New Chimeric TLR7/NOD2 Agonist is a Potent Adjuvant to Induce Mucosal Immune Responses

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2020 Aug 3

PMID 32739871

Citations 14

Authors

Alice Gutjahr

Laura Papagno

Fabienne Vernejoul

Thierry Lioux

Fabienne Jospin

Blandine Chanut

Eric Perouzel

Nicolas Rochereau

Victor Appay

Bernard Verrier

Stephane Paul

Affiliations

Soon will be listed here.

Abstract

Background: PRR (Pattern Recognition Receptor) agonists have been widely tested as potent vaccine adjuvants. TLR7 (Toll-Like Receptor 7) and NOD2 (nucleotide-binding oligomerization domain 2) are key innate receptors widely expressed at mucosal levels.

Methods: Here, we evaluated the immunostimulatory properties of a novel hybrid chemical compound designed to stimulate both TLR7 and NOD2 receptors.

Finding: The combined TLR7/NOD2 agonist showed increase efficacy than TLR7L or NOD2L agonists alone or combined in different in vitro models. Dual TLR7/NOD2 agonist efficiently stimulates TLR7 and NOD2, and promotes the maturation and reprogramming of human dendritic cells, as well as the secretion of pro-inflammatory or adaptive cytokines. This molecule also strongly induces autophagy in human cells which is a major intracellular degradation system that delivers cytoplasmic constituents to lysosomes in both MHC class I and II-restricted antigen presentation. In vivo, TLR7/NOD2L agonist is a potent adjuvant after intranasal administration with NP-p24 HIV vaccine, inducing high-quality humoral and adaptive responses both in systemic and mucosal compartments. Use of TLR7/NOD2L adjuvant improves very significantly the protection of mice against an intranasal challenge with a vaccinia virus expressing the p24.

Interpretation: Dual TLR7/NOD2L agonist is a very potent and versatile vaccine adjuvant and promote very efficiently both systemic and mucosal immunity.

Funding: This work was supported by Sidaction.

Citing Articles

Linker Chemistry and Connectivity Fine-Tune the Immune Response and Kinetic Solubility of Conjugated NOD2/TLR7 Agonists.

Janez S, Guzelj S, Jakopin Z Bioconjug Chem. 2024; 35(11):1723-1731.

PMID: 39388220 PMC: 11583123. DOI: 10.1021/acs.bioconjchem.4c00321.

Distinctive Immune Signatures Driven by Structural Alterations in Desmuramylpeptide NOD2 Agonists.

Janez S, Guzelj S, Kocbek P, de Vlieger E, Slutter B, Jakopin Z J Med Chem. 2024; 67(19):17585-17607.

PMID: 39344184 PMC: 11472310. DOI: 10.1021/acs.jmedchem.4c01577.

Synergistic Targeting of Innate Receptors TLR7 and NOD2 for Therapeutic Intervention in Multiple Sclerosis.

Dubik M, Marczynska-Grzelak J, Sorensen M, Dieu R, Rusin D, Schioth E Int J Mol Sci. 2024; 25(13).

PMID: 39000569 PMC: 11242768. DOI: 10.3390/ijms25137462.

TLR agonists as vaccine adjuvants in the prevention of viral infections: an overview.

Kayesh M, Kohara M, Tsukiyama-Kohara K Front Microbiol. 2024; 14:1249718.

PMID: 38179453 PMC: 10764465. DOI: 10.3389/fmicb.2023.1249718.

Poloxamers Have Vaccine-Adjuvant Properties by Increasing Dissemination of Particulate Antigen at Distant Lymph Nodes.

Lamrayah M, Phelip C, Rovera R, Coiffier C, Lazhar N, Bartolomei F Molecules. 2023; 28(12).

PMID: 37375333 PMC: 10304813. DOI: 10.3390/molecules28124778.

References

Lovgren T, Sarhan D, Truxova I, Choudhary B, Maas R, Melief J . Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists. Cancer Immunol Immunother. 2017; 66(10):1333-1344. PMC: 5626805. DOI: 10.1007/s00262-017-2029-4. View

Netea M, Ferwerda G, de Jong D, Jansen T, Jacobs L, Kramer M . Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release. J Immunol. 2005; 174(10):6518-23. DOI: 10.4049/jimmunol.174.10.6518. View

Boyaka P . Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems. J Immunol. 2017; 199(1):9-16. PMC: 5719502. DOI: 10.4049/jimmunol.1601775. View

Kornbluth R, Stone G . Immunostimulatory combinations: designing the next generation of vaccine adjuvants. J Leukoc Biol. 2006; 80(5):1084-102. DOI: 10.1189/jlb.0306147. View

Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan T . Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and.... J Clin Oncol. 2010; 29(3):330-6. PMC: 3056467. DOI: 10.1200/JCO.2010.30.7744. View

Takata H, Takiguchi M . Three memory subsets of human CD8+ T cells differently expressing three cytolytic effector molecules. J Immunol. 2006; 177(7):4330-40. DOI: 10.4049/jimmunol.177.7.4330. View

Gutjahr A, Tiraby G, Perouzel E, Verrier B, Paul S . Triggering Intracellular Receptors for Vaccine Adjuvantation. Trends Immunol. 2016; 37(10):716. DOI: 10.1016/j.it.2016.08.005. View

Geeraedts F, Goutagny N, Hornung V, Severa M, de Haan A, Pool J . Superior immunogenicity of inactivated whole virus H5N1 influenza vaccine is primarily controlled by Toll-like receptor signalling. PLoS Pathog. 2008; 4(8):e1000138. PMC: 2516931. DOI: 10.1371/journal.ppat.1000138. View

Gutjahr A, Papagno L, Nicoli F, Lamoureux A, Vernejoul F, Lioux T . Cutting Edge: A Dual TLR2 and TLR7 Ligand Induces Highly Potent Humoral and Cell-Mediated Immune Responses. J Immunol. 2017; 198(11):4205-4209. DOI: 10.4049/jimmunol.1602131. View

10.

Willinger T, Freeman T, Hasegawa H, McMichael A, Callan M . Molecular signatures distinguish human central memory from effector memory CD8 T cell subsets. J Immunol. 2005; 175(9):5895-903. DOI: 10.4049/jimmunol.175.9.5895. View

11.

McKee A, Marrack P . Old and new adjuvants. Curr Opin Immunol. 2017; 47:44-51. PMC: 5724967. DOI: 10.1016/j.coi.2017.06.005. View

12.

Xiang S, Scholzen A, Minigo G, David C, Apostolopoulos V, Mottram P . Pathogen recognition and development of particulate vaccines: does size matter?. Methods. 2006; 40(1):1-9. DOI: 10.1016/j.ymeth.2006.05.016. View

13.

Kim D, Kim Y, Seo S, Kim D, Kamada N, Prescott D . Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin. Nat Med. 2016; 22(5):524-30. PMC: 4860092. DOI: 10.1038/nm.4075. View

14.

Matzinger P . The danger model: a renewed sense of self. Science. 2002; 296(5566):301-5. DOI: 10.1126/science.1071059. View

15.

Pavot V, Climent N, Rochereau N, Garcia F, Genin C, Tiraby G . Directing vaccine immune responses to mucosa by nanosized particulate carriers encapsulating NOD ligands. Biomaterials. 2015; 75:327-339. DOI: 10.1016/j.biomaterials.2015.10.034. View

16.

Wille-Reece U, Flynn B, Lore K, Koup R, Kedl R, Mattapallil J . HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates. Proc Natl Acad Sci U S A. 2005; 102(42):15190-4. PMC: 1257732. DOI: 10.1073/pnas.0507484102. View

17.

Hung I, Zhang A, To K, Chan J, Li C, Zhu H . Immunogenicity of intradermal trivalent influenza vaccine with topical imiquimod: a double blind randomized controlled trial. Clin Infect Dis. 2014; 59(9):1246-55. DOI: 10.1093/cid/ciu582. View

18.

Kuo T, Baker K, Yoshida M, Qiao S, Aveson V, Lencer W . Neonatal Fc receptor: from immunity to therapeutics. J Clin Immunol. 2010; 30(6):777-89. PMC: 2970823. DOI: 10.1007/s10875-010-9468-4. View

19.

Rochereau N, Pavot V, Verrier B, Ensinas A, Genin C, Corthesy B . Secretory IgA as a vaccine carrier for delivery of HIV antigen to M cells. Eur J Immunol. 2014; 45(3):773-9. DOI: 10.1002/eji.201444816. View

20.

Janeway Jr C . Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989; 54 Pt 1:1-13. DOI: 10.1101/sqb.1989.054.01.003. View