Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
Associated disease: respiratory infections [ICD11:
CA45 
];
infection due to Bordetella bronchiseptica [ICD11:
XN173 ]
NCBI PubMed ID: 34053396Publication DOI: 10.1080/21505594.2021.1929037Journal NLM ID: 101531386Publisher: Philadelphia, PA: Taylor & Francis
Correspondence: j.p.m.tommassen
uu.nl
Institutions: Section Molecular Microbiology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands, Institute of Biomembranes, Utrecht University, Utrecht, The Netherlands, Section of Molecular Host Defense, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
Whole-cell vaccines against Gram-negative bacteria commonly display high reactogenicity caused by the endotoxic activity of lipopolysaccharide (LPS), one of the major components of the bacterial outer membrane. Underacylation of the lipid A moiety of LPS has been related with reduced endotoxicity in several Gram-negative species. Here, we evaluated whether the inactivation of two genes encoding lipid A acylases of Bordetella bronchiseptica, i.e. pagP and lpxL1, could be used for the development of less reactogenic vaccines against this pathogen for livestock and companion animals. Inactivation of pagP resulted in the loss of the secondary palmitate chain at position 3' of lipid A, but hardly affected the potency of the LPS to activate the Toll-like receptor 4 (TLR4). Inactivation of lpxL1 resulted in the loss of the secondary 2-hydroxy laurate group present at position 2 of lipid A and, unexpectedly, in the additional loss of the glucosamines that decorate the phosphate groups at positions 1 and 4' and in an increase in LPS molecules carrying O-antigen. The resulting LPS showed greatly reduced potency to activate TLR4 in HEK-Blue reporter cells expressing human or mouse TLR4 as well as in porcine macrophages. Characterization of the lpxL1 mutant revealed many pleiotropic phenotypes, including increased resistance to SDS and rifampicin, increased susceptibility to cationic antimicrobial peptides, decreased auto-aggregation and biofilm formation, and a tendency to decreased infectivity of macrophages, which are all related to the altered LPS structure. We suggest that the lpxL1 mutant will be useful for the generation of safer vaccines.
LPS, lipid A, Bordetella, vaccine, biofilms, PagP, TLR4, endotoxicity, antimicrobial susceptibility, autoaggregation, LpxL1
Structure type: oligomer
Location inside paper: Fig. 1
Compound class: lipid A
Contained glycoepitopes: IEDB_141181,IEDB_141807,IEDB_151531,IEDB_176772
Methods: PCR, SDS-PAGE, DNA techniques, ELISA, HPLC, LC-MS, cytokine production, TLR4 activation assay
Enzymes that release or process the structure: PagP, LpxL2, LpxL1 (acyl transferases)
NCBI Taxonomy refs (TaxIDs): 518
Show glycosyltransferases
There is only one chemically distinct structure:
Found 
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