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Research Paper

Anti-S-layer monoclonal antibodies impact Clostridioides difficile physiology

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Article: 2301147 | Received 11 Sep 2023, Accepted 28 Dec 2023, Published online: 30 Jan 2024
 

ABSTRACT

Clostridioides difficile (C. difficile), a gram-positive anaerobic and spore-forming bacterium, is the leading cause of nosocomial antibiotic-associated diarrhea in adults which is characterized by high levels of recurrence and mortality. Surface (S)-layer Protein A (SlpA), the most abundantly expressed protein on the bacterial surface, plays a crucial role in the early stages of infection although the nature of its involvement in C. difficile physiology is yet to be fully understood. Anti-S-layer antibodies have been identified in the sera of convalescent patients and have been correlated with improved outcomes of C. difficile infection (CDI). However, the precise mechanisms by which anti-S-layer antibodies confer protection to the host remain unknown. In this study, we report the first monoclonal antibodies (mAbs) targeting the S-layer of reference strain 630. Characterization of these mAbs unraveled important roles for the S-layer protein in growth, toxin secretion, and biofilm formation by C. difficile, with differential and even opposite effects of various anti-SlpA mAbs on these functions. Moreover, one anti-SlpA mAb impaired C. difficile growth and conferred sensitivity to lysozyme-induced lysis. The results of this study show that anti-S-layer antibody responses can be beneficial or harmful for the course of CDI and provide important insights for the development of adequate S-layer-targeting therapeutics.

Acknowledgments

The authors wish to thank Hans Yssel for thoughtful suggestions on data interpretation and final editing of the manuscript. We would also like to thank the animal facility of Institut Pasteur for hosting and taking care of the mice, the technologic platform of production and purification of recombinant proteins of Institut Pasteur for their help in producing the LMW30, the MIMA2 platform of INRAE for their support with biofilm imaging, Dr. Jazmin Meza-Torres for her help on C. difficile microscopy experiments, Léo Caulat for his help with the LDH and toxins’ assays and Pierre-Alexandre Lacotte for his suggestions on the lysozyme assay.

Disclosure statement

Unrelated to the submitted work, P.B. received consulting fees from Regeneron Pharmaceuticals. The other authors have no conflicts of interest to declare.

Data availability statement

The authors confirm that data supporting the findings of this study are available within the article and its supplementary materials.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2301147

Additional information

Funding

LH is a doctoral fellow of Sorbonne Université. DS was partly supported by a poste d’accueil Institut Pasteur – Assistance Publique des Hôpitaux de Paris (APHP) and by the Agence Nationale de la Recherche (ANR) program Résilience-Covid- 19 MUCOVID. Work in the Bruhns’ lab was supported by the Fondation Janssen Horizon (grant #2018-102415235), Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (Inserm), Fondation pour la Recherche Médicale, Paris, France (Programme Equipe FRM grant EQU202203014631), Agence Nationale de la Recherche (ANR grant ANR-21-CE15-0027). Work in the G. Gorochov’s team is supported by Institut National de la Santé et de la Recherche Médicale (Inserm), Sorbonne Université, Fondation pour la Recherche Médicale (FRM), Paris, France, program ‘‘Investissement d’Avenir’’ launched by the French Government and implemented by the Agence Nationale de la Recherche (ANR) with the reference COFIFERON ANR- 21-RHUS-08, by EU Horizon HLTH-2021-DISEASE-04 UNDINE project, by programme DIM Ile de France thérapie cellulaire et génique, by Fondation pour la Recherche Médicale, Paris, France (Programme Equipe FRM 2022) and by the Département Médico-Universitaire de Biologie et Génomique Médicales (DMU BioGen), APHP, Paris, France.