Abstract
Background Leptospira interrogans is the major causative agent of leptospirosis. Phagocytosis plays important roles in the innate immune responses to L. interrogans infection, and L. interrogans can evade the killing of phagocytes. However, little is known about the adaptation of L. interrogans during this process.Methodology/Principal FindingsTo better understand the interaction of pathogenic Leptospira and innate immunity, we employed microarray and comparative genomics analyzing the responses of L. interrogans to macrophage-derived cells. During this process, L. interrogans altered expressions of many genes involved in carbohydrate and lipid metabolism, energy production, signal transduction, transcription and translation, oxygen tolerance, and outer membrane proteins. Among them, the catalase gene expression was significantly up-regulated, suggesting it may contribute to resisting the oxidative pressure of the macrophages. The expressions of several major outer membrane protein (OMP) genes (e.g., ompL1, lipL32, lipL41, lipL48 and ompL47) were dramatically down-regulated (10–50 folds), consistent with previous observations that the major OMPs are differentially regulated in vivo. The persistent down-regulations of these major OMPs were validated by immunoblotting. Furthermore, to gain initial insight into the gene regulation mechanisms in L. interrogans, we re-defined the transcription factors (TFs) in the genome and identified the major OmpR TF gene (LB333) that is concurrently regulated with the major OMP genes, suggesting a potential role of LB333 in OMPs regulation.Conclusions/SignificanceThis is the first report on global responses of pathogenic Leptospira to innate immunity, which revealed that the down-regulation of the major OMPs may be an immune evasion strategy of L. interrogans, and a putative TF may be involved in governing these down-regulations. Alterations of the leptospiral OMPs up interaction with host antigen-presenting cells (APCs) provide critical information for selection of vaccine candidates. In addition, genome-wide annotation and comparative analysis of TFs set a foundation for further studying regulatory networks in Leptospira spp.
Highlights
Leptospirosis, which is characterized by hemorrhage, diarrhea, jaundice, severe renal impairment, and aseptic meningitis, etc., has emerged as a global zoonotic infectious disease in the past decade [1]
We found a dramatic influence of L. interrogans gene expression by host macrophage interaction, including genes of the major outer membrane protein (OMP)
We focused on annotating the hypothetical ORFs, which comprises about 40% of total ORFs of the genome of L. interrogans Serovar Lai Strain Lai 56601 [3]
Summary
Leptospirosis, which is characterized by hemorrhage, diarrhea, jaundice, severe renal impairment, and aseptic meningitis, etc., has emerged as a global zoonotic infectious disease in the past decade [1]. Several pathogenic Leptospira species cause infection, which include more than 15 genospecies and 230 serovars distributed geographically. Other free-living saprophytic Leptospira species, such as Leptospira biflexa, do not infect humans and animals. The pathogenic, saprophytic Leptospira and several other intermediate species all belong to the Spirochaetes, a unique phylum in eubacteria including other pathogens, such as Borrelia burgdorferi and Treponema pallidum. Leptospira interrogans is the most prevalent pathogenic Leptospira species which survives in natural environments and animal reservoir hosts, and infects humans through abrasions in the skin or mucous membrane. The main reservoir hosts of L. interrogans are wild rodents and domestic animals, which can persistently excrete L. interrogans through urine. Leptospira interrogans is the major causative agent of leptospirosis. Little is known about the adaptation of L. interrogans during this process
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