Kelly Ben L, Stetson Daniel B, Locksley Richard M
Howard Hughes Medical Institute, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
J Exp Med. 2003 Dec 1;198(11):1689-98. doi: 10.1084/jem.20031162.
The Leishmania major LACK antigen is a key target of the immune response in susceptible BALB/c mice and remains a viable vaccine candidate for human leishmaniasis. We describe the genomic organization of the four lack genes in the L. major diploid genome together with results of selected lack gene targeting. Parasites containing a single lack gene in either the upstream or downstream locus grew comparably to wild-type promastigotes in vitro, but failed to parasitize BALB/c mice efficiently, even in a T cell-deficient environment. The replication of single copy lack mutants as amastigotes was attenuated in macrophages in vitro, and parasites failed to increase in numbers in immunodeficient mice, despite their persistence over months. Complementation with an additional lack copy was sufficient to induce robust lesion development, which also occurred using parasites with two lack genes. Conversely, attempts to generate lack-null parasites failed, suggesting that LACK is required for parasite viability. These data suggest that LACK is critical for effective mammalian parasitization and thus represents a potential drug target for leishmaniasis.
硕大利什曼原虫的LACK抗原是易感BALB/c小鼠免疫反应的关键靶点，仍然是人类利什曼病可行的疫苗候选物。我们描述了硕大利什曼原虫二倍体基因组中四个lack基因的基因组结构以及选定的lack基因靶向结果。在上游或下游位点含有单个lack基因的寄生虫在体外与野生型前鞭毛体生长相当，但即使在T细胞缺陷环境中也无法有效地寄生BALB/c小鼠。单拷贝lack突变体作为无鞭毛体在体外巨噬细胞中的复制减弱，并且寄生虫在免疫缺陷小鼠中的数量未能增加，尽管它们持续存在数月。用额外的lack拷贝进行互补足以诱导强烈的病变发展，使用具有两个lack基因的寄生虫也会出现这种情况。相反，产生lack缺失寄生虫的尝试失败了，这表明LACK是寄生虫生存所必需的。这些数据表明，LACK对于有效的哺乳动物寄生至关重要，因此是利什曼病的潜在药物靶点。
