Modulation of outer membrane vesicle-based immune responses by cathelicidins

Melanie D Balhuizen, Chantal M Versluis, Monica O van Grondelle, Edwin J A Veldhuizen, Henk P Haagsman

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Antibiotic resistance is increasing and one strategy to prevent resistance development is the use of bacterial vaccines. For Gram-negative bacteria, natural outer membrane vesicles (OMVs) could be used for vaccine development. These vesicular structures are naturally produced by all Gram-negative bacteria and contain several antigens in their native environment. However, despite that the presence of lipopolysaccharide (LPS) may aid as intrinsic adjuvant, there is a risk that it may also cause undesired immune responses. Therefore, molecules to dampen LPS-induced toll-like receptor (TLR) 4 activation may be needed. Here host defense peptides (HDPs), like cathelicidins, can play an important role. They have been shown to interact with LPS and thereby neutralize LPS-induced TLR4 activation. However, there is currently no knowledge about neutralization in an OMV-based setting. Therefore, in this paper the immune modulating capacity of HDPs was investigated after macrophage stimulation with either spontaneous or heat-induced B. bronchiseptica OMVs. This revealed that the cathelicidins LL-37, CATH-2, PMAP-36 and K9CATH were able to modulate immune responses. Interestingly, immune modulation by these cathelicidins was different for spontaneous compared to heat-induced OMVs. Interaction studies revealed that the mode of binding of cathelicidins to OMVs slightly differed between OMV classes. Furthermore, TLR screening revealed that TLR2, 4, 5 and 9 were involved in stimulation of macrophages by OMVs, with TLR4-mediated activation being the most important pathway. Uptake of OMVs did not play a major role in macrophage activation. Taken together, this study shows how OMVs can activate macrophages and how cathelicidins may modulate these immune responses.

Original languageEnglish
Pages (from-to)2399-2408
Number of pages10
JournalVaccine
Volume40
Issue number16
Early online date17 Mar 2022
DOIs
Publication statusPublished - 6 Apr 2022

Bibliographical note

Publisher Copyright:
© 2022 The Authors

Funding

This research was supported in part by NWO-TTW grant 14924 to the Bac-Vactory program.

FundersFunder number
NWO-TTW14924

    Keywords

    • Bordetella bronchiseptica
    • Host Defense Peptides
    • Innate immune response
    • Outer Membrane Vesicles
    • TLR activation

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