Programming Bordetella pertussis lipid A to promote adjuvanticity.
Lipid A
/ analogs & derivatives
Bordetella pertussis
/ immunology
Humans
Toll-Like Receptor 4
/ metabolism
Adjuvants, Immunologic
/ pharmacology
Adaptor Proteins, Vesicular Transport
/ metabolism
Pertussis Vaccine
/ immunology
Lipopolysaccharides
Interferon Regulatory Factor-3
/ metabolism
Whooping Cough
/ prevention & control
Interleukin-6
/ metabolism
Bordetella pertussis
Adjuvant
Lipid A modification
Lipopolysaccharide
MPLA
Vaccine
Journal
Microbial cell factories
ISSN: 1475-2859
Titre abrégé: Microb Cell Fact
Pays: England
ID NLM: 101139812
Informations de publication
Date de publication:
14 Sep 2024
14 Sep 2024
Historique:
received:
18
06
2024
accepted:
31
08
2024
medline:
14
9
2024
pubmed:
14
9
2024
entrez:
13
9
2024
Statut:
epublish
Résumé
Bordetella pertussis is the causative agent of whooping cough or pertussis. Although both acellular (aP) and whole-cell pertussis (wP) vaccines protect against disease, the wP vaccine, which is highly reactogenic, is better at preventing colonization and transmission. Reactogenicity is mainly attributed to the lipid A moiety of B. pertussis lipooligosaccharide (LOS). Within LOS, lipid A acts as a hydrophobic anchor, engaging with TLR4-MD2 on host immune cells to initiate both MyD88-dependent and TRIF-dependent pathways, thereby influencing adaptive immune responses. Lipid A variants, such as monophosphoryl lipid A (MPLA) can also act as adjuvants. Adjuvants may overcome the shortcomings of aP vaccines. This work used lipid A modifying enzymes from other bacteria to produce an MPLA-like adjuvant strain in B. pertussis. We created B. pertussis strains with distinct lipid A modifications, which were validated using MALDI-TOF. We engineered a hexa-acylated monophosphorylated lipid A that markedly decreased human TLR4 activation and activated the TRIF pathway. The modified lipooligosaccharide (LOS) promoted IRF3 phosphorylation and type I interferon production, similar to MPLA responses. We generated three other variants with increased adjuvanticity properties and reduced endotoxicity. Pyrogenicity studies using the Monocyte Activation Test (MAT) revealed that these four lipid A variants significantly decreased the IL-6, a marker for fever, response in peripheral blood mononuclear cells (PBMCs). These findings pave the way for developing wP vaccines that are possibly less reactogenic and designing adaptable adjuvants for current vaccine formulations, advancing more effective immunization strategies against pertussis.
Sections du résumé
BACKGROUND
BACKGROUND
Bordetella pertussis is the causative agent of whooping cough or pertussis. Although both acellular (aP) and whole-cell pertussis (wP) vaccines protect against disease, the wP vaccine, which is highly reactogenic, is better at preventing colonization and transmission. Reactogenicity is mainly attributed to the lipid A moiety of B. pertussis lipooligosaccharide (LOS). Within LOS, lipid A acts as a hydrophobic anchor, engaging with TLR4-MD2 on host immune cells to initiate both MyD88-dependent and TRIF-dependent pathways, thereby influencing adaptive immune responses. Lipid A variants, such as monophosphoryl lipid A (MPLA) can also act as adjuvants. Adjuvants may overcome the shortcomings of aP vaccines.
RESULTS
RESULTS
This work used lipid A modifying enzymes from other bacteria to produce an MPLA-like adjuvant strain in B. pertussis. We created B. pertussis strains with distinct lipid A modifications, which were validated using MALDI-TOF. We engineered a hexa-acylated monophosphorylated lipid A that markedly decreased human TLR4 activation and activated the TRIF pathway. The modified lipooligosaccharide (LOS) promoted IRF3 phosphorylation and type I interferon production, similar to MPLA responses. We generated three other variants with increased adjuvanticity properties and reduced endotoxicity. Pyrogenicity studies using the Monocyte Activation Test (MAT) revealed that these four lipid A variants significantly decreased the IL-6, a marker for fever, response in peripheral blood mononuclear cells (PBMCs).
CONCLUSION
CONCLUSIONS
These findings pave the way for developing wP vaccines that are possibly less reactogenic and designing adaptable adjuvants for current vaccine formulations, advancing more effective immunization strategies against pertussis.
Identifiants
pubmed: 39272136
doi: 10.1186/s12934-024-02518-7
pii: 10.1186/s12934-024-02518-7
doi:
Substances chimiques
Lipid A
0
Toll-Like Receptor 4
0
Adjuvants, Immunologic
0
monophosphoryl lipid A
MWC0ET1L2P
TLR4 protein, human
0
Adaptor Proteins, Vesicular Transport
0
Pertussis Vaccine
0
lipid-linked oligosaccharides
0
Lipopolysaccharides
0
Interferon Regulatory Factor-3
0
TICAM1 protein, human
0
Interleukin-6
0
IRF3 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
250Subventions
Organisme : Michael Smith Health Research BC
ID : RT-2021-1655
Organisme : CIHR
ID : PG-53242
Pays : Canada
Informations de copyright
© 2024. The Author(s).
Références
Melvin JA, et al. Bordetella pertussis pathogenesis: current and future challenges. Nat Rev Microbiol. 2014;12(4):274–88.
pubmed: 24608338
pmcid: 4205565
doi: 10.1038/nrmicro3235
Mohamed YF, Manivannan K, Fernandez RC. Bordetella pertussis. Trends Microbiol; 2023.
Fullen AR, et al. Whoop! There it is: the surprising resurgence of pertussis. PLoS Pathog. 2020;16(7):e1008625.
pubmed: 32702023
pmcid: 7377359
doi: 10.1371/journal.ppat.1008625
Esposito S, et al. Pertussis Prevention: reasons for resurgence, and differences in the current Acellular Pertussis vaccines. Front Immunol. 2019;10:1344.
pubmed: 31333640
pmcid: 6616129
doi: 10.3389/fimmu.2019.01344
Belcher T, et al. Pathogenicity and virulence of Bordetella pertussis and its adaptation to its strictly human host. Virulence. 2021;12(1):2608–32.
pubmed: 34590541
pmcid: 8489951
doi: 10.1080/21505594.2021.1980987
Cherry JD. The 112-Year odyssey of Pertussis and Pertussis vaccines-mistakes made and implications for the future. J Pediatr Infect Dis Soc. 2019;8(4):334–41.
doi: 10.1093/jpids/piz005
Preston A, Maskell DJ. A new era of research into Bordetella pertussis pathogenesis. J Infect. 2002;44(1):13–6.
pubmed: 11972412
doi: 10.1053/jinf.2001.0933
Locht C, Mielcarek N. New pertussis vaccination approaches: en route to protect newborns? FEMS Immunol Med Microbiol. 2012;66(2):121–33.
pubmed: 22574832
doi: 10.1111/j.1574-695X.2012.00988.x
Ausiello CM, Cassone A. Acellular pertussis vaccines and pertussis resurgence: revise or replace? MBio. 2014;5(3):e01339–14.
pubmed: 24917600
pmcid: 4056554
doi: 10.1128/mBio.01339-14
Saso A, Kampmann B, Roetynck S. Vaccine-Induced Cellular immunity against Bordetella pertussis: harnessing lessons from Animal and Human studies to improve design and testing of Novel Pertussis vaccines. Vaccines (Basel), 2021. 9(8).
Althouse BM, Scarpino SV. Asymptomatic transmission and the resurgence of Bordetella pertussis. BMC Med. 2015;13:146.
pubmed: 26103968
pmcid: 4482312
doi: 10.1186/s12916-015-0382-8
Warfel JM, Zimmerman LI, Merkel TJ. Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model. Proc Natl Acad Sci U S A. 2014;111(2):787–92.
pubmed: 24277828
doi: 10.1073/pnas.1314688110
Brummelman J, et al. Roads to the development of improved pertussis vaccines paved by immunology. Pathog Dis. 2015;73(8):ftv067.
pubmed: 26347400
pmcid: 4626578
doi: 10.1093/femspd/ftv067
Nikaido H. Molecular basis of bacterial outer membrane permeability revisited. Microbiol Mol Biol Rev. 2003;67(4):593–656.
pubmed: 14665678
pmcid: 309051
doi: 10.1128/MMBR.67.4.593-656.2003
Beutler B. TLR4 as the mammalian endotoxin sensor. Curr Top Microbiol Immunol. 2002;270:109–20.
pubmed: 12467247
Park BS, Lee JO. Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp Mol Med. 2013;45:e66.
pubmed: 24310172
pmcid: 3880462
doi: 10.1038/emm.2013.97
Maeshima N, Fernandez RC. Recognition of lipid A variants by the TLR4-MD-2 receptor complex. Front Cell Infect Microbiol. 2013;3:3.
pubmed: 23408095
pmcid: 3569842
doi: 10.3389/fcimb.2013.00003
Mata-Haro V, et al. The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science. 2007;316(5831):1628–32.
pubmed: 17569868
doi: 10.1126/science.1138963
Hu W, et al. Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation. Proc Natl Acad Sci U S A. 2015;112(45):13994–9.
pubmed: 26508631
pmcid: 4653191
doi: 10.1073/pnas.1510760112
Santini SM, et al. Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell development and activity in vitro and in Hu-PBL-SCID mice. J Exp Med. 2000;191(10):1777–88.
pubmed: 10811870
pmcid: 2193160
doi: 10.1084/jem.191.10.1777
Allen A, Maskell D. The identification, cloning and mutagenesis of a genetic locus required for lipopolysaccharide biosynthesis in Bordetella pertussis. Mol Microbiol. 1996;19(1):37–52.
pubmed: 8821935
doi: 10.1046/j.1365-2958.1996.354877.x
Preston A, Maskell D. The molecular genetics and role in infection of lipopolysaccharide biosynthesis in the Bordetellae. J Endotoxin Res. 2001;7(4):251–61.
pubmed: 11717578
Marr N, et al. Substitution of the Bordetella pertussis lipid a phosphate groups with glucosamine is required for robust NF-kappaB activation and release of proinflammatory cytokines in cells expressing human but not murine toll-like receptor 4-MD-2-CD14. Infect Immun. 2010;78(5):2060–9.
pubmed: 20176798
pmcid: 2863497
doi: 10.1128/IAI.01346-09
Needham BD, et al. Modulating the innate immune response by combinatorial engineering of endotoxin. Proc Natl Acad Sci U S A. 2013;110(4):1464–9.
pubmed: 23297218
pmcid: 3557076
doi: 10.1073/pnas.1218080110
Casella CR, Mitchell TC. Putting endotoxin to work for us: monophosphoryl lipid A as a safe and effective vaccine adjuvant. Cell Mol Life Sci. 2008;65(20):3231–40.
pubmed: 18668203
pmcid: 2647720
doi: 10.1007/s00018-008-8228-6
Romerio A, Peri F. Increasing the Chemical Variety of small-molecule-based TLR4 modulators: an overview. Front Immunol. 2020;11:1210.
pubmed: 32765484
pmcid: 7381287
doi: 10.3389/fimmu.2020.01210
Weaver KL, et al. Long-term analysis of Pertussis Vaccine Immunity to identify potential markers of Vaccine-Induced Memory Associated with whole cell but not acellular pertussis immunization in mice. Front Immunol. 2022;13:838504.
pubmed: 35211125
pmcid: 8861382
doi: 10.3389/fimmu.2022.838504
Shah NR, et al. Minor modifications to the phosphate groups and the C3’ acyl chain length of lipid A in two Bordetella pertussis strains, BP338 and 18–323, independently affect toll-like receptor 4 protein activation. J Biol Chem. 2013;288(17):11751–60.
pubmed: 23467413
pmcid: 3636864
doi: 10.1074/jbc.M112.434365
Schulke S, et al. A Fusion protein consisting of the vaccine adjuvant monophosphoryl lipid A and the Allergen Ovalbumin boosts allergen-specific Th1, Th2, and Th17 responses in Vitro. J Immunol Res. 2016;2016:4156456.
pubmed: 27340679
pmcid: 4908266
doi: 10.1155/2016/4156456
Bishop RE, et al. Transfer of palmitate from phospholipids to lipid A in outer membranes of gram-negative bacteria. EMBO J. 2000;19(19):5071–80.
pubmed: 11013210
pmcid: 302101
doi: 10.1093/emboj/19.19.5071
Geurtsen J, et al. Expression of the lipopolysaccharide-modifying enzymes PagP and PagL modulates the endotoxic activity of Bordetella pertussis. Infect Immun. 2006;74(10):5574–85.
pubmed: 16988232
pmcid: 1594925
doi: 10.1128/IAI.00834-06
Preston A, et al. Bordetella bronchiseptica PagP is a bvg-regulated lipid a palmitoyl transferase that is required for persistent colonization of the mouse respiratory tract. Mol Microbiol. 2003;48(3):725–36.
pubmed: 12694617
doi: 10.1046/j.1365-2958.2003.03484.x
Needham BD, Trent MS. Fortifying the barrier: the impact of lipid a remodelling on bacterial pathogenesis. Nat Rev Microbiol. 2013;11(7):467–81.
pubmed: 23748343
pmcid: 6913092
doi: 10.1038/nrmicro3047
Wang X, et al. MsbA transporter-dependent lipid A 1-dephosphorylation on the periplasmic surface of the inner membrane: topography of francisella novicida LpxE expressed in Escherichia coli. J Biol Chem. 2004;279(47):49470–8.
pubmed: 15339914
doi: 10.1074/jbc.M409078200
Bishop RE. The lipid a palmitoyltransferase PagP: molecular mechanisms and role in bacterial pathogenesis. Mol Microbiol. 2005;57(4):900–12.
pubmed: 16091033
doi: 10.1111/j.1365-2958.2005.04711.x
Raetz CR, et al. Lipid A modification systems in gram-negative bacteria. Annu Rev Biochem. 2007;76:295–329.
pubmed: 17362200
pmcid: 2569861
doi: 10.1146/annurev.biochem.76.010307.145803
Geurtsen J, et al. Dissemination of lipid A deacylases (pagL) among gram-negative bacteria: identification of active-site histidine and serine residues. J Biol Chem. 2005;280(9):8248–59.
pubmed: 15611102
doi: 10.1074/jbc.M414235200
Simpson BW, Trent MS. Pushing the envelope: LPS modifications and their consequences. Nat Rev Microbiol. 2019;17(7):403–16.
pubmed: 31142822
pmcid: 6913091
doi: 10.1038/s41579-019-0201-x
El Hamidi A, et al. Microextraction of bacterial lipid A: easy and rapid method for mass spectrometric characterization. J Lipid Res. 2005;46(8):1773–8.
pubmed: 15930524
doi: 10.1194/jlr.D500014-JLR200
Marr N, et al. Variability in the lipooligosaccharide structure and endotoxicity among Bordetella pertussis strains. J Infect Dis. 2010;202(12):1897–906.
pubmed: 21050116
doi: 10.1086/657409
Bolourani S, Brenner M, Wang P. The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis. J Mol Med (Berl). 2021;99(10):1373–84.
pubmed: 34258628
doi: 10.1007/s00109-021-02113-y
Arenas J et al. Shortening the lipid A acyl chains of Bordetella pertussis enables depletion of Lipopolysaccharide Endotoxic Activity. Vaccines (Basel), 2020. 8(4).
Pilz A, et al. Phosphorylation of the Stat1 transactivating domain is required for the response to type I interferons. EMBO Rep. 2003;4(4):368–73.
pubmed: 12671680
pmcid: 1319158
doi: 10.1038/sj.embor.embor802
Facchini FA, et al. Synthetic glycolipids as Molecular Vaccine adjuvants: mechanism of action in human cells and in vivo activity. J Med Chem. 2021;64(16):12261–72.
pubmed: 34382796
pmcid: 8404200
doi: 10.1021/acs.jmedchem.1c00896
Oliver D, Fernandez RC. Unpublished observations.
Nilsberth C, et al. The role of interleukin-6 in lipopolysaccharide-induced fever by mechanisms independent of prostaglandin E2. Endocrinology. 2009;150(4):1850–60.
pubmed: 19022895
doi: 10.1210/en.2008-0806
Fernandez RC, Weiss AA. Serum resistance in bvg-regulated mutants of Bordetella pertussis. FEMS Microbiol Lett. 1998;163(1):57–63.
pubmed: 9631546
doi: 10.1111/j.1574-6968.1998.tb13026.x
Finn TM, Stevens LA. Tracheal colonization factor: a Bordetella pertussis secreted virulence determinant. Mol Microbiol. 1995;16(4):625–34.
pubmed: 7476158
doi: 10.1111/j.1365-2958.1995.tb02425.x
Wang YQ, et al. MPL Adjuvant contains competitive antagonists of human TLR4. Front Immunol. 2020;11:577823.
pubmed: 33178204
pmcid: 7596181
doi: 10.3389/fimmu.2020.577823
Bosshart H, Heinzelmann M. THP-1 cells as a model for human monocytes. Ann Transl Med. 2016;4(21):438.
pubmed: 27942529
pmcid: 5124613
doi: 10.21037/atm.2016.08.53
Lin A, et al. Live attenuated pertussis vaccine BPZE1 induces a broad antibody response in humans. J Clin Invest. 2020;130(5):2332–46.
pubmed: 31945015
pmcid: 7190984
doi: 10.1172/JCI135020
Debrie AS, et al. Construction and evaluation of Bordetella pertussis live attenuated vaccine strain BPZE1 producing Fim3. Vaccine. 2018;36(11):1345–52.
pubmed: 29433898
doi: 10.1016/j.vaccine.2018.02.017
Dunne A, et al. A novel TLR2 agonist from Bordetella pertussis is a potent adjuvant that promotes protective immunity with an acellular pertussis vaccine. Mucosal Immunol. 2015;8(3):607–17.
pubmed: 25315966
doi: 10.1038/mi.2014.93
Jiang W, et al. Intranasal Immunization with a c-di-GMP-Adjuvanted Acellular Pertussis Vaccine provides Superior Immunity against Bordetella pertussis in a mouse model. Front Immunol. 2022;13:878832.
pubmed: 35493458
pmcid: 9043693
doi: 10.3389/fimmu.2022.878832
Stainer DW, Scholte MJ. A simple chemically defined medium for the production of phase I Bordetella pertussis. J Gen Microbiol. 1970;63(2):211–20.
pubmed: 4324651
doi: 10.1099/00221287-63-2-211
Weiss AA, et al. Characterization of human bactericidal antibodies to Bordetella pertussis. Infect Immun. 1999;67(3):1424–31.
pubmed: 10024590
pmcid: 96476
doi: 10.1128/IAI.67.3.1424-1431.1999
Li C, et al. FastCloning: a highly simplified, purification-free, sequence- and ligation-independent PCR cloning method. BMC Biotechnol. 2011;11:92.
pubmed: 21992524
pmcid: 3207894
doi: 10.1186/1472-6750-11-92
Cohen SN, Chang AC, Hsu L. Nonchromosomal antibiotic resistance in bacteria: genetic transformation of Escherichia coli by R-factor DNA. Proc Natl Acad Sci U S A. 1972;69(8):2110–4.
pubmed: 4559594
pmcid: 426879
doi: 10.1073/pnas.69.8.2110
Ifill G, et al. RNase III and RNase E influence Posttranscriptional Regulatory Networks involved in virulence factor production, metabolism, and Regulatory RNA Processing in Bordetella pertussis. mSphere. 2021;6(4):e0065021.
pubmed: 34406853
doi: 10.1128/mSphere.00650-21
Marolda CL, et al. Micromethods for the characterization of lipid A-core and O-antigen lipopolysaccharide. Methods Mol Biol. 2006;347:237–52.
pubmed: 17072014
de Jonge EF, et al. Heat shock enhances outer-membrane vesicle release in Bordetella spp. Curr Res Microb Sci. 2021;2:100009.
pubmed: 34841303
Lee CH, Tsai CM. Quantification of bacterial lipopolysaccharides by the purpald assay: measuring formaldehyde generated from 2-keto-3-deoxyoctonate and heptose at the inner core by periodate oxidation. Anal Biochem. 1999;267(1):161–8.
pubmed: 9918668
doi: 10.1006/abio.1998.2961
Solati S, et al. An improved monocyte activation test using cryopreserved pooled human mononuclear cells. Innate Immun. 2015;21(7):677–84.
pubmed: 25907070
doi: 10.1177/1753425915583365