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Structure type: oligomer
Compound class: lipid A
Contained glycoepitopes: IEDB_135394,IEDB_135515,IEDB_141807,IEDB_151531,IEDB_176772

• Article ID: 5725
  Arenas J, Pupo E, Phielix C, David D, Zariri A, Zamyatina A, Tommassen J, van der Ley P "Shortening the Lipid A Acyl Chains of Bordetella pertussis Enables Depletion of Lipopolysaccharide Endotoxic Activity" - Vaccine 8(4) (2020) 594
  

  Whooping cough, or pertussis, is an acute respiratory infectious disease caused by the Gram-negative bacterium Bordetella pertussis. Whole-cell vaccines, which were introduced in the fifties of the previous century and proved to be effective, showed considerable reactogenicity and were replaced by subunit vaccines around the turn of the century. However, there is a considerable increase in the number of cases in industrialized countries. A possible strategy to improve vaccine-induced protection is the development of new, non-toxic, whole-cell pertussis vaccines. The reactogenicity of whole-cell pertussis vaccines is, to a large extent, derived from the lipid A moiety of the lipopolysaccharides (LPS) of the bacteria. Here, we engineered B. pertussis strains with altered lipid A structures by expressing genes for the acyltransferases LpxA, LpxD, and LpxL from other bacteria resulting in altered acyl-chain length at various positions. Whole cells and extracted LPS from the strains with shorter acyl chains showed reduced or no activation of the human Toll-like receptor 4 in HEK-Blue reporter cells, whilst a longer acyl chain increased activation. Pyrogenicity studies in rabbits confirmed the in vitro assays. These findings pave the way for the development of a new generation of whole-cell pertussis vaccines with acceptable side effects.

  LPS, Bordetella pertussis, endotoxin, lipid A engineering, reactogenicity, whole-cell vaccine

  NCBI PubMed ID: 33050234
  Publication DOI: 10.3390/vaccines8040594
  Journal NLM ID: 8406899
  Publisher: Elsevier
  Correspondence: Jesús Arenas
  Institutions: Department of Molecular Microbiology and Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands, Unit of Microbiology and Immunology, Faculty of Veterinary, University of Zaragoza, 500017 Zaragoza, Spain, Institute for Translational Vaccinology (Intravacc), 3721 MA Bilthoven, The Netherlands, Department of Chemistry, University of Natural Resources and Life Sciences, 1190 Vienna, Austria
  Methods: PCR, DNA sequencing, ESI-MS, Western blotting, biological assays, genetic methods, statistical analysis
  
   
  
  Bordetella pertussis B213-pLpxD(Pa)
  CSDB ID 3263 (all data & tools)
• Article ID: 6082
  Kawahara K "Variation, Modification and Engineering of Lipid A in Endotoxin of Gram-Negative Bacteria" - International Journal of Molecular Sciences 22(5) (2021) 2281
  

  Lipid A of Gram-negative bacteria is known to represent a central role for the immunological activity of endotoxin. Chemical structure and biosynthetic pathways as well as specific receptors on phagocytic cells had been clarified by the beginning of the 21st century. Although the lipid A of enterobacteria including Escherichia coli share a common structure, other Gram-negative bacteria belonging to various classes of the phylum Proteobacteria and other taxonomical groups show wide variety of lipid A structure with relatively decreased endotoxic activity compared to that of E. coli. The structural diversity is produced from the difference of chain length of 3-hydroxy fatty acids and non-hydroxy fatty acids linked to their hydroxyl groups. In some bacteria, glucosamine in the backbone is substituted by another amino sugar, or phosphate groups bound to the backbone are modified. The variation of structure is also introduced by the enzymes that can modify electrostatic charges or acylation profiles of lipid A during or after its synthesis. Furthermore, lipid A structure can be artificially modified or engineered by the disruption and introduction of biosynthetic genes especially those of acyltransferases. These technologies may produce novel vaccine adjuvants or antagonistic drugs derived from endotoxin in the future.

  Lipopolysaccharide, lipid A, endotoxin, chemical structure, fatty acid, engineering

  NCBI PubMed ID: 33668925
  Publication DOI: 10.3390/ijms22052281
  Journal NLM ID: 101092791
  Publisher: Basel, Switzerland: MDPI
  Correspondence: kawahara@kanto-gakuin.ac.jp
  Institutions: Department of Biosciences, College of Science and Engineering, Kanto Gakuin University, Yokohama, Kanagawa 236-8501, Japan
  
   
  
  Bordetella pertussis * Pseudomonas aeruginosa
  CSDB ID 5868 (all data & tools)