Cryo-EM structures of type IV pili complexed with nanobodies reveal immune escape mechanisms

David Fernandez-Martinez, Youxin Kong, Sylvie Goussard, Agustin Zavala, Pauline Gastineau, Martial Rey, Gabriel Ayme, Julia Chamot-Rooke, Pierre Lafaye, Matthijn Vos, Ariel Mechaly and Guillaume Duménil ()
Additional contact information
David Fernandez-Martinez: Pathogenesis of Vascular Infections
Youxin Kong: Pathogenesis of Vascular Infections
Sylvie Goussard: Pathogenesis of Vascular Infections
Agustin Zavala: Pathogenesis of Vascular Infections
Pauline Gastineau: Pathogenesis of Vascular Infections
Martial Rey: Mass Spectrometry for Biology
Gabriel Ayme: Antibody Engineering Platform
Julia Chamot-Rooke: Mass Spectrometry for Biology
Pierre Lafaye: Antibody Engineering Platform
Matthijn Vos: Institut Pasteur
Ariel Mechaly: Université Paris Cité
Guillaume Duménil: Pathogenesis of Vascular Infections

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Type IV pili (T4P) are prevalent, polymeric surface structures in pathogenic bacteria, making them ideal targets for effective vaccines. However, bacteria have evolved efficient strategies to evade type IV pili-directed antibody responses. Neisseria meningitidis are prototypical type IV pili-expressing Gram-negative bacteria responsible for life threatening sepsis and meningitis. This species has evolved several genetic strategies to modify the surface of its type IV pili, changing pilin subunit amino acid sequence, nature of glycosylation and phosphoforms, but how these modifications affect antibody binding at the structural level is still unknown. Here, to explore this question, we determine cryo-electron microscopy (cryo-EM) structures of pili of different sequence types with sufficiently high resolution to visualize posttranslational modifications. We then generate nanobodies directed against type IV pili which alter pilus function in vitro and in vivo. Cryo-EM in combination with molecular dynamics simulation of the nanobody-pilus complexes reveals how the different types of pili surface modifications alter nanobody binding. Our findings shed light on the impressive complementarity between the different strategies used by bacteria to avoid antibody binding. Importantly, we also show that structural information can be used to make informed modifications in nanobodies as countermeasures to these immune evasion mechanisms.

Date: 2024
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DOI: 10.1038/s41467-024-46677-y

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