A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants

Diard, Médéric; Bakkeren, Erik; Lentsch, Verena; Rocker, Andrea; Bekele, Nahimi Amare; Hoces, Daniel; Aslani, Selma; Arnoldini, Markus; Böhi, Flurina; Moor, Kathrin; Adamčík, Jozef; Piccoli, Luca; Lanzavecchia, Antonio; Stadtmueller, Beth M.; Donohue, Nicholas; Woude, Marjan W. van der; Hockenberry, Alyson M.; Viollier, Patrick H.; Falquet, Laurent; Wüthrich, Daniel; Bonfiglio, Ferdinando; Loverdo, Claude; Egli, Adrian; Zandomeneghi, Giorgia; Mezzenga, Raffaele; Holst, Otto; Meier, Beat H.; Hardt, Wolf Dietrich; Slack, Emma

doi:10.1038/s41564-021-00911-1

Cited by 25 publications

(54 citation statements)

References 69 publications

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“…The resulting strain is fully avirulent 18 ( Fig. S1 ), fast-growing 18 , and less bound by IgA induced by a wild-type O:5,12-0 Salmonella vaccine than the isogenic wild-type strain 20 . The resulting mutant S .Tm hilD ssaV oafA was used as niche competitor hereafter named S .Tm Comp .…”

Section: Resultsmentioning

confidence: 99%

“…This has been demonstrated to grow well in S .Tm-permissive conditions 28 and could limit S .Tm infection after dietary perturbation 29 . Moreover, this E. coli produces an unrelated O-antigen structure, allowing us to use an “evolutionary trap” version 20 of our S .Tm vaccine covering all possible variations of the S .Tm O-antigen. This adds robustness to the technique as selective pressure exerted by vaccine-induced IgA can provide a selective advantage both to the competitor strain, and to naturally emerging S .Tm variants with a short O-antigen.…”

Section: Resultsmentioning

confidence: 99%

“…High-affinity intestinal IgA, induced by oral vaccination with whole-cell inactivated vaccines, can increase S .Tm clearance rates by generating bacterial clumps (via enchained growth or agglutination) that are more efficiently cleared in the flow of the fecal stream 16 . We have recently demonstrated that this IgA-mediated selective pressure can be used to manipulate the evolutionary trajectory of Salmonella enterica subspecies enterica serovar Typhimurium ( S .Tm) in the gut lumen 20 . Moreover, part of this work demonstrated the ability of IgA to generate a more than a million-fold ratio of a targeted S .Tm strain over a non-bound strain 20 .…”

Section: Introductionmentioning

confidence: 99%

“…We have recently demonstrated that this IgA-mediated selective pressure can be used to manipulate the evolutionary trajectory of Salmonella enterica subspecies enterica serovar Typhimurium ( S .Tm) in the gut lumen 20 . Moreover, part of this work demonstrated the ability of IgA to generate a more than a million-fold ratio of a targeted S .Tm strain over a non-bound strain 20 . Therefore, IgA protects the intestinal environment not only via immune exclusion (i.e.…”

Section: Introductionmentioning

confidence: 99%

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Combined oral vaccination with niche competition can generate sterilizing immunity against entero-pathogenic bacteria

Lentsch

Woller

Moresi

et al. 2022

Preprint

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Widespread antimicrobial resistance generates an urgent need to develop better disease prophylaxis for intestinal bacterial pathogens. While the first phase of infection with any bacterial pathogen is typically colonization of the mucosal surfaces, current vaccine strategies typically target invasive stages of disease. Here we demonstrate the ability to specifically generate sterilizing immunity against Salmonella enterica subspecies enterica serovar Typhimurium (S.Tm) at the level of gut lumen colonization using a combination of oral vaccination and a rationally-designed niche competitor strain. This is based on the proven ability of specific secretory IgA to generate a fitness disadvantage for a targeted bacterium, allowing a non-targeted competitor to rapidly overtake its niche. By hugely decreasing the population size of an intestinal pathogen during the early stages of infection, this improves protection of gut tissue compared to standard licensed animal vaccines. We demonstrate that most effective protection is generated when the niche competitor is derived from the pathogen and therefore occupies an identical niche. However, as this is unrealistic in real-world infections, we further demonstrate that robust protection can also be generated with a more distantly related “probiotic” niche competitor from a distinct species. Interestingly, focusing prophylaxis on the gut lumen reveals an uncoupling of protective mechanisms required for protection in the gut and gut tissues and those required for protecting against colonization of the spleen and liver. Therefore, while there is still potential to improve this approach by adding systemic immune activation, we nevertheless believe this is a fundamental step forward in our ability to manipulate colonization of intestinal bacteria with potential application to a wide-range of entero-pathogens, as well as to manipulation of microbiota composition.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Combined oral vaccination with niche competition can generate sterilizing immunity against entero-pathogenic bacteria

Lentsch

Woller

Moresi

et al. 2022

Preprint

Self Cite

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“…The dependency on exogenous GlcNAc/GalNAc for peptidoglycan synthesis may support this notion. Alternatively, it can be imagined that successful adaptation to sialidase-mediated inhibition may alter the bacterium’s physiology (e.g., capsule or membrane structure) in such a way that this renders it more susceptible to other even stronger selective pressures such as phage predation or host immune responses 52 .…”

Section: Discussionmentioning

confidence: 99%

Growth inhibition of Akkermansia muciniphila by a secreted pathobiont sialidase

Muijlwijk

Bröring

Mierlo

et al. 2022

Preprint

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Akkermansia muciniphila is considered a key constituent of a healthy gut microbiota. In inflammatory bowel disease (IBD), A. muciniphila has a reduced abundance while other, putative pathogenic, mucus colonizers bloom. We hypothesized that interbacterial competition may contribute to this observation. By screening the supernatants of a panel of enteric bacteria, we discovered that a previously uncharacterized Allobaculum species potently inhibits the growth of A. muciniphila. Mass spectrometry analysis identified a secreted Allobaculum sialidase as inhibitor of A. muciniphila growth. The sialidase targets sialic acids on casein O-glycans, thereby altering the accessibility of nutrients critical for A. muciniphila. The altered glycometabolic niche results in distorted A. muciniphila cell division and efficiently arrests its growth. The identification of a novel mechanism of A. muciniphila growth inhibition by a competing bacterial pathobiont may provide a rationale for interventions aimed at restoring and maintaining a healthy microbiota symbiosis in patients with intestinal disease.

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Therapeutic targeting of gut‐originating regulatory B cells in neuroinflammatory diseases

Neziraj,

Siewert,

Pössnecker

et al. 2023

Eur J Immunol

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Regulatory B cells (Bregs) are immunosuppressive cells that support immunological tolerance by the production of interleukin (IL)‐10, IL‐35, and transforming growth factor β (TGF‐β). Bregs arise from different developmental stages in response to inflammatory stimuli. In that regard, mounting evidence points towards a direct influence of gut microbiota on mucosal B cell development, activation, and regulation in health and disease. While an increasing number of diseases are associated with alterations in gut microbiome (dysbiosis), little is known about the role of microbiota on Breg development and induction in neuroinflammatory disorders. Notably, gut‐originating, IL‐10‐ and immunoglobulin A (IgA)‐producing regulatory plasma cells have recently been demonstrated to egress from the gut to suppress inflammation in the central nervous system (CNS) raising fundamental questions about the triggers and functions of mucosal‐originating Bregs in systemic inflammation. Advancing our understanding of regulatory B cells in neuroinflammatory diseases could lead to novel therapeutic approaches.Here, we summarize main aspects about regulatory B cell differentiation and functions and evidence about their involvement in neuroinflammatory diseases. Further, we highlight current data of gut‐originating regulatory B cells and their microbial interactions and discuss future microbiota‐/regulatory B cell‐targeted therapies in immune‐mediated diseases.This article is protected by copyright. All rights reserved

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A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants

Cited by 25 publications

References 69 publications

Combined oral vaccination with niche competition can generate sterilizing immunity against entero-pathogenic bacteria

Combined oral vaccination with niche competition can generate sterilizing immunity against entero-pathogenic bacteria

Growth inhibition of Akkermansia muciniphila by a secreted pathobiont sialidase

Therapeutic targeting of gut‐originating regulatory B cells in neuroinflammatory diseases

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