Evaluation of Recombinant Attenuated Salmonella Vaccine Strains for Broad Protection against Extraintestinal Pathogenic Escherichia coli.
Evaluation of Recombinant Attenuated Salmonella Vaccine Strains for Broad Protection against Extraintestinal Pathogenic Escherichia coli.
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DOI：
10.3389/fimmu.2017.01280
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发表时间：
2017
影响因子：
7.3
通讯作者：
Mellata M
中科院分区：
文献类型：
--
作者：
Maddux JT;Stromberg ZR;Curtiss Iii R;Mellata M
抗生素耐药性细菌感染难以治疗，给医疗保健和经济带来负担。肠外致病性大肠杆菌 (ExPEC) 菌株经常携带抗生素抗性基因，引起肠外感染，并且是医院获得性感染的病原体。由于这种病原体的抗生素耐药性和抗原多样性，制定针对这种病原体的预防策略具有挑战性。大肠杆菌普通菌毛 (ECP) 常见于 ExPEC 菌株中，可作为常见抗原来诱导针对多种 ExPEC 血清型的保护。此外，活重组减毒沙门氏菌疫苗（RASV）菌株已被用于预防沙门氏菌感染，并且还可以进行修饰以传递外源抗原。因此，本研究的目的是设计一种RASV，在其表面产生ECP，并评估其提供针对ExPEC感染的保护的能力。为了在RASV菌株中组成型展示ECP，我们对含有天冬氨酸-β-半醛脱氢酶和大肠杆菌ecp基因的载体（pYA4428）进行了基因工程改造，并将其引入RASV χ9558中。含有空载体 (pYA3337) 的 RASV χ9558 用作对照，以评估无 ECP 的 RASV 菌株所赋予的保护作用。我们在体外细菌抑制试验和 ExPEC 相关人类感染的小鼠模型中评估了疫苗的功效。我们发现RASV χ9558(pYA4428)在细菌表面合成了主要菌毛蛋白(EcpA)和尖端菌毛粘附素(EcpD)。小鼠口服接种RASV χ9558(pYA3337)（不含ECP）或χ9558(pYA4428)（含ECP），产生抗沙门氏菌LPS和抗大肠杆菌。大肠杆菌 EcpA 和 EcpD IgG 和 IgA 抗体。根据体外测定的评估，RASV 菌株显示出针对某些大肠杆菌和沙门氏菌菌株的保护潜力。在小鼠败血症和尿路感染攻击模型中，两种疫苗对某些内脏器官具有显着的保护作用。总体而言，这项工作表明，RASV 可以在一些小鼠中引发对大肠杆菌和沙门氏菌抗原的免疫反应，在 ExPEC 攻击期间为一些内脏器官提供显着的保护，因此这项研究是开发预防 ExPEC 感染的疫苗的一个有前景的第一步。未来的研究应该优化 RASV 菌株展示的 ExPEC 抗原，以获得更强大的免疫反应并增强对 ExPEC 感染的保护。
Antibiotic-resistant bacterial infections are difficult to treat, producing a burden on healthcare and the economy. Extraintestinal pathogenic Escherichia coli (ExPEC) strains frequently carry antibiotic resistance genes, cause infections outside of the intestine, and are causative agents of hospital-acquired infections. Developing a prevention strategy against this pathogen is challenging due to its antibiotic resistance and antigenic diversity. E. coli common pilus (ECP) is frequently found in ExPEC strains and may serve as a common antigen to induce protection against several ExPEC serotypes. In addition, live recombinant attenuated Salmonella vaccine (RASV) strains have been used to prevent Salmonella infection and can also be modified to deliver foreign antigens. Thus, the objective of this study was to design a RASV to produce ECP on its surface and assess its ability to provide protection against ExPEC infections. To constitutively display ECP in a RASV strain, we genetically engineered a vector (pYA4428) containing aspartate-β-semialdehyde dehydrogenase and E. coli ecp genes and introduced it into RASV χ9558. RASV χ9558 containing an empty vector (pYA3337) was used as a control to assess protection conferred by the RASV strain without ECP. We assessed vaccine efficacy in in vitro bacterial inhibition assays and mouse models of ExPEC-associated human infections. We found that RASV χ9558(pYA4428) synthesized the major pilin (EcpA) and tip pilus adhesin (EcpD) on the bacterial surface. Mice orally vaccinated with RASV χ9558(pYA3337) without ECP or χ9558(pYA4428) with ECP, produced anti-Salmonella LPS and anti-E. coli EcpA and EcpD IgG and IgA antibodies. RASV strains showed protective potential against some E. coli and Salmonella strains as assessed using in vitro assays. In mouse sepsis and urinary tract infection challenge models, both vaccines had significant protection in some internal organs. Overall, this work showed that RASVs can elicit an immune response to E. coli and Salmonella antigens in some mice, provide significant protection in some internal organs during ExPEC challenge, and thus this study is a promising initial step toward developing a vaccine for prevention of ExPEC infections. Future studies should optimize the ExPEC antigens displayed by the RASV strain for a more robust immune response and enhanced protection against ExPEC infection.
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影响因子：
3.7
作者：
Kalyoussef S;Nieves E;Dinerman E;Carpenter C;Shankar V;Oh J;Burd B;Angeletti RH;Buckheit KW;Fredricks DN;Madan RP;Keller MJ;Herold BC
通讯作者：
Herold BC
影响因子：
1.8
作者：
Hays MP;Ericsson AC;Yang Y;Hardwidge PR
通讯作者：
Hardwidge PR
影响因子：
--
作者：
Gunn, Bronwyn M.;Wanda, Soo-Young;Curtiss, Roy, III
通讯作者：
Curtiss, Roy, III
影响因子：
3.1
作者：
Dolores Juarez-Rodriguez, Maria;Arteaga-Cortes, Lourdes T.;Clark-Curtiss, Josephine E.
通讯作者：
Clark-Curtiss, Josephine E.
影响因子：
5.5
作者：
Galen, James E.;Curtiss, Roy, III
通讯作者：
Curtiss, Roy, III