Garbom Sara, Forsberg Ake, Wolf-Watz Hans, Kihlberg Britt-Marie
Department of Molecular Biology, Umeå University, S-901 87 Umeå, Sweden.
Infect Immun. 2004 Mar;72(3):1333-40. doi: 10.1128/IAI.72.3.1333-1340.2004.
The sequencing of bacterial genomes has opened new perspectives for identification of targets for treatment of infectious diseases. We have identified a set of novel virulence-associated genes (vag genes) by comparing the genome sequences of six human pathogens that are known to cause persistent or chronic infections in humans: Yersinia pestis, Neisseria gonorrhoeae, Helicobacter pylori, Borrelia burgdorferi, Streptococcus pneumoniae, and Treponema pallidum. This comparison was limited to genes annotated as hypothetical in the T. pallidum genome project. Seventeen genes with unknown functions were found to be conserved among these pathogens. Insertional inactivation of 14 of these genes generated nine mutants that were attenuated for virulence in a mouse infection model. Out of these nine genes, five were found to be specifically associated with virulence in mice as demonstrated by infection with Yersinia pseudotuberculosis in-frame deletion mutants. In addition, these five vag genes were essential only in vivo, since all the mutants were able to grow in vitro. These genes are broadly conserved among bacteria. Therefore, we propose that the corresponding vag gene products may constitute novel targets for antimicrobial therapy and that some vag mutants could serve as carrier strains for live vaccines.
细菌基因组测序为确定传染病治疗靶点开辟了新的前景。通过比较六种已知会在人类中引起持续性或慢性感染的人类病原体的基因组序列，我们鉴定出了一组新的毒力相关基因（vag基因）：鼠疫耶尔森菌、淋病奈瑟菌、幽门螺杆菌、伯氏疏螺旋体、肺炎链球菌和梅毒螺旋体。这种比较仅限于梅毒螺旋体基因组计划中注释为假设性的基因。发现有17个功能未知的基因在这些病原体中是保守的。对其中14个基因进行插入失活产生了9个在小鼠感染模型中毒力减弱的突变体。在这9个基因中，有5个基因被发现与小鼠的毒力特别相关，这通过用假结核耶尔森菌框内缺失突变体感染得到了证实。此外，这5个vag基因仅在体内是必需的，因为所有突变体都能够在体外生长。这些基因在细菌中广泛保守。因此，我们提出相应的vag基因产物可能构成抗菌治疗的新靶点，并且一些vag突变体可以作为活疫苗的载体菌株。
