不同动物源性致病性钩端螺旋体遗传变异规律和致病差异的分子机制研究

不同宿主来源的钩端螺旋体引起人类疾病的临床表现和病理变化各有不同，但其分子基础和影响机制尚不清楚。本项目以几种主要的动物宿主（鼠、犬和猪）来源的致病性钩端螺旋体为研究对象，以钩端螺旋体进化变异规律和跨种间致病差异的分子机制这两个关键科学问题为核心，从病原菌分离鉴定、流行规律、生态分布和基因组序列变异等研究内容入手，在课题组已经完成的多株鼠源性钩端螺旋体基因测序和功能研究的基础上，通过全基因组重测序、比较基因组学和蛋白质组学、分子生物学和动物模型等技术手段，建立不同动物宿主的钩端螺旋体特异性基因组和表面暴露蛋白质组分析和整合研究体系。根据不同宿主的钩端螺旋体特异性SNP和IS重复序列系统谱描绘钩端螺旋体基因组进化与种系发生、进化起源以及菌株与宿主协同进化之间的相互关系；解析不同宿主来源钩端螺旋体的致病差异的分子基础；阐明致病性钩体与不同宿主相互作用的分子机制及其对致病性的影响。

The clinical manifestations and disease courses in human are quite different between the leptospira isolated from different hosts. This project focus on these pathogenic leptospira isolated from several major animal hosts (mouse, dog and pig). The two key scientific issues of the project, the evolutionary pattern of genetic variation and molecular mechanism of differences in pathogenicity between pathogenic Leptospira from different animal host, are the center of whole procedure. It is the first time that epidemiological information including identification, collection, epidemic patterns and ecological distribution of Epidemic Leptospira strains, genome sequence variation, differences in animal host and pathogenicity were all integrated into our study. Multiscale technical approaches such as whole genome resequencing, comparative genomics and proteomics, molecular biology and animal models are utilized to create the high-throughput integrating platform for charactering the different animal-associated specific genomes and surface-exposed proteomes of pathogenic leptospira. Furthermore, according to the phylogenetic profiles of different animal-associated specific SNPs and IS repeat sequences between pathogenic leptospira, we try to depict the dynamic variations and phylogenetic evolution of pathogenic leptospira, origin of strains and host-strain co-evolution at a genomic level. At the same time, we try to identify key pathogenic factors of different animal-associated pathogenic leptospira leading to differences in pathogenicity, in order to clarify the specific interaction and molecular pathogenesis between pathogenic leptospira and human as well as impact on differences in pathogenicity.