Comparison of school outbreaks of MTB. Comparison of school outbreaks of MTB

main research interests focus on host-pathogen interactions in tuberculosis and in particular I have been involved in investigating some recent outbreaks of tuberculosis in the UK (school outbreak in Leicester with Profs Mike Barer and Robert Wilkinson, Newton et al., PNAS 2006 103(42): 15594-8; school outbreak in Harrow with Robert Wilkinson, Anderson AJRCCM 2006 173(9):1038-42; outbreak in a Nepalese community living in London, unpublished) in which very high rates of infection occurred in tuberculosis patient contacts and /or unusually severe disease presented. These outbreaks have been well characterised clinically and phenotypically in vitro. All three were caused by distinct strains of MTB each with previously unreported genomic deletions (LSP) as determined through DNA microarray analysis and each appearing to subvert proinflammatory cytokine responses in vitro by macrophages. In collaboration with the University of Leicester we showed that one of the genomic LSP in the outbreak strain (Rv1519) was associated with an immune subverting phenotype. However I would now like to further investigate the cellular and molecular mechanisms by which the strains subvert the host immune response. To do this and as a starting point I think it would be ideal to sequence the genomes of the strains responsible for the outbreak in a school in Harrow and in the Nepalese community outbreak (the strain responsible for the school outbreak in Leicester has already been sequenced by Professor Mike Barer's group, Leicester and the Sanger Centre) and compare to reference strain H37Rv. This would in itself provide a wealth of clues to further study the genotypic-phenotypic relationships of these strains and specifically the mechanisms involved in subversion of the immune response.

本人主要研究方向为结核病中的宿主-病原体相互作用，具体而言，曾参与英国近期多起结核病暴发的调查工作：包括与Mike Barer教授、Robert Wilkinson教授合作开展的莱斯特学校暴发相关研究（相关成果发表于《美国国家科学院院刊》（PNAS）2006年，103(42): 15594-8，作者为Newton等）；与Robert Wilkinson教授合作完成的哈罗学校暴发调查（相关成果发表于《美国呼吸与危重症医学杂志》（AJRCCM）2006年，173(9):1038-42，作者为Anderson）；以及伦敦尼泊尔裔社区的结核病暴发调查（尚未发表）。
上述暴发中，结核病患者接触者的感染率极高，且/或出现了异常严重的临床病症。
上述暴发均已完成详尽的临床表征与体外表型分析。三起暴发均由不同的结核分枝杆菌（MTB）菌株引发，经DNA微阵列分析证实，这些菌株均携带此前未被报道的基因组缺失（LSP），且均可在体外抑制巨噬细胞的促炎细胞因子应答。本人与莱斯特大学合作证实，其中一株暴发菌株的基因组LSP位点Rv1519与免疫逃逸表型存在关联。
但本人目前计划进一步探究这些菌株逃避免疫宿主应答的细胞与分子机制。为此，作为起始研究步骤，拟对引发哈罗学校暴发与伦敦尼泊尔裔社区暴发的菌株进行基因组测序，并与参考菌株H37Rv进行比对——莱斯特学校暴发的菌株基因组测序工作已由莱斯特大学Mike Barer教授团队与桑格中心（Sanger Centre）完成。该研究将为深入解析这些菌株的基因型-表型关联，尤其是其免疫逃逸相关机制提供丰富的研究线索。