Humanized TLR4/MD-2 mice reveal LPS recognition differentially impacts susceptibility to Yersinia pestis and Salmonella enterica.
Humanized TLR4/MD-2 mice reveal LPS recognition differentially impacts susceptibility to Yersinia pestis and Salmonella enterica.
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DOI：
10.1371/journal.ppat.1002963
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Wilson CB
中科院分区：
文献类型：
--
作者：
Hajjar AM;Ernst RK;Fortuno ES 3rd;Brasfield AS;Yam CS;Newlon LA;Kollmann TR;Miller SI;Wilson CB
虽然脂多糖（LPS）通过Toll样受体（TLR）-4/MD-2受体复合物的刺激激活宿主对革兰氏阴性细菌病原体的防御，但LPS识别的种特异性差异如何影响宿主防御仍不清楚。在此，我们建立了鼠疫耶尔森氏菌LPS的脂质A中的温度依赖性变化如何差异地影响小鼠与人TLR 4/MD-2的识别，从而决定感染易感性。在37°C生长时，Y.与鼠TLR 4/MD-2相比，鼠疫菌LPS是低酰化的，并且对人的刺激性较低。相比之下，当在降低的温度下生长时，Y.鼠疫菌LPS被更多地酰化，并且通过人和小鼠TLR 4/MD-2同等地刺激细胞。为了研究LPS的这些温度依赖性变化如何影响感染易感性，产生了表达人而不是小鼠TLR 4/MD-2的转基因小鼠。我们发现对Y的易感性增加。鼠疫杆菌对“人源化”TLR 4/MD-2小鼠的感染直接抑制了响应于纯化LPS刺激的炎性细胞因子的产生。相比之下，对于具有高度酰化脂质A的其他革兰氏阴性病原体，包括肠道沙门氏菌或大肠杆菌，感染易感性和用LPS刺激后的反应在表达人或小鼠TLR 4/MD-2的小鼠之间是无法区分的。因此，Y.鼠疫杆菌利用LPS酰化中的温度依赖性变化来选择性地逃避用“人源化”TLR 4/MD-2转基因小鼠暴露的人TLR 4/MD-2的识别。革兰氏阴性菌外膜的外小叶主要由脂多糖（LPS，内毒素）组成。LPS的生物活性成分脂质A的结构在细菌之间变化，甚至在不同环境条件下生长的同一物种内也是如此。鼠疫耶尔森菌与过去的高致命性腺鼠疫有关。它根据温度改变LPS的结构。当在与温带气候中的跳蚤相当的环境温度下生长时，LPS主要是六酰化的。然而，当在37°C下生长时，哺乳动物宿主温度、Y.鼠疫杆菌转换合成低酰化LPS，与由Toll样受体（TLR）4和MD-2组成的鼠LPS受体复合物相比，低酰化LPS对人的刺激性较小。为了测试在哺乳动物温度下与复制相关的LPS结构的变化是否促进Y。通过逃避人受体复合物的识别，我们产生了表达人而不是小鼠TLR 4和MD-2的“人源化”小鼠。我们发现，这些小鼠确实对Y。鼠疫菌感染的小鼠比野生型小鼠更少，这支持了逃避TLR 4/MD-2的识别促进鼠疫菌感染的观点。鼠疫对人类的毒性
Although lipopolysaccharide (LPS) stimulation through the Toll-like receptor (TLR)-4/MD-2 receptor complex activates host defense against Gram-negative bacterial pathogens, how species-specific differences in LPS recognition impact host defense remains undefined. Herein, we establish how temperature dependent shifts in the lipid A of Yersinia pestis LPS that differentially impact recognition by mouse versus human TLR4/MD-2 dictate infection susceptibility. When grown at 37°C, Y. pestis LPS is hypo-acylated and less stimulatory to human compared with murine TLR4/MD-2. By contrast, when grown at reduced temperatures, Y. pestis LPS is more acylated, and stimulates cells equally via human and mouse TLR4/MD-2. To investigate how these temperature dependent shifts in LPS impact infection susceptibility, transgenic mice expressing human rather than mouse TLR4/MD-2 were generated. We found the increased susceptibility to Y. pestis for “humanized” TLR4/MD-2 mice directly paralleled blunted inflammatory cytokine production in response to stimulation with purified LPS. By contrast, for other Gram-negative pathogens with highly acylated lipid A including Salmonella enterica or Escherichia coli, infection susceptibility and the response after stimulation with LPS were indistinguishable between mice expressing human or mouse TLR4/MD-2. Thus, Y. pestis exploits temperature-dependent shifts in LPS acylation to selectively evade recognition by human TLR4/MD-2 uncovered with “humanized” TLR4/MD-2 transgenic mice. The outer leaflet of the outer membrane of Gram-negative bacteria is mainly composed of lipopolysaccharide (LPS, endotoxin). The structure of the bioactive component of LPS, lipid A, varies between bacteria and even within the same species grown under different environmental conditions. Yersinia pestis has been associated with highly lethal bubonic plagues of the past. It alters the structure of its LPS based on temperature. When grown at ambient temperatures comparable to fleas in temperate climates, the LPS is mainly hexa-acylated. However, upon growth at 37°C, the mammalian host temperature, Y. pestis switches to synthesize a hypo-acylated LPS that is less stimulatory to the human compared with murine LPS receptor complex composed of Toll-like receptor (TLR) 4 and MD-2. To test whether the change in LPS structure associated with replication at mammalian temperature promotes Y. pestis virulence by evading recognition by the human receptor complex, we generated “humanized” mice that express human rather than mouse TLR4 and MD-2. We find that these mice are indeed more sensitive to Y. pestis infection than WT mice supporting the notion that evasion of recognition by TLR4/MD-2 promotes Y. pestis virulence in humans.
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影响因子：
7.3
作者：
Bowen WS;Minns LA;Johnson DA;Mitchell TC;Hutton MM;Evans JT
通讯作者：
Evans JT
DOI：
10.4049/jimmunol.0901481
发表时间：
2009-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kollmann TR;Crabtree J;Rein-Weston A;Blimkie D;Thommai F;Wang XY;Lavoie PM;Furlong J;Fortuno ES 3rd;Hajjar AM;Hawkins NR;Self SG;Wilson CB
通讯作者：
Wilson CB
影响因子：
6.7
作者：
Fransen, Floris;Heckenberg, Sebastiaan G. B.;van der Ley, Peter
通讯作者：
van der Ley, Peter
影响因子：
56.9
作者：
Mata-Haro, Veronica;Cekic, Caglar;Mitchell, Thomas C.
通讯作者：
Mitchell, Thomas C.
影响因子：
6.4
作者：
Ernst, Robert K.;Moskowitz, Samuel M.;Miller, Samuel I.
通讯作者：
Miller, Samuel I.