Shortening the Lipid A Acyl Chains of Bordetella pertussis Enables Depletion of Lipopolysaccharide Endotoxic Activity

被引:16
作者
Arenas, Jesus [1 ,2 ,3 ]
Pupo, Elder [4 ]
Phielix, Coen [4 ]
David, Dionne [4 ]
Zariri, Afshin [4 ]
Zamyatina, Alla [5 ]
Tommassen, Jan [1 ,2 ]
van der Ley, Peter [4 ]
机构
[1] Univ Utrecht, Dept Mol Microbiol, NL-3584 CH Utrecht, Netherlands
[2] Univ Utrecht, Inst Biomembranes, NL-3584 CH Utrecht, Netherlands
[3] Univ Zaragoza, Unit Microbiol & Immunol, Fac Vet, Zaragoza 500017, Spain
[4] Inst Translat Vaccinol Intravacc, NL-3721 MA Bilthoven, Netherlands
[5] Univ Nat Resources & Life Sci, Dept Chem, A-1190 Vienna, Austria
基金
奥地利科学基金会;
关键词
Bordetella pertussis; LPS; lipid A engineering; endotoxin; whole-cell vaccine; reactogenicity; TOLL-LIKE RECEPTOR; STRUCTURAL BASIS; BACTERIAL LIPOPOLYSACCHARIDES; LIPOOLIGOSACCHARIDE STRUCTURE; MOLECULAR-CLONING; ESCHERICHIA-COLI; HUMAN MD-2; ACTIVATION; EXPRESSION; MIMETICS;
D O I
10.3390/vaccines8040594
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:1 / 20
页数:20
相关论文
共 62 条
[1]   Development of αGlcN(1⇆1)αMan-Based Lipid A Mimetics as a Novel Class of Potent Toll-like Receptor 4 Agonists [J].
Adanitsch, Florian ;
Ittig, Simon ;
Stoeckl, Johannes ;
Oblak, Alja ;
Haegman, Mira ;
Jerala, Roman ;
Beyaert, Rudi ;
Kosma, Paul ;
Zamyatina, Alla .
JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (19) :8056-8071
[2]   Human MD-2 confers on mouse Toll-like receptor 4 species-specific lipopolysaccharide recognition [J].
Akashi, S ;
Nagai, Y ;
Ogata, H ;
Oikawa, M ;
Fukase, K ;
Kusumoto, S ;
Kawasaki, K ;
Nishijima, M ;
Hayashi, S ;
Kimoto, M ;
Miyake, K .
INTERNATIONAL IMMUNOLOGY, 2001, 13 (12) :1595-1599
[3]  
Alexander C, 2001, J ENDOTOXIN RES, V7, P167, DOI 10.1177/09680519010070030101
[4]   Substrate specificity of the pyrophosphohydrolase LpxH determines the asymmetry of Bordetella pertussis lipid A [J].
Arenas, Jesus ;
Pupo, Elder ;
de Jonge, Eline ;
Perez-Ortega, Jesus ;
Schaarschmidt, Joerg ;
van der Ley, Peter ;
Tommassen, Jan .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2019, 294 (20) :7982-7989
[5]   Expression of the Gene for Autotransporter AutB of Neisseria meningitidis Affects Biofilm Formation and Epithelial Transmigration [J].
Arenas, Jesus ;
Paganelli, Fernanda L. ;
Rodriguez-Castano, Patricia ;
Cano-Crespo, Sara ;
van der Ende, Arie ;
van Putten, Jos P. M. ;
Tommassen, Jan .
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, 2016, 6
[6]   The meningococcal autotransporter AutA is implicated in autoaggregation and biofilm formation [J].
Arenas, Jesus ;
Cano, Sara ;
Nijland, Reindert ;
van Dongen, Verene ;
Rutten, Lucy ;
van der Ende, Arie ;
Tommassen, Jan .
ENVIRONMENTAL MICROBIOLOGY, 2015, 17 (04) :1321-1337
[7]  
Arenas Jesus, 2012, Endocrine Metabolic & Immune Disorders-Drug Targets, V12, P221
[8]   Conformationally Constrained Lipid A Mimetics for Exploration of Structural Basis of TLR4/MD-2 Activation by Lipopolysaccharide [J].
Artner, Daniel ;
Oblak, Alja ;
Ittig, Simon ;
Garate, Jose Antonio ;
Horvat, Simon ;
Arrieumerlou, Cecile ;
Hofinger, Andreas ;
Oostenbrink, Chris ;
Jerala, Roman ;
Kosma, Paul ;
Zamyatina, Alla .
ACS CHEMICAL BIOLOGY, 2013, 8 (11) :2423-2432
[9]   Complete Genome Sequences of Bordetella pertussis Isolates B1917 and B1920, Representing Two Predominant Global Lineages [J].
Bart, Marieke J. ;
Zeddeman, Anne ;
van der Heide, Han G. J. ;
Heuvelman, Kees ;
van Gent, Marjolein ;
Mooi, Frits R. .
GENOME ANNOUNCEMENTS, 2014, 2 (06)
[10]   Crystal Structure and Acyl Chain Selectivity of Escherichia coli LpxD, the N-Acyltransferase of Lipid A Biosynthesis [J].
Bartling, Craig M. ;
Raetz, Christian R. H. .
BIOCHEMISTRY, 2009, 48 (36) :8672-8683