Braun/murein lipoprotein (Lpp) is involved in inflammatory responses and septic shock. We previously characterized a lpp mutant of Yersinia pestis CO92 and found that this mutant was defective in surviving in macrophages and was attenuated in a mouse inhalation model of plague when compared to the highly virulent wild-type (WT) bacterium. We performed global transcriptional profiling of WT Y. pestis and its lpp mutant using microarrays. The organisms were cultured at 26 and 37 degrees Celsius to simulate the flea vector and mammalian host environments, respectively. Our data revealed vastly different effects of lpp mutation on the transcriptomes of Y. pestis grown at 37 versus . While the absence of Lpp resulted mainly in the downregulation of metabolic genes at , the Y. pestislpp mutant cultured at exhibited profound alterations in stress response and virulence genes, compared to WT bacteria. We investigated one of the stress-related genes (htrA) downregulated in the lpp mutant relative to WT Y. pestis. Indeed, complementation of the lpp mutant with the htrA gene restored intracellular survival of the Y. pestislpp mutant. Our results support a role for Lpp in Y. pestis adaptation to the host environment, possibly via transcriptional activation of htrA.