An Oral Nanovaccine Secreted by Genetically Engineered and Ultrasound‐Responsive Bacteria for Colon Cancer Immunotherapy DOI
Jiexin Li, Ruiqi Yang, Yihang Yuan

et al.

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 4, 2024

Abstract Colorectal cancers represent a major global morbidity and mortality burden, neccessitating improved treatment paradigms. In this work, an ingestible, genetically engineered Escherichia coli ( E. ) 1917 termed “ (AH1‐CDA‐Co1)” is designed that upon ultrasound exposure secretes bacterial outer membrane vesicles (OMV) incorporating the AH1 tumor rejection epitope, enzyme producing stimulator of interferon genes (STING) agonist CDA, microfold cell‐targeting peptide Co1. For oral administration, polydopamine system (iPDA) coating on bacteria exploited to resist acidic condition in stomach, increase survival, prolong intestinal transit time. Upon harmless exposure, sustained secretion OMV vaccines triggered efficiently cross epithelium. Both cyclic GMP–AMP synthase (cGAS)‐STING TLR4 innate immune signaling pathways are activated, triggering long‐term antigen‐specific responses overcome immunosuppressive microenvironment. subcutaneous orthotopic murine colorectal models, (AH1‐CDA‐Co1)@iPDA inhibits growth prolongs survival without recurrence. also recurrence postoperative colonrectal model lymph node metastases. Taken together, demonstrates potent vaccine for colon cancer immunotherapy.

Language: Английский

Bioinformatics Analysis of Diadenylate Cyclase Regulation on Cyclic Diadenosine Monophosphate Biosynthesis in Exopolysaccharide Production by Leuconostoc mesenteroides DRP105 DOI Creative Commons

Wenna Yu,

Liansheng Yu,

Tao Li

et al.

Fermentation, Journal Year: 2025, Volume and Issue: 11(4), P. 196 - 196

Published: April 7, 2025

Lactic acid bacteria exopolysaccharides (EPS) have a variety of excellent biological functions and are widely used in the food pharmaceutical industries. The complex metabolic system lactic mechanism EPS biosynthesis not been fully analyzed, which limits wider application EPS. synthesis is regulated by cyclic diadenosine monophosphate (c-di-AMP), but exact remains unclear. Dac pde c-di-AMP anabolic genes, gtfA, gtfB gtfC gene clusters, among was key for Leuconostoc mesenteroides DRP105. In order to explore whether diadenylate cyclase (DAC) can catalyze from ATP, sequence DAC analyzed bioinformatics based on whole genome sequence. CdaA type containing classical domain DisA_N DGA RHR motifs. secondary structure mainly composed α-helices, AlphaFold2 model 3D protein evaluate rationality model. A total 8 salt bridges, 21 hydrogen bonds 221 non-bonded interactions were found between GtfC. Molecular docking simulations revealed ATP1 ATP2 occupied binding pocket interacted directly with site residues DAC. molecular dynamics showed that ATP molecules relatively stable. Gene enzyme correlation analysis dac expression significantly positively correlated activity, content production, had no significant PDE activity responsible degradation. Bioinformatics regulatory role helpful reveal biosynthetic provide theoretical basis large-scale industrial production

Language: Английский

Citations

0
Coordinated regulation of osmotic imbalance by c-di-AMP shapes ß-lactam tolerance in Group B Streptococcus DOI Creative Commons
Terry Brissac, Cécile Guyonnet,

Aymane Sadouni

et al.

microLife, Journal Year: 2024, Volume and Issue: 5

Published: Jan. 1, 2024

Abstract Streptococcus agalactiae is among the few pathogens that have not developed resistance to ß-lactam antibiotics despite decades of clinical use. The molecular basis this long-lasting susceptibility has been investigated, and it known whether specific mechanisms constrain emergence resistance. In study, we first report tolerance due inactivation c-di-AMP phosphodiesterase GdpP. Mechanistically, depends on antagonistic regulation by repressor BusR, which activated negatively regulates through BusAB osmolyte transporter AmaP/Asp23/GlsB cell envelope stress complex. BusR transcriptional response synergistic with simultaneous allosteric inhibition potassium transporters c-di-AMP, individually contribute low-level tolerance. Genome-wide transposon mutagenesis confirms role GdpP highlights functional interactions between a lysozyme-like hydrolase, KhpAB RNA chaperone protein S immunomodulator in GBS ß-lactam. Overall, demonstrate acts as turgor pressure rheostat, coordinating an integrated at post-translational levels wall weakening caused activity, reveal additional could foster

Language: Английский

Citations

1
Borrelia burgdorferi Secretes c-di-AMP as an Extracellular Pathogen-Associated Molecular Pattern to Elicit Type I Interferon Responses in Mammalian Hosts DOI Creative Commons
Raj Priya,

Meiping Ye,

Sajith Raghunanadanan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 16, 2024

ABSTRACT Borrelia burgdorferi ( B. ), an extracellular spirochetal pathogen, elicits a type-I interferon (IFN-I) response that contributes to the pathology of Lyme disease, including development and severity arthritis. However, specific Pathogen-Associated Molecular Patterns (PAMPs) responsible for triggering IFN-I are not well understood. Previous studies have identified unknown, nuclease-resistant component in culture supernatants significantly stimulates response, but its identity remains unknown. In this study, we reveal secretes cyclic-di-adenosine monophosphate (c-di-AMP) as key PAMP, inducing host macrophages. Using genetically manipulated strains, demonstrate requirement c-di-AMP stimulating by macrophages ex vivo . Additionally, infecting mice with alongside exogenous resulted markedly increased mouse tissues. Furthermore, inactivation or inhibition STING signaling pathway reduced indicating c-di-AMP-induced production is STING-dependent. Our findings identify crucial PAMP secreted elicit via activation pathway, suggesting targeting could represent novel therapeutic strategy against SUMMARY , bacteria causes induces robust immune (IFN-I). While helps combat infection, it also complications such research aimed bacterial triggers response. We discovered releases second messenger molecule, (c-di-AMP), which recognized cells subsequently production. This finding significant advances our understanding disease pathogenesis offers new tackle c-di-AMP, may be able reduce mitigate long-term tissue damage. One sentence summary Type I IFN

Language: Английский

Citations

0
An Oral Nanovaccine Secreted by Genetically Engineered and Ultrasound‐Responsive Bacteria for Colon Cancer Immunotherapy DOI
Jiexin Li, Ruiqi Yang, Yihang Yuan

et al.

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 4, 2024

Abstract Colorectal cancers represent a major global morbidity and mortality burden, neccessitating improved treatment paradigms. In this work, an ingestible, genetically engineered Escherichia coli ( E. ) 1917 termed “ (AH1‐CDA‐Co1)” is designed that upon ultrasound exposure secretes bacterial outer membrane vesicles (OMV) incorporating the AH1 tumor rejection epitope, enzyme producing stimulator of interferon genes (STING) agonist CDA, microfold cell‐targeting peptide Co1. For oral administration, polydopamine system (iPDA) coating on bacteria exploited to resist acidic condition in stomach, increase survival, prolong intestinal transit time. Upon harmless exposure, sustained secretion OMV vaccines triggered efficiently cross epithelium. Both cyclic GMP–AMP synthase (cGAS)‐STING TLR4 innate immune signaling pathways are activated, triggering long‐term antigen‐specific responses overcome immunosuppressive microenvironment. subcutaneous orthotopic murine colorectal models, (AH1‐CDA‐Co1)@iPDA inhibits growth prolongs survival without recurrence. also recurrence postoperative colonrectal model lymph node metastases. Taken together, demonstrates potent vaccine for colon cancer immunotherapy.

Language: Английский

Citations

0