ArticleThe Journal of biological chemistry2014
Modulation of endotoxicity of Shigella generalized modules for membrane antigens (GMMA) by genetic lipid A modifications: relative activation of TLR4 and TLR2 pathways in different mutants.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 99 citations in OpenAlex.
- Engineered Bacterial Membranes as Next-Generation Platforms for Cancer Immunotherapy.Small science · 2026Review
- Bacterial extracellular vesicles as central mediators of microbiota-host communication.Frontiers in microbiology · 2026Review
- Microbial extracellular vesicles in the lung: friends in health, agents in disease.Extracellular vesicles and circulating nucleic acids · 2026Review
- Tiny packages, big potential: bacterial membrane vesicles in vaccinology.Microbial cell factories · 2025Review
- Article
- Development of a Promising Bivalent Vaccine AgainstExploration (Beijing, China) · 2025Article
- Generalized Modules for Membrane Antigens (GMMA) Elicit Mild Local Reactogenicity After Intramuscular Injection in Absence of Aluminum Salt Adjuvant.Immunity, inflammation and disease · 2025Article
- Characterization ofApplied and environmental microbiology · 2025Article
- Bioengineering Outer-Membrane Vesicles for Vaccine Development: Strategies, Advances, and Perspectives.Vaccines · 2025Review
- A novel GMMA-based gonococcal vaccine demonstrates functional immune responses in mice.NPJ vaccines · 2025Article
- BECC-engineered live-attenuated Shigella vaccine candidates display reduced endotoxicity with robust immunogenicity in mice.Vaccine · 2025Article
- Exploration of a GMMA-Based Bivalent Vaccine AgainstVaccines · 2025Article
- GMMA-based vaccine candidates against invasive nontyphoidal salmonellosis elicit bactericidal antibodies against a panel of epidemiologically relevantFrontiers in immunology · 2025Article
- Construction and Characterization of an lpxM-DeficientInfection and drug resistance · 2025Article
- Immune Responses Elicited by Outer Membrane Vesicles of Gram-Negative Bacteria: Important Players in Vaccine Development.Life (Basel, Switzerland) · 2024Review
- BECC-engineered live-attenuatedResearch square · 2024Article
- Quality by Design Framework Applied to GMMA Purification.The AAPS journal · 2024Article
- Putative correlates of protection against shigellosis assessing immunomarkers across responses to S. sonnei investigational vaccine.NPJ vaccines · 2024Article
- Molecular Signature of Monocytes Shaped by theInternational journal of molecular sciences · 2024Article
- Outer Membrane Vesicle Vaccine Platforms.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024Review
7 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Outer membrane particles from Gram-negative bacteria are attractive vaccine candidates as they present surface antigens in their natural context. We previously developed a high yield production process for genetically derived particles, called generalized modules for membrane antigens (GMMA), from Shigella. As GMMA are derived from the outer membrane, they contain immunostimulatory components, especially lipopolysaccharide (LPS). We examined ways of reducing their reactogenicity by modifying lipid A, the endotoxic part of LPS, through deletion of late acyltransferase genes, msbB or htrB, in GMMA-producing Shigella sonnei and Shigella flexneri strains. GMMA with resulting penta-acylated lipid A from the msbB mutants showed a 600-fold reduced ability, and GMMA from the S. sonnei ΔhtrB mutant showed a 60,000-fold reduced ability compared with GMMA with wild-type lipid A to stimulate human Toll-like receptor 4 (TLR4) in a reporter cell line. In human peripheral blood mononuclear cells, GMMA with penta-acylated lipid A showed a marked reduction in induction of inflammatory cytokines (S. sonnei ΔhtrB, 800-fold; ΔmsbB mutants, 300-fold). We found that the residual activity of these GMMA is largely due to non-lipid A-related TLR2 activation. In contrast, in the S. flexneri ΔhtrB mutant, a compensatory lipid A palmitoleoylation resulted in GMMA with hexa-acylated lipid A with ∼10-fold higher activity to stimulate peripheral blood mononuclear cells than GMMA with penta-acylated lipid A, mostly due to retained TLR4 activity. Thus, for use as vaccines, GMMA will likely require lipid A penta-acylation. The results identify the relative contributions of TLR4 and TLR2 activation by GMMA, which need to be taken into consideration for GMMA vaccine development.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.