Transcriptional response of Leptospira interrogans to iron limitation and characterization of a PerR homolog

Leptospirosis is a globally significant zoonosis caused by Leptospira spp. Iron is essential for growth of most bacterial species. Since iron availability is low in the host, pathogens have evolved complex iron acquisition mechanisms to survive and establish infection. In many bacteria, expression of iron-uptake and storage proteins is regulated by Fur. L. interrogans encodes four predicted Fur homologs; we have constructed a mutant in one of these, la1857. We conducted microarray analysis to identify iron-responsive genes and to study the effects of la1857 mutation on gene expression. Under iron-limiting conditions, 43 genes were up- and 49 genes were down-regulated in the wild type. Genes encoding proteins with predicted involvement in inorganic ion transport and metabolism (including TonB-dependent proteins and outer membrane transport proteins) were over-represented in the up-regulated list, while 54 of differentially expressed genes had no known function. There were 16 up-regulated genes of unknown function which are absent from the saprophyte L. biflexa and therefore may encode virulence-associated factors. Expression of iron-responsive genes was not significantly affected by mutagenesis of la1857, indicating that LA1857 is not a global regulator of iron homeostasis. Up-regulation of heme biosynthetic genes and a putative catalase in the mutant suggested LA1857 is more similar to PerR, a regulator of the oxidative stress response. Indeed the la1857 mutant was more resistant to peroxide stress than the wild-type. Our results provide insights into the role of iron in leptospiral metabolism and regulation of oxidative stress response, including genes likely to be important for virulence.