Virulence of Pseudomonas aeruginosa in a murine model of gastrointestinal colonization and dissemination in neutropenia
Virulence of Pseudomonas aeruginosa in a murine model of gastrointestinal colonization and dissemination in neutropenia
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DOI：
10.1128/iai.73.4.2262-2272.2005
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发表时间：
2005-04-01
影响因子：
3.1
通讯作者：
Pier, GB
中科院分区：
文献类型：
--
作者：
Koh, AY;Priebe, GP;Pier, GB
癌症患者中的铜绿假单胞菌菌血症是在化疗诱导的中性粒细胞减少症和胃肠道粘膜损伤的情况下，从最初的胃肠道（GI）定植移位到血流中发展而来的。我们建立了一个可重复的小鼠模型，铜绿假单胞菌胃肠道定植和全身传播的中性粒细胞减少症。小鼠接受2 mg链霉素/ml饮用水和1，500 U青霉素G/ml持续4天，然后摄入10（7）CFU铜绿假单胞菌/ml饮用水持续5天。在确定GI定殖水平后，然后将环磷酰胺（Cy）腹膜内（i. p.）每隔一天注射三次，或者腹膜内注射抗神经递质单克隆抗体RB 6 - 8 C5一次。传播定义为濒死或死亡小鼠脾脏中存在铜绿假单胞菌。在该小鼠模型中，铜绿假单胞菌定殖于胃肠道，然后一旦施用Cy或RB 6 - 8 C5就全身性传播。发现与Cy剂量相关的中性粒细胞减少症的持续时间和强度是比较不同铜绿假单胞菌菌株的毒力的手段，如通过比较缺乏或产生增强毒力的ExoU细胞毒素的菌株所展示的。脂多糖外核多糖和0侧链在建立GI定殖中是关键的，并且缺乏aroA基因（合成芳香族氨基酸所必需的）的铜绿假单胞菌突变体能够建立GI定殖，但不能传播。在该模型中可以研究铜绿假单胞菌发病机制的定殖和传播阶段，这应该被证明对评估发病机制、治疗和控制铜绿假单胞菌医院感染的相关手段是有用的。
Pseudomonas aeruginosa bacteremia in cancer patients develops from initial gastrointestinal (GI) colonization with translocation into the bloodstream in the setting of chemotherapy-induced neutropenia and GI mucosal damage. We established a reproducible mouse model of P. aeruginosa GI colonization and systemic spread during neutropenia. Mice received 2 mg of streptomycin/ml of drinking water and 1,500 U of penicillin G/ml for 4 days and then ingested 10(7) CFU of A aeruginosa per ml of drinking water for 5 days. After GI colonization levels were determined, cyclophosphamide (Cy) was then injected intraperitoneally (i.p.) three times every other day or an antineutrophil monoclonal antibody, RB6-8C5, was injected i.p. once. Dissemination was defined by the presence of P. aeruginosa in spleens of moribund or dead mice. In this mouse model, P. aeruginosa colonizes the GI tract and then disseminates systemically once Cy or RB6-8C5 is administered. The duration and intensity of neutropenia, related to Cy dose, was found to be a means to compare the virulence of different P. aeruginosa strains, as exhibited by comparisons of strains lacking or producing the virulence-enhancing ExoU cytotoxin. The lipopolysaccharide outer core polysaccharide and 0 side chains were critical in establishing GI colonization, and P. aeruginosa mutants lacking the aroA gene (necessary for synthesizing aromatic amino acids) were able to establish GI colonization but unable to disseminate. Both the colonization and dissemination phases of P. aeruginosa pathogenesis can be studied in this model, which should prove useful for evaluating pathogenesis, therapies, and associated means to control P. aeruginosa nosocomial infections.