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NANOSYM Report Summary

Project ID: 282312
Funded under: FP7-IDEAS-ERC
Country: Belgium

Final Report Summary - NANOSYM (Symbiotic bacteria as a delivery system for Nanobodies that target the insect-parasite interplay)

African trypanosomes are unicellular parasites that cause devastating diseases (African Trypanosomiasis) in humans and livestock on the African continent. These parasites are exclusively transmitted by an obligatory blood feeding insect, the tsetse fly, in which the parasite has to go through a complex development. The major aim of the ERC-NANOSYM project was to develop a paratransgenic methodology to block parasite transmission i.e. exploiting a bacterial symbiont of the fly, Sodalis glossinidius, for the in situ delivery of small antigen-recognizing Nanobodies (Nb), that target parasite development in the fly.
We have demonstrated the proof-of-concept that the Sodalis symbiont can be genetically engineered to express and release a detectable amount (ng/μl range) of functional anti-trypanosome Nbs in in vitro culture as well as in vivo in different tissues of the tsetse fly. We successfully optimized a Tn7-based methodology for the chromosomal integration of the transgene in a transcriptionally highly active region of the bacterial genome allowing a strong and constitutive expression of the anti-parasite protein. The sustainable colonization of the fly and its subsequent generations with the genetically engineered Sodalis could be achieved through microinjection of the bacterium into newborn tsetse fly larvae allowing the Sodalis to establish and proliferate in the different tissues at a normal density level. Beside, we demonstrated that the Sodalis symbiont is also paternally transmitted to the offspring through the male-to-female delivery of a Sodalis-containing sperm package. A series of different Nbs against the T.brucei midgut procyclic stage (i.e. the first essential developmental stage of the parasite in the tsetse fly) were selected that i) bind to the parasite surface and/or ii) compromise the growth of these trypanosomes in in vitro condition. However, none of these Nbs compromised the parasite development in vivo in the tsetse fly midgut. Unexpectedly, one of the nanobodies (Nb19) exerted a trypanosome-enhancing effect in in vivo conditions in the tsetse fly.
In conclusion we can state that we were successful in the development and validation of the proof-of concept to make paratransgenic tsetse flies through the genetic engineering of the bacterial symbiont Sodalis. The main bottleneck remains the identification of a highly potent and stable trypanolytic component against the procyclic midgut trypanosomes, blocking parasite transmission by the fly.

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