Thus, gut microbial fiber/lactate conversion to SCFAs may modulate HIV-associated comorbidity risk.

Keywords:  CP: Microbiology; HIV; microbiome; short-chain fatty acids

DOI:  https://doi.org/10.1016/j.celrep.2023.113336
Front Cell Infect Microbiol. 2023 ;13 1308419

Editorial: The spatial-temporal dynamics of host-pathogen interaction during inflammatory disease.

Donglei Sun, Xue Liu, Xiuli Yang.



Keywords:  fluorescence; host-pathogen interaction; imaging; intravital; microscopy

DOI:  https://doi.org/10.3389/fcimb.2023.1308419
Front Immunol. 2023 ;14 1264609

An optimized cocktail of small molecule inhibitors promotes the maturation of dendritic cells in GM-CSF mouse bone marrow culture.

Shintaro Matsuba, Hiroki Ura, Fumiji Saito, Chie Ogasawara, Shigetaka Shimodaira, Yo Niida, Nobuyuki Onai.

  Dendritic cells (DCs) are the most potent antigen-presenting cells, playing an essential role in the pathogen and tumor recognition, and anti-tumor immunity, and linking both the innate and adaptive immunity. The monocyte-derived DCs generated by ex vivo culture, have been used for cancer immunotherapy to eliminate tumor; however, the clinical efficacies are not sufficient, and further improvement is essential. In this study, we established a method to generate DCs using small molecule compounds for cancer immunotherapy. We observed an increase in the percentage of CD11c+I-A/I-Ehigh cells, representing DCs, by adding four small molecular inhibitors: Y27632, PD0325901, PD173074, and PD98059 (abbreviated as YPPP), in mouse bone marrow (BM) culture with granulocyte-macrophage colony stimulating factor (GM-CSF). BM-derived DCs cultured with YPPP (YPPP-DCs) showed high responsiveness to lipopolysaccharide stimulation, resulting in increased interleukin (IL) -12 production and enhanced proliferation activity when co-cultured with naïve T cells compared with the vehicle control. RNA-seq analysis revealed an upregulation of peroxisome proliferator - activated receptor (PPAR) γ associated genes increased in YPPP-DCs. In tumor models treated with anti-programmed death (PD) -1 therapies, mice injected intratumorally with YPPP-DCs as a DCs vaccine exhibited reduced tumor growth and increased survival. These findings suggested that our method would be useful for the induction of DCs that efficiently activate effector T cells for cancer immunotherapy.

Keywords:  cytokine production; dendritic cells; immunotherapy; mixed lymphoid reaction; small molecule inhibitor

DOI:  https://doi.org/10.3389/fimmu.2023.1264609
Immun Inflamm Dis. 2023 10;11(10): e1045

Mechanistic insights into the role of probiotics in modulating immune cells in ulcerative colitis.

Ni Guo, Lu-Lu Lv.

   BACKGROUND: Ulcerative colitis (UC) is a persistent inflammatory disorder that affects the gastrointestinal tract, mainly the colon, which is defined by inflammatory responses and the formation of ulcers. Probiotics have been shown to directly impact various immune cells, including dendritic cells (DCs), macrophages, natural killer (NK) cells, and T and B cells. By interacting with cell surface receptors, they regulate immune cell activity, produce metabolites that influence immune responses, and control the release of cytokines and chemokines.
METHODS: This article is a comprehensive review wherein we conducted an exhaustive search across published literature, utilizing reputable databases like PubMed and Web of Science. Our focus centered on pertinent keywords, such as "UC," 'DSS," "TNBS," "immune cells," and "inflammatory cytokines," to compile the most current insights regarding the therapeutic potential of probiotics in managing UC.
RESULTS: This overview aims to provide readers with a comprehensive understanding of the effects of probiotics on immune cells in relation to UC. Probiotics have a crucial role in promoting the proliferation of regulatory T cells (Tregs), which are necessary for preserving immunological homeostasis and regulating inflammatory responses. They also decrease the activation of pro-inflammatory cells like T helper 1 (Th1) and Th17 cells, contributing to UC development. Thus, probiotics significantly impact both direct and indirect pathways of immune cell regulation in UC, promoting Treg differentiation, inhibiting pro-inflammatory cell activation, and regulating cytokine and chemokine release.
CONCLUSION: Probiotics demonstrate significant potential in modulating the immune reactions in UC. Their capacity to modulate different immune cells and inflammation-related processes makes them a promising therapeutic approach for managing UC. However, further studies are warranted to optimize their use and fully elucidate the molecular mechanisms underlying their beneficial effects in UC treatment.

Keywords:  gut microbiota; immune cells; inflammatory cytokines; probiotics; ulcerative colitis

DOI:  https://doi.org/10.1002/iid3.1045
Front Microbiol. 2023 ;14 1155388

Microbiota as key factors in inflammatory bowel disease.

Zachary White, Ivan Cabrera, Isabel Kapustka, Teruyuki Sano.

  Inflammatory Bowel Disease (IBD) is characterized by prolonged inflammation of the gastrointestinal tract, which is thought to occur due to dysregulation of the immune system allowing the host's cells to attack the GI tract and cause chronic inflammation. IBD can be caused by numerous factors such as genetics, gut microbiota, and environmental influences. In recent years, emphasis on commensal bacteria as a critical player in IBD has been at the forefront of new research. Each individual harbors a unique bacterial community that is influenced by diet, environment, and sanitary conditions. Importantly, it has been shown that there is a complex relationship among the microbiome, activation of the immune system, and autoimmune disorders. Studies have shown that not only does the microbiome possess pathogenic roles in the progression of IBD, but it can also play a protective role in mediating tissue damage. Therefore, to improve current IBD treatments, understanding not only the role of harmful bacteria but also the beneficial bacteria could lead to attractive new drug targets. Due to the considerable diversity of the microbiome, it has been challenging to characterize how particular microorganisms interact with the host and other microbiota. Fortunately, with the emergence of next-generation sequencing and the increased prevalence of germ-free animal models there has been significant advancement in microbiome studies. By utilizing human IBD studies and IBD mouse models focused on intraepithelial lymphocytes and innate lymphoid cells, this review will explore the multifaceted roles the microbiota plays in influencing the immune system in IBD.

Keywords:  IELs; ILCs; gut innate immunity; host-pathogen interaction; protective bacteria for IBD

DOI:  https://doi.org/10.3389/fmicb.2023.1155388
Front Cell Infect Microbiol. 2023 ;13 1227581

Characteristics of the pulmonary microbiota in patients with mild and severe pulmonary infection.

Danting Zhan, Dan Li, Ke Yuan, Yihua Sun, Lijuan He, Jiacheng Zhong, Lingwei Wang.

   Background: Lung infection is a global health problem associated with high morbidity and mortality and increasing rates of hospitalization. The correlation between pulmonary microecology and infection severity remains unclear. Therefore, the purpose of this study was to investigate the differences in lung microecology and potential biomarkers in patients with mild and severe pulmonary infection.
Method: Patients with pulmonary infection or suspected infection were divided into the mild group (140 cases) and the severe group (80 cases) according to pneomonia severity index (PSI) scores. Here, we used metagenomic next-generation sequencing (mNGS) to detect DNA mainly from bronchoalveolar lavage fluid (BALF) collected from patients to analyze changes in the lung microbiome of patients with different disease severity.
Result: We used the mNGS to analyze the pulmonary microecological composition in patients with pulmonary infection. The results of alpha diversity and beta diversity analysis showed that the microbial composition between mild and severe groups was similar on the whole. The dominant bacteria were Acinetobacter, Bacillus, Mycobacterium, Staphylococcus, and Prevotella, among others. Linear discriminant analysis effect size (LEfSe) results showed that there were significant differences in virus composition between the mild and severe patients, especially Simplexvirus and Cytomegalovirus, which were prominent in the severe group. The random forest model screened 14 kinds of pulmonary infection-related pathogens including Corynebacterium, Mycobacterium, Streptococcus, Klebsiella, and Acinetobacter. In addition, it was found that Rothia was negatively correlated with Acinetobacter, Mycobacterium, Bacillus, Enterococcus, and Klebsiella in the mild group through co-occurrence network, while no significant correlation was found in the severe group.
Conclusion: Here, we describe the composition and diversity of the pulmonary microbiome in patients with pulmonary infection. A significant increase in viral replication was found in the severe group, as well as a significant difference in microbial interactions between patients with mild and severe lung infections, particularly the association between the common pathogenic bacteria and Rothia. This suggests that both pathogen co-viral infection and microbial interactions may influence the course of disease. Of course, more research is needed to further explore the specific mechanisms by which microbial interactions influence disease severity.

Keywords:   pulmonary infection; biomarker; network; pulmonary microbiota; severity

DOI:  https://doi.org/10.3389/fcimb.2023.1227581
J Clin Invest. 2023 Nov 01. pii: e174540. [Epub ahead of print]133(21):

GLUT3 regulates alternative macrophage signaling through a glucose transport-independent role.

Peng Zhang, Jason Miska, Amy B Heimberger.

Macrophages are key mediators of innate immunity whose functional state can be regulated by glucose transporters. Although abundantly expressed in macrophages, the specific function of GLUT3, an isoform of facilitative glucose transporters, has not been clearly established. In this issue of the JCI, Dong-Min Yu and colleagues identify an alternative role for GLUT3 in promoting M2 macrophage polarization. The authors demonstrated that GLUT3 was upregulated upon M2 stimulation and was required for efficient alternative macrophage polarization and function. They further showed that GLUT3-induced M2 polarization was independent of glucose transport and functioned through Ras-mediated regulation of IL-4R endocytosis and IL-4/STAT6 activation. These findings may guide the development of macrophage-targeted treatments.

DOI: https://doi.org/10.1172/JCI174540
Bio Protoc. 2023 Oct 20. 13(20): e4851

Human Dendritic Cell Subset Isolation by Magnetic Bead Sorting: A Protocol to Efficiently Obtain Pure Populations.

Georgina Flórez-Grau, Jorge Cuenca Escalona, Helena Lacasta-Mambo, Daphne Roelofs, Johanna Bödder, Ruben Beuk, Gerty Schreibelt, Jolanda I M De Vries.

  Dendritic cells have been investigated for cell-based immunotherapy for various applications. The low abundance of dendritic cells in blood hampers their clinical application, resulting in the use of monocyte-derived dendritic cells as an alternative cell type. Limited knowledge is available regarding blood-circulating human dendritic cells, which can be divided into three subsets: type 2 conventional dendritic cells, type 1 conventional dendritic cells, and plasmacytoid dendritic cells. These subsets exhibit unique and desirable features for dendritic cell-based therapies. To enable efficient and reliable human research on dendritic cell subsets, we developed an efficient isolation protocol for the three human dendritic cell subsets, resulting in pure populations. The sequential steps include peripheral blood mononuclear cell isolation, magnetic-microbead lineage depletion (CD14, CD56, CD3, and CD19), and individual magnetic-microbead isolation of the three human dendritic cell subsets.

Keywords:  Dendritic cell subsets; Human blood; Immunotherapy; Magnetic microbeads; Sequential isolation

DOI:  https://doi.org/10.21769/BioProtoc.4851
Proc Natl Acad Sci U S A. 2023 Nov 14. 120(46): e2316830120

Discovering unknown associations between prokaryotic receptors and their ligands.

Mensur Dlakić.

DOI: https://doi.org/10.1073/pnas.2316830120
Arch Microbiol. 2023 Oct 31. 205(12): 362

Strategies adopted by Salmonella to survive in host: a review.

Wanwu Li, Qili Ren, Ting Ni, Yifei Zhao, Zichun Sang, Renli Luo, Zhongjie Li, Sanqiang Li.

  Salmonella, a Gram-negative bacterium that infects humans and animals, causes diseases ranging from gastroenteritis to severe systemic infections. Here, we discuss various strategies used by Salmonella against host cell defenses. Epithelial cell invasion largely depends on a Salmonella pathogenicity island (SPI)-1-encoded type 3 secretion system, a molecular syringe for injecting effector proteins directly into host cells. The internalization of Salmonella into macrophages is primarily driven by phagocytosis. After entering the host cell cytoplasm, Salmonella releases many effectors to achieve intracellular survival and replication using several secretion systems, primarily an SPI-2-encoded type 3 secretion system. Salmonella-containing vacuoles protect Salmonella from contacting bactericidal substances in epithelial cells and macrophages. Salmonella modulates the immunity, metabolism, cell cycle, and viability of host cells to expand its survival in the host, and the intracellular environment of Salmonella-infected cells promotes its virulence. This review provides insights into how Salmonella subverts host cell defenses for survival.

Keywords:  Cell death; Effector; Host cell; Infection; Metabolism; Salmonella

DOI:  https://doi.org/10.1007/s00203-023-03702-w