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Frontiers in Cellular and Infection... 2023The polysaccharide capsule of plays a major role in virulence, adherence to epithelial cells, and overall survival of the bacterium in the human host. Galactose,...
BACKGROUND
The polysaccharide capsule of plays a major role in virulence, adherence to epithelial cells, and overall survival of the bacterium in the human host. Galactose, mannose, and N-acetylglucosamine (GlcNAc) are likely to be relevant for metabolization in the nasopharynx, while glucose is the primary carbon source in the blood. In this study, we aim to further the understanding of the influence of carbon sources on pneumococcal growth, capsule biosynthesis, and subsequent adherence potential.
METHODS
We tested the growth behavior of clinical wild-type and capsule knockout strains, using galactose, GlcNAc, mannose, and glucose as carbon source for growth. We measured capsule thickness and quantified capsule precursors by fluorescein isothiocyanate (FITC)-dextran exclusion assays and P-nuclear magnetic resonance measurements, respectively. We also performed epithelial adherence assays using Detroit 562 cells and performed a transcriptome analysis (RNA sequencing).
RESULTS
We observed a reduced growth in galactose, mannose, and GlcNAc compared to growth in glucose and found capsular size reductions in mannose and GlcNAc compared to galactose and glucose. Additionally, capsular precursor measurements of uridine diphosphate-(UDP)-glucose and UDP-galactose showed less accumulation of precursors in GlcNAc or mannose than in glucose and galactose, indicating a possible link with the received capsular thickness measurements. Epithelial adherence assays showed an increase in adherence potential for a pneumococcal strain, when grown in mannose compared to glucose. Finally, transcriptome analysis of four clinical isolates revealed not only strain specific but also common carbon source-specific gene expression.
CONCLUSION
Our findings may indicate a careful adaption of the lifestyle of according to the monosaccharides encountered in the respective human niche.
Topics: Humans; Streptococcus pneumoniae; Galactose; Carbon; Mannose; Glucose; Uridine Diphosphate; Bacterial Capsules
PubMed: 38094742
DOI: 10.3389/fcimb.2023.1279119 -
Biomolecules Jan 2024While extensive research highlighted the involvement of metabolism and immune cells in female reproductive diseases, causality remains unestablished. (Meta-Analysis)
Meta-Analysis
BACKGROUND
While extensive research highlighted the involvement of metabolism and immune cells in female reproductive diseases, causality remains unestablished.
METHODS
Instrumental variables for 486 circulating metabolites ( = 7824) and 731 immunophenotypes ( = 3757) were derived from a genome-wide association study (GWAS) meta-analysis. FinnGen contributed data on 14 female reproductive disorders. A bidirectional two-sample Mendelian randomization study was performed to determine the relationships between exposures and outcomes. The robustness of results, potential heterogeneity, and horizontal pleiotropy were examined through sensitivity analysis.
RESULTS
High levels of mannose were found to be causally associated with increased risks of gestational diabetes (GDM) (OR [95% CI], 6.02 [2.85-12.73], = 2.55 × 10). A genetically predicted elevation in the relative count of circulating CD28CD25CD8 T cells was causally related to increased female infertility risk (OR [95% CI], 1.26 [1.14-1.40], = 1.07 × 10), whereas a high absolute count of NKT cells reduced the risk of ectopic pregnancy (OR [95% CI], 0.87 [0.82-0.93], = 5.94 × 10). These results remained consistent in sensitivity analyses.
CONCLUSIONS
Our study supports mannose as a promising GDM biomarker and intervention target by integrating metabolomics and genomics.
Topics: Pregnancy; Humans; Female; CD8-Positive T-Lymphocytes; Genome-Wide Association Study; Mannose; Mendelian Randomization Analysis; CD28 Antigens; Diabetes, Gestational
PubMed: 38254716
DOI: 10.3390/biom14010116 -
Seminars in Immunology Jul 2023Dendritic cells (DCs) are a complex network of specialised antigen-presenting cells that are critical initiators of adaptive immunity. Targeting antigen directly to DCs... (Review)
Review
Dendritic cells (DCs) are a complex network of specialised antigen-presenting cells that are critical initiators of adaptive immunity. Targeting antigen directly to DCs in situ is a vaccination strategy that selectively delivers antigen to receptors expressed by DC subtypes. This approach exploits specific DC subset functions of antigen uptake and presentation. Here, we review DC-targeted vaccination strategies that are designed to elicit effective cross-presentation for CD8 T cell immunity. In particular, we focus on approaches that exploit receptors highly expressed by mouse and human cDCs equipped with superior cross-presentation capacity. These receptors include DEC205, Clec9A and XCR1. Targeting DC receptors Clec12A, Clec4A4 and mannose receptor is also reviewed. Outcomes of DC-targeted vaccination in mouse models through to human clinical trials is discussed. This is a promising new vaccination approach capable of directly targeting the cross-presentation pathway for prevention and treatment of tumours and infectious diseases.
Topics: Animals; Humans; Mice; Cross-Priming; Antigen Presentation; CD8-Positive T-Lymphocytes; Antigens; Vaccination; Dendritic Cells
PubMed: 37167898
DOI: 10.1016/j.smim.2023.101762 -
Journal of Controlled Release :... Jun 2024In the pursuit of achieving better therapeutic outcomes in the treatment of HIV, innovative drug delivery strategies have been extensively explored. Mannose receptors,... (Review)
Review
In the pursuit of achieving better therapeutic outcomes in the treatment of HIV, innovative drug delivery strategies have been extensively explored. Mannose receptors, which are primarily found on macrophages and dendritic cells, offer promising targets for drug delivery due to their involvement in HIV pathogenesis. This review article comprehensively evaluates recent drug delivery system advancements targeting the mannose receptor. We have systematically described recent developments in creating and utilizing drug delivery platforms, including nanoparticles, liposomes, micelles, noisomes, dendrimers, and other nanocarrier systems targeted at the mannose receptor. These strategies aim to enhance drug delivery specificity, bioavailability, and therapeutic efficacy while decreasing off-target effects and systemic toxicity. Furthermore, the article delves into how mannose receptors and HIV interact, highlighting the potential for exploiting this interaction to enhance drug delivery to infected cells. The review covers essential topics, such as the rational design of nanocarriers for mannose receptor recognition, the impact of physicochemical properties on drug delivery performance, and how targeted delivery affects the pharmacokinetics and pharmacodynamics of anti-HIV agents. The challenges of these novel strategies, including immunogenicity, stability, and scalability, and future research directions in this rapidly growing area are discussed. The knowledge synthesis presented in this review underscores the potential of mannose receptor-based targeted drug delivery as a promising avenue for advancing HIV treatment. By leveraging the unique properties of mannose receptors, researchers can design drug delivery systems that cater to individual needs, overcome existing limitations, and create more effective and patient-friendly treatments in the ongoing fight against HIV/AIDS.
PubMed: 38849091
DOI: 10.1016/j.jconrel.2024.06.002 -
MBio Jan 2024messenger RNA (mRNA) vaccines are a key technology in combating existing and emerging infectious diseases. However, the inherent instability of mRNA and the...
messenger RNA (mRNA) vaccines are a key technology in combating existing and emerging infectious diseases. However, the inherent instability of mRNA and the nonspecificity of lipid nanoparticle-encapsulated (LNP) delivery systems result in the need for cold storage and a relatively short-duration immune response to mRNA vaccines. Herein, we develop a novel vaccine in the form of circRNAs encapsulated in LNPs, and the circular structure of the circRNAs enhances their stability. Lyophilization is considered the most effective method for the long-term preservation of RNA vaccines. However, this process may result in irreversible damage to the nanoparticles, particularly the potential disruption of targeting modifications on LNPs. During the selection of lymph node-targeting ligands, we found that LNPs modified with mannose maintained their physical properties almost unchanged after lyophilization. Additionally, the targeting specificity and immunogenicity remained unaffected. In contrast, even with the addition of cryoprotectants such as sucrose, the physical properties of LNPs were impaired, leading to an obvious decrease in immunogenicity. This may be attributed to the protective role of mannose on the surface of LNPs during lyophilization. Freshly prepared and lyophilized mLNP-circRNA vaccines elicited comparable immune responses in both the rabies virus model and the SARS-CoV-2 model. Our data demonstrated that mLNP-circRNA vaccines elicit robust immune responses while improving stability after lyophilization, with no compromise in tissue targeting specificity. Therefore, mannose-modified LNP-circRNA vaccines represent a promising vaccine design strategy.
Topics: RNA, Circular; Mannose; Vaccines; Immunity; Freeze Drying; RNA, Messenger
PubMed: 38078742
DOI: 10.1128/mbio.01775-23 -
The Senior Care Pharmacist Aug 2023Urinary tract infections (UTIs) are the most prevalent infections in older patients with the potential for morbidity and mortality. Antibiotics are not generally... (Review)
Review
Urinary tract infections (UTIs) are the most prevalent infections in older patients with the potential for morbidity and mortality. Antibiotics are not generally recommended for UTI prophylaxis in this population. There is interest among the public and health providers to try over-the-counter products, such as cranberry, D-mannose, and vitamin C. The objective of this analysis was to review the literature for the efficacy and tolerability of these supplements in older individuals. A literature review was conducted on PubMed using the search terms urinary tract infection or UTI, prevention/prophylaxis, cranberry, D-mannose, vitamin C/ascorbic acid. Few studies were conducted among older people; therefore, the authors included studies of all adults who had recurrent UTIs or were at increased risk of UTIs. Level (quality) of evidence were determined using the ACC/AHA Clinical Practice Guideline Recommendation Classification System. A total of 24 studies were included. This review captured all studies in previous reviews as well as recent publications. The authors determined that there were limited data for D-mannose and vitamin C, and randomized data for cranberry as defined by the classification system. The three supplements reviewed appear not to be strongly supported by clinical data. For those who are interested in trying these products despite the lack of robust evidence for clinical efficacy, it may be helpful to know that the studies included in this review did not identify any clinically important signs of harm, to the extent that safety data were documented and reported.
Topics: Humans; Aged; Vaccinium macrocarpon; Mannose; Ascorbic Acid; Urinary Tract Infections; Anti-Bacterial Agents
PubMed: 37496168
DOI: 10.4140/TCP.n.2023.315 -
Advanced Science (Weinheim,... Oct 2023Accurate delineation of glioma infiltrative margins remains a challenge due to the low density of cancer cells in these regions. Here, a hierarchical imaging strategy to...
Accurate delineation of glioma infiltrative margins remains a challenge due to the low density of cancer cells in these regions. Here, a hierarchical imaging strategy to define glioma margins by locating the immunosuppressive tumor-associated macrophages (TAMs) is proposed. A pH ratiometric fluorescent probe CP2-M that targets immunosuppressive TAMs by binding to mannose receptor (CD206) is developed, and it subsequently senses the acidic phagosomal lumen, resulting in a remarkable fluorescence enhancement. With assistance of CP2-M, glioma xenografts in mouse models with a tumor-to-background ratio exceeding 3.0 for up to 6 h are successfully visualized. Furthermore, by intra-operatively mapping the pH distribution of exposed tissue after craniotomy, the glioma allograft in rat models is precisely excised. The overall survival of rat models significantly surpasses that achieved using clinically employed fluorescent probes. This work presents a novel strategy for locating glioma margins, thereby improving surgical outcomes for tumors with infiltrative characteristics.
Topics: Mice; Humans; Rats; Animals; Tumor-Associated Macrophages; Glioma; Fluorescent Dyes; Mannose Receptor
PubMed: 37544917
DOI: 10.1002/advs.202304020 -
Cell Reports Dec 2023Chromosome instability (CIN) contributes to resistance to therapies and tumor evolution. Although natural killer (NK) cells can eliminate cells with complex karyotypes,...
Chromosome instability (CIN) contributes to resistance to therapies and tumor evolution. Although natural killer (NK) cells can eliminate cells with complex karyotypes, high-CIN human tumors have an immunosuppressive phenotype. To understand which CIN-associated molecular features alter immune recognition during tumor evolution, we overexpress Polo-like kinase 1 (Plk1) in a Her2 breast cancer model. These high-CIN tumors activate a senescence-associated secretory phenotype (SASP), upregulate PD-L1 and CD206, and induce non-cell-autonomous nuclear factor κB (NF-κβ) signaling, facilitating immune evasion. Single-cell RNA sequencing from pre-neoplastic mammary glands unveiled the presence of Arg1 macrophages, NK cells with reduced effector functions, and increased resting regulatory T cell infiltration. We further show that high PLK1-expressing human breast tumors display gene expression patterns associated with SASP, NF-κβ signaling, and immune suppression. These findings underscore the need to understand the immune landscape in CIN tumors to identify more effective therapies, potentially combining immune checkpoint or NF-κβ inhibitors with current treatments.
Topics: Chromosomal Instability; Breast Neoplasms; Immune Tolerance; Humans; Animals; Mice; Polo-Like Kinase 1; Cell Line, Tumor; Receptor, ErbB-2; NF-kappa B; B7-H1 Antigen; Mannose Receptor; Killer Cells, Natural; Tumor Escape; Heterografts; MCF-7 Cells; Female
PubMed: 37979172
DOI: 10.1016/j.celrep.2023.113266 -
ELife Jul 2023Mannose has anticancer activity that inhibits cell proliferation and enhances the efficacy of chemotherapy. How mannose exerts its anticancer activity, however, remains...
Mannose has anticancer activity that inhibits cell proliferation and enhances the efficacy of chemotherapy. How mannose exerts its anticancer activity, however, remains poorly understood. Here, using genetically engineered human cancer cells that permit the precise control of mannose metabolic flux, we demonstrate that the large influx of mannose exceeding its metabolic capacity induced metabolic remodeling, leading to the generation of slow-cycling cells with limited deoxyribonucleoside triphosphates (dNTPs). This metabolic remodeling impaired dormant origin firing required to rescue stalled forks by cisplatin, thus exacerbating replication stress. Importantly, pharmacological inhibition of de novo dNTP biosynthesis was sufficient to retard cell cycle progression, sensitize cells to cisplatin, and inhibit dormant origin firing, suggesting dNTP loss-induced genomic instability as a central mechanism for the anticancer activity of mannose.
Topics: Humans; Mannose; Cisplatin; Genomic Instability; Nucleotides; DNA Replication; Neoplasms
PubMed: 37461317
DOI: 10.7554/eLife.83870 -
BioRxiv : the Preprint Server For... Aug 2023ESCRTs (Endosomal Sorting Complex Required for Transport) are a modular set of protein complexes with membrane remodeling activities that include the formation and...
ESCRTs (Endosomal Sorting Complex Required for Transport) are a modular set of protein complexes with membrane remodeling activities that include the formation and release of intralumenal vesicles (ILVs) to generate multivesicular endosomes. While most of the 12 ESCRT-III proteins are known to play roles in ILV formation, IST1 has been associated with a wider range of endosomal remodeling events. Here, we extend previous studies of IST1 function in endosomal trafficking and confirm that IST1, along with its binding partner CHMP1B, contributes to scission of early endosomal carriers. Depleting IST1 impaired delivery of transferrin receptor from early/sorting endosomes to the endocytic recycling compartment and instead increased its rapid recycling to the plasma membrane via peripheral endosomes enriched in the clathrin adaptor AP-1. IST1 is also important for export of mannose 6-phosphate receptor from early/sorting endosomes. Examination of IST1 binding partners on endosomes revealed that IST1 interacts with the MIT domain-containing sorting nexin SNX15, a protein previously reported to regulate endosomal recycling. Our kinetic and spatial analyses establish that SNX15 and IST1 occupy a clathrin-containing subdomain on the endosomal perimeter distinct from those previously implicated in cargo retrieval or degradation. Using live-cell microscopy we see that SNX15 and CHMP1B alternately recruit IST1 to this subdomain or the base of endosomal tubules. These findings indicate that IST1 contributes to a subset of recycling pathways from the early/sorting endosome.
PubMed: 37577466
DOI: 10.1101/2023.07.31.551359