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This research was carried out in the frame of projects PID2023-146797OB-C31, PID2023-146797OB-C32, PID2019-107601RB-C31 and PID2019-107601RA-C32 financed by MCIN/AEI/10.1303910.13039/501100011033. A.E-B's work was supported by a postdoctoral contract under the REPRODIVAC project Grant Agreement No. 10106081 through the HORIZON-CL6-2021-FARM2FORK-01-06 Call. The work of P.M.M. and M.J.d.M. (CITA) was also supported by the Aragon Government (Grupo de Investigacion A21_23R).

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Disruption of Erythritol Catabolism via the Deletion of Fructose-Bisphosphate Aldolase (Fba) and Transaldolase (Tal) as a Strategy to Improve the Brucella Rev1 Vaccine

Publicado en:International Journal Of Molecular Sciences. 25 (20): 11230- - 2024-10-01 25(20), DOI: 10.3390/ijms252011230

Autores: Elizalde-Bielsa, Aitor; Lazaro-Anton, Leticia; de Miguel, Maria Jesus; Munoz, Pilar M; Conde-Alvarez, Raquel; Zuniga-Ripa, Amaia

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Resumen

Brucellosis is a bacterial zoonosis caused by the genus Brucella, which mainly affects domestic animals. In these natural hosts, brucellae display a tropism towards the reproductive organs, such as the placenta, replicating in high numbers and leading to placentitis and abortion, an ability also exerted by the B. melitensis live-attenuated Rev1 strain, the only vaccine available for ovine brucellosis. It is broadly accepted that this tropism is mediated, at least in part, by the presence of certain preferred nutrients in the placenta, particularly erythritol, a polyol that is ultimately incorporated into the Brucella central carbon metabolism via two reactions dependent on transaldolase (Tal) or fructose-bisphosphate aldolase (Fba). In the light of these remarks, we propose that blocking the incorporation of erythritol into the central carbon metabolism of Rev1 by deleting the genes encoding Tal and Fba may impair the ability of the vaccine to proliferate massively in the placenta. Therefore, a Rev1 Delta fba Delta tal double mutant was generated and confirmed to be unable to use erythritol. This mutant exhibited a reduced intracellular fitness both in BeWo trophoblasts and THP-1 macrophages. In the murine model, Rev1 Delta fba Delta tal provided comparable protection to the Rev1 reference vaccine while inducing fewer adverse reproductive events in pregnant animals. Altogether, these results postulate the Rev1 Delta fba Delta tal mutant as a reproductively safer Rev1-derived vaccine candidate to be studied in the natural host.

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