Sammons-Jackson Wendy L, McClelland Karen, Manch-Citron Jean N, Metzger Dennis W, Bakshi Chandra Shekhar, Garcia Emilio, Rasley Amy, Anderson Burt E
Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
DNA Cell Biol. 2008 Jul;27(7):387-403. doi: 10.1089/dna.2007.0687.
Francisella tularensis is a zoonotic bacterium that must exist in diverse environments ranging from arthropod vectors to mammalian hosts. To better understand how virulence genes are regulated in these different environments, a transcriptional response regulator gene (genome locus FTL0552) was deleted in F. tularensis live vaccine strain (LVS). The FTL0552 deletion mutant exhibited slightly reduced rates of extracellular growth but was unable to replicate or survive in mouse macrophages and was avirulent in the mouse model using either BALB/c or C57BL/6 mice. Mice infected with the FTL0552 mutant produced reduced levels of inflammatory cytokines, exhibited reduced histopathology, and cleared the bacteria quicker than mice infected with LVS. Mice that survived infection with the FTL0552 mutant were afforded partial protection when challenged with a lethal dose of the virulent SchuS4 strain (4 of 10 survivors, day 21 postinfection) when compared to naive mice (0 of 10 survivors by day 7 postinfection). Microarray experiments indicate that 148 genes are regulated by FTL0552. Most of the genes are downregulated, indicating that FTL0552 controls transcription of genes in a positive manner. Genes regulated by FTL0552 include genes located within the Francisella pathogenicity island that are essential for intracellular survival and virulence of F. tularensis. Further, a mutant in FTL0552 or the comparable locus in SchuS4 (FTT1557c) may be an alternative candidate vaccine for tularemia.
土拉弗朗西斯菌是一种人畜共患病细菌，必须存在于从节肢动物媒介到哺乳动物宿主等多种环境中。为了更好地了解毒力基因在这些不同环境中是如何被调控的，在土拉弗朗西斯菌活疫苗株（LVS）中删除了一个转录反应调节基因（基因组位点FTL0552）。FTL0552缺失突变体的细胞外生长速率略有降低，但无法在小鼠巨噬细胞中复制或存活，并且在使用BALB/c或C57BL/6小鼠的小鼠模型中无毒力。感染FTL0552突变体的小鼠产生的炎性细胞因子水平降低，组织病理学表现减轻，并且比感染LVS的小鼠更快清除细菌。与未感染的小鼠（感染后第7天10只小鼠均未存活）相比，感染FTL0552突变体后存活的小鼠在用致死剂量的强毒株SchuS4攻击时获得了部分保护（感染后第21天10只存活小鼠中有4只）。微阵列实验表明，有148个基因受FTL0552调控。大多数基因被下调，表明FTL0552以正向方式控制基因转录。受FTL0552调控的基因包括位于弗朗西斯菌致病岛内的基因，这些基因对土拉弗朗西斯菌的细胞内存活和毒力至关重要。此外，FTL0552或SchuS4中可比位点（FTT1557c）的突变体可能是兔热病的替代候选疫苗。
