The highest priority: what microbial genomes are telling us about immunity.

Study of microbial genomes has provided new insight into the functions that pathogens require for survival in the animal host. Small genome bacterial pathogens, defined as those < or = 1/3 the size of Escherichia coli, include chlamydiae, rickettsiae and ehrlichiae, mycoplasmas, and spirochetes. The small genome size is believed to result from reductive evolution, a process of initial mutation with loss of function followed by progressive accumulation of mutations and eventual gene deletion. This is most notable in the 1.1 Mb genome of Rickettsia prowazekki in which 24% of the genome is non-coding, as compared to approximately 10% in the 4.4 Mb E. coli. Consequently, these pathogens are thus presumed to retain only the most important functions for survival and propagation. There is consistent evidence from small genomes that the genetic deletion is primarily related to the loss of metabolic function and especially reduction of multiple overlapping pathways and duplicated genes. Thus, these pathogens undergo progressive reduction in their genomes yet maintain the ability to infect, survive within, and cause disease in animals. In the face of this reductive process, what genes and associated functions are maintained? Strikingly, these pathogens devote a high percentage of their genomes to paralogous families of polymorphic surface molecules. This retention suggests that evasion of the immune response is the highest priority of obligate microbial pathogens and provides a strategy for identifying protective antigens for vaccine development to control disease.