Ma Hansong, Hagen Ferry, Stekel Dov J, Johnston Simon A, Sionov Edward, Falk Rama, Polacheck Itzhack, Boekhout Teun, May Robin C
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12980-5. doi: 10.1073/pnas.0902963106. Epub 2009 Jul 27.
In 1999, the population of Vancouver Island, Canada, began to experience an outbreak of a fatal fungal disease caused by a highly virulent lineage of Cryptococcus gattii. This organism has recently spread to the Canadian mainland and Pacific Northwest, but the molecular cause of the outbreak remains unknown. Here we show that the Vancouver Island outbreak (VIO) isolates have dramatically increased their ability to replicate within macrophages of the mammalian immune system in comparison with other C. gattii strains. We further demonstrate that such enhanced intracellular parasitism is directly linked to virulence in a murine model of cryptococcosis, suggesting that this phenotype may be the cause of the outbreak. Finally, microarray studies on 24 C. gattii strains reveals that the hypervirulence of the VIO isolates is characterized by the up-regulation of a large group of genes, many of which are encoded by mitochondrial genome or associated with mitochondrial activities. This expression profile correlates with an unusual mitochondrial morphology exhibited by the VIO strains after phagocytosis. Our data thus demonstrate that the intracellular parasitism of macrophages is a key driver of a human disease outbreak, a finding that has significant implications for a wide range of other human pathogens.
1999年，加拿大温哥华岛的居民开始遭遇由高毒力的新型隐球菌谱系引发的致命真菌病疫情。这种病原体最近已传播至加拿大本土及太平洋西北部地区，但疫情爆发的分子原因仍不明晰。在此，我们表明，与其他新型隐球菌菌株相比，温哥华岛疫情（VIO）分离株在哺乳动物免疫系统的巨噬细胞内的复制能力显著增强。我们进一步证明，这种增强的细胞内寄生作用与隐球菌病小鼠模型中的毒力直接相关，这表明该表型可能是疫情爆发的原因。最后，对24株新型隐球菌菌株的微阵列研究显示，VIO分离株的高毒力特征是一大组基因的上调，其中许多基因由线粒体基因组编码或与线粒体活动相关。这种表达谱与吞噬作用后VIO菌株呈现的异常线粒体形态相关。因此，我们的数据表明，巨噬细胞的细胞内寄生作用是人类疾病爆发的关键驱动因素，这一发现对众多其他人类病原体具有重要意义。
