RegA, of the redox-sensing system RegB/A, is a key regulator in oxygen-dependent establishment of Brucella suis persistence.

Oxygen deficiency is one important parameter during human chronic infection by Brucella, which can reside in hypoxic immune structures and become resistant to the clinically used antibiotics. Our studies demonstrated the high metabolic flexibility of Brucella suis with respect to oxygen deprivation. We evidenced the central role of the two-component system RegBA in the coordinated control of oxidative respiration and denitrification, and its requirement for B. suis persistence in mice. RegA was essential for optimal long-lasting persistence in our original in vitro model, characterized by progressive oxygen deprivation. With this model, global transcriptome and proteome analyses comparing the wild-type and regA B. suis strains showed that genes or proteins involved in secretion (type IV), envelope biogenesis and in division were down-regulated by RegA. Importantly, the greatest number of the RegA-repressed genes and proteins, including aceA encoding the functional IsoCitrate Lyase (ICL), were involved in energy production. Moreover, ICL is an essential determinant of pathogenesis and long-term interactions with the host, as demonstrated by the strict dependence of B. suis on ICL activity for multiplication and persistence in vivo. RegA-dependent regulation of genes and proteins belonging to all functional groups (potentially 12% of the B. suis genes) makes the two-component system RegBA a main regulatory system required for adaptation of B. suis to oxygen depletion. This function may contribute to the establishment of a non-replicative state, typical of chronic infection.