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,鼠疫杆菌合成具有低Toll样受体4 (TLR4) 刺激活性的脂多糖 (LPS)-脂质A。为了解决弱TLR4刺激对毒力的影响,我们对鼠疫耶尔森氏菌进行了修饰,以产生有效的TLR4-stimulating LPS。即使在高攻击剂量下,改良的鼠疫耶尔森氏菌在皮下感染后也完全无毒。对疾病的抵抗力需要TLR4,衔接子蛋白MyD88和共受体MD-2,并且CD14和衔接子Mal显着增强。对于针对改良菌株的免疫灭菌,需要先天和适应性反应,并且可以保护恢复期小鼠免受野生型鼠疫耶尔森氏菌的皮下和呼吸攻击。尽管存在其他已建立的免疫逃避机制,但改良的鼠疫耶尔森氏菌无法引起全身性疾病,这表明逃避LPS诱导的炎症反应的能力对于鼠疫耶尔森氏菌的毒力至关重要。通过脂质A改变逃避TLR4激活可能有助于各种革兰氏阴性细菌的毒力。

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