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Engineering Microbes for Therapy

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Front. Microbiol. | doi: 10.3389/fmicb.2018.03075

A new Bifidobacteria Expression SysTem (BEST) to produce and deliver interleukin-10 in Bifidobacterium bifidum

  • 1Faculté de pharmacie de Paris, Université Paris Descartes, France
  • 2Micalis Institute, INRA Centre Jouy-en-Josas, France

In the last years there has been a growing interest in the use of genetically modified bacteria to deliver molecules of therapeutic concern at mucosal surfaces. Due to well-recognized probiotic properties of some strains, bifidobacteria represent excellent candidates for the development of live vehicles to produce and deliver heterologous proteins. However, very few studies have considered this genus because of its complexity to be genetically manipulated. In this study, we report the development of a new Bifidobacteria Expression SysTem (BEST) allowing the production of proteins of medical interest in Bifidobacterium bifidum. This system is based on the broad host range plasmid pWV01, a stress-inducible promoter, and two different signal peptides (SPs): SPExp4 issued from Lactococcus lactis and SPBL1181 issued from Bifidobacterium longum. The functionality of BEST system was validated by cloning murine interleukin-10 (IL-10) and establishing the resulting plasmids (i.e. pBESTExp4:IL-10 and pBESTBL1181:IL-10) in B. bifidum. We demonstrated in vitro that a recombinant strain of B. bifidum BS42 harboring pBESTBL1181:IL-10 plasmid efficiently secreted IL-10 and this secretion was significantly higher (7-fold) than its counterpart B. bifidum BS42 harboring pBESTExp4:IL-10 plasmid. Finally, we validated in vivo that recombinant B. bifidum strains producing IL-10 using BEST system efficiently delivered this cytokine at mucosal surfaces and exhibit beneficial effects in a murine model of low-grade intestinal inflammation.

Keywords: microbiota, Recombinant bacteria, IL-10, Bifidobacterium spp., Heterologous expression system, IBS

Received: 07 May 2018; Accepted: 29 Nov 2018.

Edited by:

Aleš Berlec, Jožef Stefan Institute (IJS), Slovenia

Reviewed by:

Andrey Shkoporov, University College Cork, Ireland
Gi-Seong Moon, Korea National University of Transportation, South Korea  

Copyright: © 2018 Mauras, Chain, Faucheux, Ruffié, Butel, Langella, Bermúdez-Humarán and Waligora-Dupriet. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Luis G. Bermúdez-Humarán, INRA Centre Jouy-en-Josas, Micalis Institute, Jouy-en-Josas, 78350, France,
Dr. Anne-Judith Waligora-Dupriet, Faculté de pharmacie de Paris, Université Paris Descartes, Paris, 75006, France,