At mammalian body temperature, the plague bacillus Yersinia pestis synthesizes lipopolysaccharide (LPS)-lipid A with poor Toll-like receptor 4 (TLR4)-stimulating activity. To address the effect of weak TLR4 stimulation on virulence, we modified Y. pestis to produce a potent TLR4-stimulating LPS. Modified Y. pestis was completely avirulent after subcutaneous infection even at high challenge doses. Resistance to disease required TLR4, the adaptor protein MyD88 and coreceptor MD-2 and was considerably enhanced by CD14 and the adaptor Mal. Both innate and adaptive responses were required for sterilizing immunity against the modified strain, and convalescent mice were protected from both subcutaneous and respiratory challenge with wild-type Y. pestis. Despite the presence of other established immune evasion mechanisms, the modified Y. pestis was unable to cause systemic disease, demonstrating that the ability to evade the LPS-induced inflammatory response is critical for Y. pestis virulence. Evading TLR4 activation by lipid A alteration may contribute to the virulence of various Gram-negative bacteria.

译文

:在哺乳动物体温下,鼠疫耶尔森菌鼠疫杆菌合成脂多糖(LPS)-脂质A,其Toll样受体4(TLR4)刺激活性较弱。为了解决弱TLR4刺激对毒力的影响,我们修饰了鼠疫耶尔森氏菌以产生有效的TLR4刺激LPS。即使在高激发剂量下,改良的鼠疫耶尔森氏菌在皮下感染后也完全无毒。对疾病的抗性需要TLR4,衔接蛋白MyD88和共受体MD-2,并且CD14和衔接蛋白Mal大大增强了抗病性。对修饰菌株的免疫力需要先天性和适应性应答,野生型鼠疫耶尔森氏菌可以保护恢复期的小鼠免受皮下和呼吸道攻击。尽管存在其他已建立的免疫逃逸机制,但经过修饰的鼠疫耶尔森氏菌不能引起全身性疾病,这表明逃避脂多糖诱导的炎症反应的能力对鼠疫耶尔森氏菌的毒力至关重要。通过脂质A改变而避免TLR4激活可能会导致多种革兰氏阴性细菌的致病性。

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