Towards a vaccine for attaching/effacing Escherichia coli: a LEE encoded regulator (ler) mutant of rabbit enteropathogenic Escherichia coli is attenuated, immunogenic, and protects rabbits from lethal challenge with the wild-type virulent strain.
Towards a vaccine for attaching/effacing Escherichia coli: a LEE encoded regulator (ler) mutant of rabbit enteropathogenic Escherichia coli is attenuated, immunogenic, and protects rabbits from lethal challenge with the wild-type virulent strain.
复制标题
开发一种用于附着/消除大肠杆菌的疫苗：LEE 编码的兔致病性大肠杆菌的调节 (ler) 突变体具有减毒、免疫原性，可保护兔子免受野生型强毒株的致命攻击。
DOI：
10.1016/j.vaccine.2005.07.019
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发表时间：
2006
期刊：
影响因子：
5.5
通讯作者：
Boedeker,EdgarC
中科院分区：
文献类型：
--
作者：
Zhu,Chengru;Feng,Shuzhang;Thate,TimothyE;Kaper,JamesB;Boedeker,EdgarC
LER（LEE编码调节子）基因产物是包括人肠道致病性大肠杆菌在内的肠道致病性病原体附着/消失（A/E）的肠上皮细胞消失（LEE）致病岛基因座上编码的基因的中心调节子。大肠埃希菌（EPEC）和肠出血性大肠杆菌（E.大肠杆菌（EHEC）以及动物分离株。虽然在细菌毒力的Ler在体内的作用还没有记录，我们假设，一个Ler缺失突变体应减毒的毒力，但可能保留免疫原性。本研究的目的是遗传特性ler的兔EPEC（rEPEC）株（O 103：H2），检查在体内毒力的ler的影响，并确定如果胃内接种减毒rEPEC ler突变体是免疫原性的，可以保护兔对随后的挑战与野生型强毒亲本菌株。预测的rEPEC O 103：H2的ler基因产物与另一株rEPEC RDEC-1（O 15：H-）的Lers以及人EPEC和EHEC的Lers具有高度的同源性（95%以上的氨基酸同源性）。一个确定的内部ler缺失突变体的rEPEC O 103：H2表现出减少生产的分泌蛋白。虽然口服接种的家兔与有毒的亲本O 103：H2菌株诱导严重腹泻，显着的体重减轻和早期死亡率与粘附的粘膜细菌发现在牺牲，同基因的LER突变株耐受性良好。动物体重增加，未显示疾病的临床体征。肠段的组织学切片检查显示没有粘膜细菌粘附。这一结果表明Ler在A/E体内致病性中起重要作用。杆菌rEPEC ler突变体的单剂量口胃免疫诱导血清IgG抗体的全菌（但不intimin）。用WT强毒亲本菌株保护免疫动物免受肠道感染，在处死时表现出正常的体重增加、不存在腹泻和不存在粘膜粘附细菌。这种减毒的ler突变株可能具有用作口服疫苗或用作递送外源抗原的疫苗载体的潜力。这类调控突变体是否能保护不同宿主免受不同血清型A/E细菌感染仍有待确定。
The ler (LEE encoded regulator) gene product is a central regulator for the genes encoded on the locus of enterocyte effacement (LEE) pathogenicity island of attaching/effacing (A/E) pathogens, including human enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) as well as animal isolates. Although an in vivo role for Ler in bacterial virulence has not been documented, we hypothesized that a Ler deletion mutant should be attenuated for virulence but might retain immunogenicity. The goals of this study were to genetically characterize ler of a rabbit EPEC (rEPEC) strain (O103:H2), to examine the effect of ler on in vivo virulence, and to determine if intragastric inoculation of an attenuated rEPEC ler mutant was immunogenic and could protect rabbits against subsequent challenge with the wild-type virulent parent strain. The predicted ler gene product of rEPEC strain O103:H2 shares high homology (over 95% amino acid identity) with the Lers of another rEPEC strain RDEC-1 (O15:H-) and human EPEC and EHEC. A defined internal ler deletion mutant of rEPEC O103:H2 showed reduced production of secreted proteins. Although orogastric inoculation of rabbits with the virulent parent O103:H2 strain induced severe diarrhea, significant weight loss and early mortality with adherent mucosal bacteria found at sacrifice, the isogeneic ler mutant strain was well tolerated. Animals gained weight and showed no clinical signs of disease. Examination of histological sections of intestinal segments revealed the absence of mucosal bacterial adherence. This result demonstrates an essential role for Ler in in vivo pathogenicity of A/E E. coli. Single dose orogastric immunization with the rEPEC ler mutant induced serum IgG antibody to whole bacteria (but not to intimin). Immunized animals were protected against enteric infection with the WT virulent parent strain exhibiting normal weight gain, absence of diarrhea and absence of mucosally adherent bacteria at sacrifice. Such attenuated ler mutant strains may have potential for use as oral vaccines, or as vaccine vectors for delivery of foreign antigens. It remains to be determined whether such regulatory mutants can protect against infection with A/E bacteria of differing serotypes affecting different hosts.