The role of flavin metabolism in Brucella abortus virulence

BONOMI H.R.; GARCÍA-ANGULO V.A.; MARCHESINI I.; COMERCI D.; GOLDBAUM F.A.

Buenos Aires

Conferencia; Brucellosis 2011, International Research Conference Including the 64th Brucellosis Research Conference; 2011

Brucella is a successful pathogen that has been infecting animals probably for millions of years and it is extremely adapted to the intracellular lifestyle. Its virulence lays in its ability to invade the host, resist defense mechanisms, establish and replicate in the inhospitable replicative niche. The replicative niche exhibits limited nutrients availability and low oxygen tension. In spite of the fact that Brucella does not possess ?classic? virulence factors, it displays a variety of physiological mechanisms and metabolic adaptations that allows these bacteria to cope with the host?s defenses and adapt to live inside the cell. Riboflavin (vitamin B2) is the precursor of the vital cofactors FMN and FAD. The enzyme Lumazine Synthase (LS) catalyzes the penultimate step of the synthesis of riboflavin. Brucella, as well as other Rhizobiales, have two isoenzymes for the LS function, named RibH1 and RibH2 respectively. We have previously established that only RibH2 is involved in the virulence of Brucella. Here we present results that indicate that the endogenous synthesis of lumazine is essential for intracellular survival and virulence of Brucella, especially in the replicative niche. Expressing a heterologous flavin transporter from Rhizobium in survival experiments, we were able to demonstrate that there are available flavins during the course of Brucella infection in cells and mice, but the bacteria lacks flavin-transporter activities to use them. Our results clearly show that flavin biosynthesis in Brucella is essential for intracelullar survival and that flavin biosynthetic enzymes constitute attractive targets for chemotherapy and vaccine design.