A probiotic treatment increases the immune response induced by the nasal delivery of spore-adsorbed TTFC

Francisco Denis S Santos,Loredana Baccigalupi,Arianna Mazzoli,Rachele Isticato,Fabio Leite,Ana Raquel Maia,Ezio Ricca,Susanna Iossa,Anella Saggese

doi:10.1186/s12934-020-01308-1

Francisco Denis S Santos, Loredana Baccigalupi + Show 7 more

Open Access

https://doi.org/10.1186/s12934-020-01308-1

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Abstract

BackgroundSpore-forming bacteria of the Bacillus genus are widely used probiotics known to exert their beneficial effects also through the stimulation of the host immune response. The oral delivery of B. toyonensis spores has been shown to improve the immune response to a parenterally administered viral antigen in mice, suggesting that probiotics may increase the efficiency of systemic vaccines. We used the C fragment of the tetanus toxin (TTFC) as a model antigen to evaluate whether a treatment with B. toyonensis spores affected the immune response to a mucosal antigen.ResultsPurified TTFC was given to mice by the nasal route either as a free protein or adsorbed to B. subtilis spores, a mucosal vaccine delivery system proved effective with several antigens, including TTFC. Spore adsorption was extremely efficient and TTFC was shown to be exposed on the spore surface. Spore-adsorbed TTFC was more efficient than the free antigen in inducing an immune response and the probiotic treatment improved the response, increasing the production of TTFC-specific secretory immunoglobin A (sIgA) and causing a faster production of serum IgG. The analysis of the induced cytokines indicated that also the cellular immune response was increased by the probiotic treatment. A 16S RNA-based analysis of the gut microbial composition did not show dramatic differences due to the probiotic treatment. However, the abundance of members of the Ruminiclostridium 6 genus was found to correlate with the increased immune response of animals immunized with the spore-adsorbed antigen and treated with the probiotic.ConclusionOur results indicate that B. toyonensis spores significantly contribute to the humoral and cellular responses elicited by a mucosal immunization with spore-adsorbed TTFC, pointing to the probiotic treatment as an alternative to the use of adjuvants for mucosal vaccinations.

Highlights

Mucosal surfaces are the most common route used by pathogens to enter the human and animal body
We analysed the statistically relevant differences between genera in the two groups that gave better immune responses (Sp-TTFC and SpTTFC+Probiotic) respect to all other groups. By this approach we found that members of Ruminiclostridium 6 genus were abundant in the gut of animals immunized with spore-displayed TTFC that received the probiotic (Fig. 9)
The main conclusion of this manuscript is that a probiotic treatment with B. toyonensis spores positively affects a nasal immunization with the C fragment of the tetanus toxin (TTFC) displayed by B. subtilis spores

Summary

Introduction

Mucosal surfaces are the most common route used by pathogens to enter the human and animal body For this reason, it is extremely important for a vaccine to induce secretory immunoglobin A (sIgA) antibody production. Santos et al Microb Cell Fact (2020) 19:42 vaccination against viral (Rotavirus, Poliovirus, Influenza type A virus) or bacterial (Salmonella typhi, Vibrio cholerae) pathogens [3]. This is mostly due to the low immunogenicity of most mucosal antigens and to the lack of efficient adjuvants and delivery systems [4]. The oral delivery of B. toyonensis spores has been shown to improve the immune response to a parenterally administered viral antigen in mice, suggesting that probiotics may increase the efficiency of systemic vaccines. We used the C fragment of the tetanus toxin (TTFC) as a model antigen to evaluate whether a treatment with B. toyonensis spores affected the immune response to a mucosal antigen

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