Pathogen DNA as target for host-generated oxidative stress:: Role for repair of bacterial DNA damage in Helicobacter pylori colonization
Pathogen DNA as target for host-generated oxidative stress:: Role for repair of bacterial DNA damage in Helicobacter pylori colonization
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DOI：
10.1073/pnas.0337641100
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发表时间：
2003-03-04
影响因子：
11.1
通讯作者：
Radicella, JP
中科院分区：
文献类型：
--
作者：
O'Rourke, EJ;Chevalier, C;Radicella, JP
幽门螺杆菌在宿主定植过程中引起氧化应激。已知这种氧化应激会导致宿主DNA损伤。在这里，我们解决的问题，是否病原体DNA是致命的或突变的主机产生的氧化反应的损害。H.产生了不能从细菌DNA修复氧化嘧啶的pylori Hpnth突变体。H.缺乏功能性核酸内切酶III（HpNth）的幽门螺杆菌菌株显示自发和诱导突变率升高，并且比亲本菌株对暴露于氧化剂或活化的巨噬细胞的杀伤更敏感。尽管在实验室条件下，Hpnth突变株与野生型株一样生长，但在小鼠感染中，胃细菌负荷逐渐降低，而野生型株中的群体保持稳定，表明内切核酸酶III缺乏降低了病原体的定殖能力。在用野生型菌株的共感染实验中，在感染后15天（p.i.）即使当以1：9的野生型：突变菌株比例接种时，也显示出在竞争条件下反选择的诱变损伤。这些结果表明，宿主能有效地诱导H. pylori基因组。这些DNA损伤对H. pylori菌株的新宿主进行了讨论。
Helicobacter pylori elicits an oxidative stress during host colonization. This oxidative stress is known to cause lesions in the host DNA. Here we addressed the question as to whether the pathogen DNA is subject to lethal or mutational damage by the host-generated oxidative response. H. pylori Hpnth mutants unable to repair oxidized pyrimidines from the bacterial DNA were generated. H. pylori strains lacking a functional endonuclease III (HpNth) showed elevated spontaneous and induced mutation rates and were more sensitive than the parental strain to killing by exposure to oxidative agents or activated macrophages. Although under laboratory conditions the Hpnth mutant strain grows as well as the wild-type strain, in a mouse infection the stomach bacterial load gradually decreases while the population in the wild-type strain remains stable, showing that endonuclease III deficiency reduces the colonization capacity of the pathogen. In coinfection experiments with a wild-type strain, Hpnth cells are eradicated 15 days postinfection (p.i.) even when inoculated in a 1:9 wild-type:mutant strain ratio, revealing mutagenic lesions that are counterselected under competition conditions. These results show that the host effectively induces lethal and premutagenic oxidative DNA adducts on the H. pylori genome. The possible consequences of these DNA lesions on the adaptability of H. pylori strains to new hosts are discussed.