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Institute for Research in Biomedicine
Istituto di Ricerca in Biomedicina

Via Vincenzo Vela 6 - CH-6500 Bellinzona
Tel. +41 91 820 0300 - Fax +41 91 820 0302 - info [at] irb [dot] usi [dot] ch

A new generation of oral vaccines by inhibiting microbiota-derived ATP in the intestine

on Wednesday, January 16, 2019

Enteric infections affect up to 1 billion people leading to 2 million deaths per year worldwide. No effective vaccines exist against major enteric pathogens, including enterotoxigenic Escherichia coli (ETEC), Shigella, Campylobacter and Clostridium difficile. The intestine is an entry point for a multitude of foreign antigens in the form of food. The mucosal immune system should not generate pathogenic immune responses against food antigens whilst maintaining the capacity to eliminate any invading organism. Furthermore, the immune system in the gut should not destroy the trillions of commensal microorganisms, which live in symbiosis with the host and crucially contribute to its physiology. Thus, a myriad of exogenous antigens is tolerated in the gut to ensure the integrity of our organism. This peculiarity of the intestinal ecosystem limits the capacity to induce protective immune responses against enteric pathogens by oral vaccination. In fact, only two oral bacterial vaccines are effective in humans, namely live attenuated Salmonella typhi and killed Vibrio cholerae.

The group of Fabio Grassi at the IRB-USI of Bellinzona, Switzerland has uncovered that adenosine-triphosphate (ATP) released by commensal bacteria constitutes an important mediator of the relative tolerance of the gut immune system to exogenous antigens.

Figure 1. Schematic model of the release of the ATP-degrading enzyme apyrase by attenuated Salmonella transfected with the apyrase gene (right panel) (E.S., extracellular space; O.M., outer membrane; P.S., periplasmic space; I.M., inner membrane; O.M.V., outer membrane vesicles).









The predominant class of antibody found in the mucosal immune system is immunoglobulin A (IgA). IgA responses in the gut are controlled by T follicular helper (Tfh) cells, which promote generation of high-affinity IgA and maturation of antigen-specific B cells to IgA secreting plasma cells. These cells are sensitive to extracellular ATP via a receptor named P2X7 that induces cell death upon protracted stimulation by high concentrations of ATP, a peculiarity of the intestinal microenvironment.

By introducing the gene for an ATP-degrading enzyme into an attenuated strain of Salmonella Typhimurium, the IRB researchers found they could induce higher titers of high-affinity IgA, which could protect the host by the subsequent infection with a virulent Salmonella much more effectively than the ATP-releasing bacteria.

Figure 2. 3D rendering of intestinal crypts in cyan 18 h after infection with green fluorescent Salmonella. Infected mice were either non-vaccinated or vaccinated with attenuated Salmonella or apyrase expressing attenuated Salmonella, as indicated. Note that infecting Salmonella is barely detectable in crypts from mice vaccinated with apyrase expressing Salmonella. Scale bar: 5 um.










The study, published in Nature Communications and performed in collaboration with the University ‘‘Gabriele D’Annunzio’’, Chieti, University ‘‘La Sapienza’’ of Rome and University of Milan, Italy, the University of Zurich and ETH Zurich, Switzerland, shows that transient elimination of ATP in the intestinal microenvironment can dramatically improve the induction of high-affinity IgA in response to live attenuated or inactivated oral vaccines without any adverse effect. This method allows eliciting protective IgA responses against enteric pathogens and can be exploited for the design of effective oral vaccines.


ATP released by intestinal bacteria limits the generation of protective IgA against enteropathogens

Michele Proietti, Lisa Perruzza, Daniela Scribano, Giovanni Pellegrini, Rocco D’Antuono, Francesco Strati, Marco Raffaelli, Santiago F. Gonzalez, Marcus Thelen, Wolf-Dietrich Hardt, Emma Slack, Mauro Nicoletti & Fabio Grassi

Nature Communications, 10, Article number: 250 (2019), DOI: 10.1038/s41467-018-08156-z