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Open AccessArticle

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

1
Department of Molecular Microbiology and Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands
2
Unit of Microbiology and Immunology, Faculty of Veterinary, University of Zaragoza, 500017 Zaragoza, Spain
3
Institute for Translational Vaccinology (Intravacc), 3721 MA Bilthoven, The Netherlands
4
Department of Chemistry, University of Natural Resources and Life Sciences, 1190 Vienna, Austria
*
Author to whom correspondence should be addressed.
P.v.d.L. and J.T. contributed equally to this work.
Vaccines 2020, 8(4), 594; https://doi.org/10.3390/vaccines8040594
Received: 28 August 2020 / Revised: 27 September 2020 / Accepted: 29 September 2020 / Published: 9 October 2020
(This article belongs to the Special Issue Next-Generation Pertussis Vaccines)
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. View Full-Text
Keywords: Bordetella pertussis; LPS; lipid A engineering; endotoxin; whole-cell vaccine; reactogenicity Bordetella pertussis; LPS; lipid A engineering; endotoxin; whole-cell vaccine; reactogenicity
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MDPI and ACS Style

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. Vaccines 2020, 8, 594.

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