The contribution of accessory toxins of Vibrio cholerae O1 El Tor to the proinflammatory response in a murine pulmonary cholera model
The contribution of accessory toxins of Vibrio cholerae O1 El Tor to the proinflammatory response in a murine pulmonary cholera model
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DOI：
10.1084/jem.20020318
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发表时间：
2002-06-03
影响因子：
15.3
通讯作者：
Mekalanos, JJ
中科院分区：
文献类型：
--
作者：
Fullner, KJ;Boucher, JC;Mekalanos, JJ
在小鼠肺部模型中评估了辅助毒素对霍乱弧菌急性炎症反应的贡献。鼻内给予删除霍乱毒素基因 (ctxAB) 的 El Tor 01 霍乱弧菌菌株引起弥漫性肺炎，其特征是 PMN 浸润、组织损伤和出血。相比之下，肌动蛋白交联毒素重复序列（RTX）毒素基因（rtxA）额外缺失的ctxAB突变体引起的病理症状较轻，并且促炎分子白细胞介素（IL）-6和小鼠巨噬细胞炎症蛋白（MIP）-2的血清水平降低。这些数据表明 RTX 毒素会加剧急性炎症反应的严重程度。血凝素/蛋白酶 (hapA) 或溶血素 (hlyA) 基因内的缺失不会显着影响该模型中的毒力。 ctxAB、hlyA、hapA 和 rtxA 的复合缺失产生了菌株 KFV101，该菌株定植于肺部，但会诱发肺部疾病，炎症有限，并显着降低 IL-6 和 MIP-2 的血清滴度。接种 KFV101 的小鼠有 100% 存活，而接种 ctxAB 突变体的小鼠只有 20% 存活。因此，KFV101 毒力的降低使其成为多毒素删除疫苗株的原型，可用于预防霍乱弧菌，而不会产生霍乱副毒素的不利影响。
The contribution of accessory toxins to the acute inflammatory response to Vibrio cholerae was assessed in a murine pulmonary model. Intranasal administration of an El Tor 01 V. cholerae strain deleted of cholera toxin genes (ctxAB) caused diffuse pneumonia characterized by infiltration of PMNs, tissue damage, and hemorrhage. By contrast, the ctxAB mutant with an additional deletion in the actin-cross-linking repeats-in-toxin (RTX) toxin gene (rtxA) caused a less severe pathology and decreased serum levels of proinflammatory molecules interleukin (IL)-6 and murine macrophage inflammatory protein (MIP)-2. These data suggest that the RTX toxin contributes to the severity of acute inflammatory responses. Deletions within the genes for either hemagglutinin/protease (hapA) or hemolysin (hlyA) did not significantly affect virulence in this model. Compound deletion of ctxAB, hlyA, hapA, and rtxA created strain KFV101, which colonized the lung but induced pulmonary disease with limited inflammation and significantly reduced serum titers of IL-6 and MIP-2. 100% of mice inoculated with KFV101 survive, compared with 20% of mice inoculated with the ctxAB mutant. Thus, the reduced virulence of KFV101 makes it a prototype for multi-toxin deleted vaccine strains that could be used for protection against V. cholerae without the adverse effects of the accessory cholera toxins.