Soft Landing - TLR4 and Yersinia pestis

Toll样受体4及其辅助受体MD-2介导脂多糖识别 (IPS)，所有革兰氏阴性细菌的一种成分。在过去的几年里，情况变得很明显 小鼠和人TLR4/MD-2对内毒素结构的识别存在差异。 有趣的是，当鼠疫耶尔森氏菌感染哺乳动物宿主时，它会改变其内毒素的结构 它的跳蚤媒介。它从高度促炎症的结构转变为 人类受体上的拮抗剂，而不是老鼠受体上的拮抗剂。来研究这一现象的生物学后果 我们已经产生了一个表达人类受体的小鼠模型，而不是 小鼠受体。我们预测这只小鼠将更容易受到鼠疫杆菌的感染。 人类TLR4基因多态已被证明与多种疾病有关，而 MD-2中类似的编码变体尚未被描述。来自Wurfel/Martin项目的数据 表明D299G/T399I TLR4变异体对鼠疫杆菌脂多糖的反应性更低 哺乳动物的体温。因此，我们也在生成一个表达该变体的小鼠模型。 这些研究将确定TLR4在体内对鼠疫杆菌的先天和适应性反应中的作用 以及鼠伤寒沙门氏菌，第一个被证明改变其内毒素的革兰氏阴性细菌 感染哺乳动物细胞。 最后，TLR4介导的免疫调节剂已被证明可以保护小鼠免受弗朗西塞氏菌的侵袭 新城疫杆菌或鼠疫耶尔森菌感染。因此，我们将研究 人源化小鼠对这些TLR4激动剂的反应。 所有这些实验都将确定物种特定差异对 人和小鼠TLR4对各种脂多糖结构的识别。

Toll-like receptor 4 (TLR4) and its coreceptor MD-2 mediate recognition of lipopolysaccharide (IPS), a component of all Gram negative bacteria. In the last few years it has become clear that differences in recognition of LPS structures between mouse and human TLR4/MD-2 exist. Interestingly, Yersinia pestis alters the structure of its LPS when it infects the mammalian host from its flea vector. It switches from a structure that is highly proinflammatory to one that is an antagonist on the human but not mouse receptor. To study the biological consequences of this modification we have generated a mouse model that expresses the human receptor instead of the mouse receptor. We predict this mouse will be more susceptible to Y. pestis infection. Human TLR4 polymorphisms have been shown to be associated with various diseases whereas similar coding variants in MD-2 have yet to be described. Data from the Wurfel/Martin project indicates that the D299G/T399I TLR4 variant is even less responsive to Y. pestis LPS at mammalian temperature. Therefore we are also generating a mouse model expressing this variant. These studies will determine the in vivo role of TLR4 in innate and adaptive responses to Y. pestis as well as Salmonella typhimurium, the first Gram negative bacterium shown to alter its LPS upon infecting mammalian cells. Finally, TLR4-mediated immunomodulators have been shown to protect mice from Francisella novicida or Y. pestis infection upon pretreatment with the compounds. We will therefore examine the response of the humanized mice to these TLR4 agonists. All together these experiments will determine the impact of species-specific differences in the recognition of various LPS structures by human and mouse TLR4.