Graham Rachel L, Deming Damon J, Deming Meagan E, Yount Boyd L, Baric Ralph S
Department of Epidemiology, The University of North Carolina at Chapel Hill, 2107 McGavran-Greenberg, CB 7435, Chapel Hill, NC, 27599, USA.
Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Commun Biol. 2018 Oct 29;1:179. doi: 10.1038/s42003-018-0175-7. eCollection 2018.
Emerging and re-emerging zoonotic viral diseases are major threats to global health, economic stability, and national security. Vaccines are key for reducing coronaviral disease burden; however, the utility of live-attenuated vaccines is limited by risks of reversion or repair. Because of their history of emergence events due to their prevalence in zoonotic pools, designing live-attenuated coronavirus vaccines that can be rapidly and broadly implemented is essential for outbreak preparedness. Here, we show that coronaviruses with completely rewired transcription regulatory networks (TRNs) are effective vaccines against SARS-CoV. The TRN-rewired viruses are attenuated and protect against lethal SARS-CoV challenge. While a 3-nt rewired TRN reverts via second-site mutation upon serial passage, a 7-nt rewired TRN is more stable, suggesting that a more extensively rewired TRN might be essential for avoiding growth selection. In summary, rewiring the TRN is a feasible strategy for limiting reversion in an effective live-attenuated coronavirus vaccine candidate that is potentially portable across the Nidovirales order.
新出现和再次出现的人畜共患病毒性疾病是对全球健康、经济稳定和国家安全的重大威胁。疫苗是减轻冠状病毒疾病负担的关键；然而，减毒活疫苗的效用受到回复突变或修复风险的限制。由于它们在人畜共患病原体库中普遍存在而导致出现疫情的历史，设计能够迅速广泛实施的减毒活冠状病毒疫苗对于疫情防范至关重要。在这里，我们表明转录调控网络（TRN）完全重新布线的冠状病毒是针对严重急性呼吸综合征冠状病毒（SARS-CoV）的有效疫苗。TRN重新布线的病毒减毒，并能抵御致死性SARS-CoV攻击。虽然一个3个核苷酸重新布线的TRN在连续传代时会通过第二位点突变回复，但一个7个核苷酸重新布线的TRN更稳定，这表明更广泛地重新布线TRN可能对于避免生长选择至关重要。总之，重新布线TRN是一种可行的策略，可用于限制一种有效的减毒活冠状病毒候选疫苗中的回复突变，该疫苗可能适用于整个尼多病毒目。
