Discovery of Brucella virulence mechanisms using mutational analysis

This overview is written with the aim of providing an introduction to and historical perspective on naturally occurring and experimentally derived Brucella mutants. Spontaneous or naturally occurring mutants have proven of value over the last century in combating animal brucellosis. The most effective of these, S19, Rev-1 and RB51 have been used as vaccines in animals, but have drawbacks that have limited their effectiveness in some hosts including humans. The spontaneous appearance of these mutants has never been genetically characterized, but is now possible with the advent of genome sequencing. However, it is possible that these strains contain multiple genetic changes and identifying the relevant defects may be exceedingly difficult. Despite early sequencing initiatives Brucella virulence remains unresolved and a limited number of molecular systems have been identified that specifically enhance growth in host cells, the so-called virulence genes. Instead, the Brucella appear to have preserved a plethora of metabolic functions from their ancestors that enhance growth and survival in specific or varied environments, some of which are even duplicated. Direct and controlled mutagenesis of Brucella remains a valuable experimental approach to characterize the role of these genes in survival and virulence.