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Leptospirosis is a globally important, neglected zoonotic infection caused by spirochetes of the genus  Leptospira . Since genetic transformation remains technically limited for pathogenic  Leptospira , a systems biology pathogenomic approach was used to infer leptospiral virulence genes by whole genome comparison of culture-attenuated  Leptospira interrogans  serovar Lai with its virulent, isogenic parent. Among the 11 pathogen-specific protein-coding genes in which non-synonymous mutations were found, a putative soluble adenylate cyclase with host cell cAMP-elevating activity, and two members of a previously unstudied ∼15 member paralogous gene family of unknown function were identified. This gene family was also uniquely found in the alpha-proteobacteria  Bartonella bacilliformis  and  Bartonella australis  that are geographically restricted to the Andes and Australia, respectively. How the pathogenic  Leptospira  and these two  Bartonella  species came to share this expanded gene family remains an evolutionary mystery.  In vivo  expression analyses demonstrated up-regulation of 10/11  Leptospira  genes identified in the attenuation screen, and profound  in vivo , tissue-specific up-regulation by members of the paralogous gene family, suggesting a direct role in virulence and host-pathogen interactions. The pathogenomic experimental design here is generalizable as a functional systems biology approach to studying bacterial pathogenesis and virulence and should encourage similar experimental studies of other pathogens.

Pathogenomic Inference of Virulence-Associated Genes in Leptospira interrogans