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Immunity Oct 2016The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in...
The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-γ-producing γδT cells in cancer lesions. The immune sensor, NOD2, limited CTX-induced cancer immunosurveillance and the bioactivity of these microbes. Finally, E. hirae and B. intestinihominis specific-memory Th1 cell immune responses selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. Altogether, E. hirae and B. intestinihominis represent valuable "oncomicrobiotics" ameliorating the efficacy of the most common alkylating immunomodulatory compound.
Topics: Animals; Colon; Cyclophosphamide; Enterococcus hirae; Immunologic Factors; Immunologic Memory; Immunotherapy; Interferon-gamma; Intestine, Small; Mice; Mice, Inbred C57BL; Monitoring, Immunologic; Neoplasms; Nod2 Signaling Adaptor Protein; Th1 Cells
PubMed: 27717798
DOI: 10.1016/j.immuni.2016.09.009 -
Cell Mar 2022Enterococci are a part of human microbiota and a leading cause of multidrug resistant infections. Here, we identify a family of Enterococcus pore-forming toxins (Epxs)...
Enterococci are a part of human microbiota and a leading cause of multidrug resistant infections. Here, we identify a family of Enterococcus pore-forming toxins (Epxs) in E. faecalis, E. faecium, and E. hirae strains isolated across the globe. Structural studies reveal that Epxs form a branch of β-barrel pore-forming toxins with a β-barrel protrusion (designated the top domain) sitting atop the cap domain. Through a genome-wide CRISPR-Cas9 screen, we identify human leukocyte antigen class I (HLA-I) complex as a receptor for two members (Epx2 and Epx3), which preferentially recognize human HLA-I and homologous MHC-I of equine, bovine, and porcine, but not murine, origin. Interferon exposure, which stimulates MHC-I expression, sensitizes human cells and intestinal organoids to Epx2 and Epx3 toxicity. Co-culture with Epx2-harboring E. faecium damages human peripheral blood mononuclear cells and intestinal organoids, and this toxicity is neutralized by an Epx2 antibody, demonstrating the toxin-mediated virulence of Epx-carrying Enterococcus.
Topics: Animals; Bacterial Toxins; Cattle; Enterococcus; Horses; Leukocytes, Mononuclear; Mice; Microbial Sensitivity Tests; Swine; Virulence Factors
PubMed: 35259335
DOI: 10.1016/j.cell.2022.02.002 -
Science (New York, N.Y.) Aug 2020Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major...
Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Mice bearing harboring this prophage mounted a TMP-specific H-2K-restricted CD8 T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Agents, Alkylating; Bacteriophages; CD8-Positive T-Lymphocytes; Cross Reactions; Cyclophosphamide; Enterococcus hirae; Epitopes; Feces; Gastrointestinal Microbiome; H-2 Antigens; Histocompatibility Antigens Class I; Humans; Immunotherapy; Mice; Neoplasms; Programmed Cell Death 1 Receptor; Viral Tail Proteins
PubMed: 32820119
DOI: 10.1126/science.aax0701 -
Cellular and Molecular Life Sciences :... May 2018Rotary ATPases are unique rotary molecular motors that function as energy conversion machines. Among all known rotary ATPases, F-ATPase is the best characterized rotary... (Review)
Review
Rotary ATPases are unique rotary molecular motors that function as energy conversion machines. Among all known rotary ATPases, F-ATPase is the best characterized rotary molecular motor. There are many high-resolution crystal structures and the rotation dynamics have been investigated in detail by extensive single-molecule studies. In contrast, knowledge on the structure and rotation dynamics of V-ATPase, another rotary ATPase, has been limited. However, recent high-resolution structural studies and single-molecule studies on V-ATPase have provided new insights on how the catalytic sites in this molecular motor change its conformation during rotation driven by ATP hydrolysis. In this review, we summarize recent information on the structural features and rotary dynamics of V-ATPase revealed from structural and single-molecule approaches and discuss the possible chemomechanical coupling scheme of V-ATPase with a focus on differences between rotary molecular motors.
Topics: Adenosine Triphosphate; Animals; Crystallography, X-Ray; Humans; Hydrolysis; Models, Molecular; Molecular Motor Proteins; Protein Conformation; Rotation; Vacuolar Proton-Translocating ATPases
PubMed: 29387903
DOI: 10.1007/s00018-018-2758-3 -
Foods (Basel, Switzerland) Nov 2022Exopolysaccharide (EPS) from probiotic WEHI01 was isolated and purified by anion exchange chromatography and gel chromatography, the results of which show that the EPS...
Exopolysaccharide (EPS) from probiotic WEHI01 was isolated and purified by anion exchange chromatography and gel chromatography, the results of which show that the EPS consists of four fractions, namely I01-1, I01-2, I01-3, and I01-4. As the main purification components, I01-2 and I01-4 were preliminarily characterized for their structure and their immunomodulatory activity was explored. The molecular weight of I01-2 was 2.28 × 10 Da, which consists mainly of galactose, and a few other sugars including glucose, arabinose, mannose, xylose, fucose, and rhamnose, while the I01-4 was composed of galactose only and has a molecular weight of 2.59 × 10 Da. Furthermore, the results of an evaluation of immunomodulatory activity revealed that I01-2 and I01-4 could improve the viability of macrophage cells, improve phagocytosis, boost NO generation, and encourage the release of cytokines including TNF-α and IL-6 in RAW 264.7 macrophages. These results imply that I01-2 and I01-4 could improve macrophage-mediated immune responses and might be useful in the production of functional food and medications.
PubMed: 36360150
DOI: 10.3390/foods11213538 -
The Journal of Membrane Biology Jun 2019Of all the macromolecular assemblies of life, the least understood is the biomembrane. This is especially true in regard to its atomic structure. Ideas on biomembranes,... (Review)
Review
Of all the macromolecular assemblies of life, the least understood is the biomembrane. This is especially true in regard to its atomic structure. Ideas on biomembranes, developed in the last 200 years, culminated in the fluid mosaic model of the membrane. In this essay, I provide a historical outline of how we arrived at our current understanding of biomembranes and the models we use to describe them. A selection of direct experimental findings on the nano-scale structure of biomembranes is taken up to discuss their physical nature, and special emphasis is put on the surprising insights that arise from atomic scale descriptions.
Topics: Cell Membrane; Crystallography, X-Ray; Enterococcus hirae; Eukaryotic Cells; Halobacterium salinarum; Humans; Hydrophobic and Hydrophilic Interactions; Membrane Lipids; Membrane Microdomains; Membrane Proteins; Models, Biological; Protein Conformation
PubMed: 30877332
DOI: 10.1007/s00232-019-00061-w -
Frontiers in Microbiology 2022Enterococci are commensal bacteria of the gastrointestinal tract of humans, animals, and insects. They are also found in soil, water, and plant ecosystems. The presence...
Enterococci are commensal bacteria of the gastrointestinal tract of humans, animals, and insects. They are also found in soil, water, and plant ecosystems. The presence of enterococci in human, animal, and environmental settings makes these bacteria ideal candidates to study antimicrobial resistance in the One-Health continuum. This study focused on isolates ( = 4,601) predominantly isolated from beef production systems including bovine feces ( = 4,117, 89.5%), catch-basin water ( = 306, 66.5%), stockpiled bovine manure ( = 24, 0.5%), and natural water sources near feedlots ( = 145, 32%), and a few isolates from urban wastewater ( = 9, 0.2%) denoted as human-associated environmental samples. Antimicrobial susceptibility profiling of a subset ( = 1,319) of isolates originating from beef production systems ( = 1,308) showed high resistance to tetracycline (65%) and erythromycin (57%) with 50.4% isolates harboring multi-drug resistance, whereas urban wastewater isolates ( = 9) were resistant to nitrofurantoin (44.5%) and tigecycline (44.5%) followed by linezolid (33.3%). Genes for tetracycline ( and ) and macrolide resistance were frequently found in beef production isolates. Antimicrobial resistance profiles of isolates recovered from different environmental settings appeared to reflect the kind of antimicrobial usage in beef and human sectors. Comparative genomic analysis of isolates showed an open pan-genome that consisted of 1,427 core genes, 358 soft core genes, 1701 shell genes, and 7,969 cloud genes. Across species comparative genomic analysis conducted on , and genomes revealed that had unique genes associated with vitamin production, cellulose, and pectin degradation, traits which may support its adaptation to the bovine digestive tract. and more frequently harbored virulence genes associated with biofilm formation, iron transport, and cell adhesion, suggesting niche specificity within these species.
PubMed: 35832805
DOI: 10.3389/fmicb.2022.859990 -
Frontiers in Microbiology 2023Ongoing extensive research in the field of gut microbiota (GM) has highlighted the crucial role of gut-dwelling microbes in human health. These microbes possess 100... (Review)
Review
Ongoing extensive research in the field of gut microbiota (GM) has highlighted the crucial role of gut-dwelling microbes in human health. These microbes possess 100 times more genes than the human genome and offer significant biochemical advantages to the host in nutrient and drug absorption, metabolism, and excretion. It is increasingly clear that GM modulates the efficacy and toxicity of drugs, especially those taken orally. In addition, intra-individual variability of GM has been shown to contribute to drug response biases for certain therapeutics. For instance, the efficacy of cyclophosphamide depends on the presence of and in the host intestine. Conversely, the presence of inappropriate or unwanted gut bacteria can inactivate a drug. For example, dehydroxylase of and A2 can metabolize L-dopa before it converts into the active form (dopamine) and crosses the blood-brain barrier to treat Parkinson's disease patients. Moreover, GM is emerging as a new player in personalized medicine, and various methods are being developed to treat diseases by remodeling patients' GM composition, such as prebiotic and probiotic interventions, microbiota transplants, and the introduction of synthetic GM. This review aims to highlight how the host's GM can improve drug efficacy and discuss how an unwanted bug can cause the inactivation of medicine.
PubMed: 38098666
DOI: 10.3389/fmicb.2023.1274925 -
Biochimica Et Biophysica Acta Jan 2015V-ATPase is an ATP-driven rotary motor that vectorially transports ions. Together with F-ATPase, a homologous protein, several models on the ion transport have been... (Review)
Review
V-ATPase is an ATP-driven rotary motor that vectorially transports ions. Together with F-ATPase, a homologous protein, several models on the ion transport have been proposed, but their molecular mechanisms are yet unknown. V-ATPase from Enterococcus hirae forms a large supramolecular protein complex (total molecular weight: ~700,000) and physiologically transports Na⁺ and Li⁺ across a hydrophobic lipid bilayer. Stabilization of these cations in the binding site has been discussed on the basis of X-ray crystal structures of a membrane-embedded domain, the K-ring (Na⁺ and Li⁺ bound forms). Sodium or lithium ion binding-induced difference FTIR spectra of the intact E. hirae V-ATPase have been measured in aqueous solution at physiological temperature. The results suggest that sodium or lithium ion binding induces the deprotonation of Glu139, a hydrogen-bonding change in the tyrosine residue and rigid α-helical structures. Identical difference FTIR spectra between the entire V-ATPase complex and K-ring strongly suggest that protein interaction with the I subunit does not cause large structural changes in the K-ring. This result supports the previously proposed Na⁺ transport mechanism by V-ATPase stating that a flip-flop movement of a carboxylate group of Glu139 without large conformational changes in the K-ring accelerates the replacement of a Na⁺ ion in the binding site. This article is part of a Special Issue entitled: Vibrational spectroscopies and bioenergetic systems.
Topics: Binding Sites; Cations, Monovalent; Enterococcus; Hydrogen Bonding; Lithium; Models, Molecular; Sodium; Spectrophotometry, Infrared; Vacuolar Proton-Translocating ATPases
PubMed: 25111748
DOI: 10.1016/j.bbabio.2014.07.020 -
The New Microbiologica Oct 2021Enterococcus cecorum and Enterococcus hirae can cause locomotor problems, septicaemia, and endocarditis in broiler chickens. Understanding transmission routes and...
Enterococcus cecorum and Enterococcus hirae can cause locomotor problems, septicaemia, and endocarditis in broiler chickens. Understanding transmission routes and resistance patterns are essential for effective treatment. The aim of this study was to follow the same animals from the breeder flock to the hatchery and up to 14-day-old broiler chickens on the farm to find the source of E. cecorum and E. hirae. During the production cycle, only faeces and organs of broilers were E. hirae positive in all three sampled farms in which recurrent enterococcal infections were previously confirmed. None of the isolates possessed virulence genes. Based on resistance profiles, a variety of different strains were present in faeces and organs of different broilers' ages. Samples from the breeder flock and hatchery were negative. Faecal shedding on the farm and tolerance of enterococci to the environmental conditions enable persistence of pathogenic enterococci in farm dust; therefore, adequate cleaning and disinfection after depopulation of the farms could prevent disease recurrence in the new cycle. Susceptibility testing of E. hirae isolates showed no resistance to the drugs of choice for the treatment of enterococcal infections in poultry.
Topics: Animals; Anti-Bacterial Agents; Chickens; Drug Resistance, Microbial; Enterococcus; Enterococcus hirae; Gram-Positive Bacterial Infections; Poultry; Poultry Diseases; Slovenia
PubMed: 34942014
DOI: No ID Found