The Genotoxin Colibactin Exacerbates Lymphopenia and Decreases Survival Rate in Mice Infected With Septicemic Escherichia coli
The Genotoxin Colibactin Exacerbates Lymphopenia and Decreases Survival Rate in Mice Infected With Septicemic Escherichia coli
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DOI：
10.1093/infdis/jiu071
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发表时间：
2014-07-15
影响因子：
6.4
通讯作者：
Oswald, Eric
中科院分区：
文献类型：
--
作者：
Marcq, Ingrid;Martin, Patricia;Oswald, Eric
脓毒症是一种危及生命的感染。大肠杆菌是导致败血症的菌血症的第一个已知原因。淋巴细胞减少症比传统的感染标志物更能预测菌血症。pks基因组岛是肠外致病性大肠杆菌所携带的。大肠杆菌（ExPEC）和编码基因毒素大肠杆菌素，是流行病学与菌血症。为了研究大肠杆菌素和淋巴细胞减少症之间可能的关系，我们检测了淋巴细胞瞬时感染产生和不产生遗传毒素的细菌的影响。使用败血症小鼠模型比较临床ExPEC分离株与其大肠杆菌素产生受损的同基因突变体的毒力。我们观察到，大肠杆菌素诱导感染的淋巴细胞的DNA双链断裂，导致细胞周期停滞和细胞凋亡的细胞死亡。E.与不能产生大肠杆菌素的同基因突变体相比，产生大肠杆菌素的大肠杆菌在败血症小鼠中诱导更严重的淋巴细胞减少。在一个脓毒症模型中，小鼠接受补液和抗生素治疗，细菌产生的大肠杆菌素与明显较低的存活率有关。总之，我们证明了大肠杆菌产大肠杆菌素。大肠杆菌会加重与败血症相关的淋巴细胞减少症，并可能降低败血症的生存机会。
Sepsis is a life-threatening infection. Escherichia coli is the first known cause of bacteremia leading to sepsis. Lymphopenia was shown to predict bacteremia better than conventional markers of infection. The pks genomic island, which is harbored by extraintestinal pathogenic E. coli (ExPEC) and encodes the genotoxin colibactin, is epidemiologically associated with bacteremia. To investigate a possible relationship between colibactin and lymphopenia, we examined the effects of transient infection of lymphocytes with bacteria that were and those that were not producing the genotoxin. A mouse model of sepsis was used to compare the virulence of a clinical ExPEC isolate with its isogenic mutant impaired for the production of colibactin. We observed that colibactin induced double-strand breaks in the DNA of infected lymphocytes, leading to cell cycle arrest and to cell death by apoptosis. E. coli producing colibactin induced a more profound lymphopenia in septicemic mice, compared with the isogenic mutant unable to produce colibactin. In a sepsis model in which the mice were treated by rehydration and antibiotics, the production of colibactin by the bacteria was associated with a significantly lower survival rate. In conclusion, we demonstrate that production of colibactin by E. coli exacerbates lymphopenia associated with septicemia and could impair the chances to survive sepsis.