Extending the host range of Listeria monocytogenes by rational protein design
Extending the host range of Listeria monocytogenes by rational protein design
复制标题
DOI：
10.1016/j.cell.2007.03.049
复制
发表时间：
2007-06-01
期刊：
影响因子：
64.5
通讯作者：
Schubert, Wolf-Dieter
中科院分区：
文献类型：
--
作者：
Wollert, Thomas;Pasche, Bastian;Schubert, Wolf-Dieter
在引起疾病的过程中，病原体通过专门的毒力决定因子库来战胜宿主的防御，这些毒力决定因子特异性地结合或修饰单个宿主分子。这种奉献将入侵者限制在一个定义的主机范围内。新出现的疾病大多涉及现有的病原体，这些病原体的武器库被改变，使它们能够感染以前无法接触的宿主。我们通过扩大人类病原体单核细胞增生李斯特菌可通过肠道途径进入的宿主范围来模拟这种偶然发生的情况，其中包括小鼠。通过分析李斯特入侵蛋白InIA及其人受体E-cadherin的识别复合物，我们假设并验证了InIA中的氨基酸取代以增加其对E-cadherin的亲和力。两个单一的取代增加了4个数量级的结合亲和力，并扩展了结合特异性，包括以前不相容的小鼠e -钙粘蛋白。通过合理地调整单一蛋白质，我们因此创建了人类李斯特菌病的多功能小鼠模型。
In causing disease, pathogens outmaneuver host defenses through a dedicated arsenal of virulence determinants that specifically bind or modify individual host molecules. This dedication limits the intruder to a defined range of hosts. Newly emerging diseases mostly involve existing pathogens whose arsenal has been altered to allow them to infect previously inaccessible hosts. We have emulated this chance occurrence by extending the host range accessible to the human pathogen Listeria monocytogenes by the intestinal route to include the mouse. Analyzing the recognition complex of the listerial invasion protein InIA and its human receptor E-cadherin, we postulated and verified amino acid substitutions in InIA to increase its affinity for E-cadherin. Two single substitutions increase binding affinity by four orders of magnitude and extend binding specificity to include formerly incompatible murine E-cadherin. By rationally adapting a single protein, we thus create a versatile murine model of human listeriosis.