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Leptospirosis is among the most important zoonotic diseases worldwide. Completion of the genomic sequences of leptospires has facilitated advances in diagnosis and prevention of the disease, and yielded insight into its pathogenesis. This article reviews this research, emphasizing recent progress.Leptospirosis is caused by a group of highly invasive spiral bacteria (spirochetes) that can infect both people and animals. Spirochetes can survive in the environment and host, and therefore outer membrane and secretory proteins that interact with the host are of considerable interest in leptospire research. The genetic approach to studying pathogenesis is hindered by fastidious growth of pathogenic leptospires. Integrated genomic and proteomic approaches, however, have yielded enhanced understanding of the pathogenesis of leptospirosis. Furthermore, studies of innate immune response to the organism have enhanced our understanding of host susceptibility and resistance to infection. In-silico analysis and high-throughput cloning and expression have had major impacts on efforts to develop vaccine candidates and diagnostic reagents.In the future, we must effectively utilize the wealth of genetic information to combat the disease. More studies into genetics, immune mechanisms that may be exploited to prevent leptospirosis, and pathogenesis of the disease are necessary.