Genetic fusions of a CFA/I/II/IV MEFA (multiepitope fusion antigen) and a toxoid fusion of heat-stable toxin (STa) and heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC) retain broad anti-CFA and antitoxin antigenicity.
Genetic fusions of a CFA/I/II/IV MEFA (multiepitope fusion antigen) and a toxoid fusion of heat-stable toxin (STa) and heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC) retain broad anti-CFA and antitoxin antigenicity.
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DOI：
10.1371/journal.pone.0121623
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Ruan X;Sack DA;Zhang W
长期以来，免疫学异质性一直是开发广泛有效的疫苗以保护人类和动物免受细菌和病毒感染的主要挑战。产肠毒素大肠杆菌（ETEC）菌株是导致人类腹泻的主要细菌，它表达至少23种免疫上不同的定植因子抗原（CFAs）和两种不同的肠毒素[热不稳定毒素（LT）和热稳定毒素Ib型（STa或hSTa）]。表达任何一种或两种CFAs和任一毒素的ETEC菌株可引起腹泻，因此疫苗可诱导对大多数CFAs（如果不是全部）和两种毒素的广泛免疫，预计对ETEC有效。在本研究中，我们采用多表位融合抗原（MEFA）策略构建ETEC抗原，并检测抗原的广泛抗cfa和抗毒素免疫原性。CFA MEFA CFA/I/II/IV [CVI, 2014, 21(2): 247 -9]携带最流行和毒力最强的ETEC菌株表达的7种CFAs [CFA/I， CFA/II (CS1, CS2, CS3), CFA/IV (CS4, CS5, CS6)]的表位，将CFA/I/II/IV- staa14q - dmlt和CFA/I/II/IV- stan12s - dmlt的类毒菌融合单体3xSTaA14Q-dmLT和CFA/I/II/IV- stan12s - dmlt基因融合到lta - sta中[IAI， 2014, 82(5):1823-32]。腹腔注射CFA/I/II/IV- sta - toxooid - dmlt MEFA的小鼠产生了针对7种CFA和这两种毒素的抗体，其水平相当于或相当于CFA/I/II/IV MEFA和类毒素融合3xSTaN12S-dmLT诱导的抗体水平。此外，诱导的抗体对表达这7种CFAs的ETEC或大肠杆菌菌株具有体外粘附抑制活性，并对这两种毒素具有中和活性。这些结果表明，CFA/I/II/IV- sta - toxooid - dmlt MEFA或CFA/I/II/IV MEFA联合3xSTaN12S-dmLT可诱导广泛保护性的抗CFA和抗毒素免疫，并提示其在广泛有效的ETEC疫苗开发中的潜在应用。这种MEFA策略通常可用于多价疫苗开发。
Immunological heterogeneity has long been the major challenge in developing broadly effective vaccines to protect humans and animals against bacterial and viral infections. Enterotoxigenic Escherichia coli (ETEC) strains, the leading bacterial cause of diarrhea in humans, express at least 23 immunologically different colonization factor antigens (CFAs) and two distinct enterotoxins [heat-labile toxin (LT) and heat-stable toxin type Ib (STa or hSTa)]. ETEC strains expressing any one or two CFAs and either toxin cause diarrhea, therefore vaccines inducing broad immunity against a majority of CFAs, if not all, and both toxins are expected to be effective against ETEC. In this study, we applied the multiepitope fusion antigen (MEFA) strategy to construct ETEC antigens and examined antigens for broad anti-CFA and antitoxin immunogenicity. CFA MEFA CFA/I/II/IV [CVI 2014, 21(2):243-9], which carried epitopes of seven CFAs [CFA/I, CFA/II (CS1, CS2, CS3), CFA/IV (CS4, CS5, CS6)] expressed by the most prevalent and virulent ETEC strains, was genetically fused to LT-STa toxoid fusion monomer 3xSTaA14Q-dmLT or 3xSTaN12S-dmLT [IAI 2014, 82(5):1823-32] for CFA/I/II/IV-STaA14Q-dmLT and CFA/I/II/IV-STaN12S-dmLT MEFAs. Mice intraperitoneally immunized with either CFA/I/II/IV-STa-toxoid-dmLT MEFA developed antibodies specific to seven CFAs and both toxins, at levels equivalent or comparable to those induced from co-administration of the CFA/I/II/IV MEFA and toxoid fusion 3xSTaN12S-dmLT. Moreover, induced antibodies showed in vitro adherence inhibition activities against ETEC or E. coli strains expressing these seven CFAs and neutralization activities against both toxins. These results indicated CFA/I/II/IV-STa-toxoid-dmLT MEFA or CFA/I/II/IV MEFA combined with 3xSTaN12S-dmLT induced broadly protective anti-CFA and antitoxin immunity, and suggested their potential application in broadly effective ETEC vaccine development. This MEFA strategy may be generally used in multivalent vaccine development.
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