Hilimire Thomas A, Nogales Aitor, Chiem Kevin, Ortego Javier, Martinez-Sobrido Luis
Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Center for Animal Health Research, INIA-CISA, 28130 Valdeolmos, Madrid, Spain.
Pathogens. 2020 Jan 29;9(2):86. doi: 10.3390/pathogens9020086.
Seasonal influenza epidemics remain one of the largest public health burdens nowadays. The best and most effective strategy to date in preventing influenza infection is a worldwide vaccination campaign. Currently, two vaccines are available to the public for the treatment of influenza infection, the chemically Inactivated Influenza Vaccine (IIV) and the Live Attenuated Influenza Vaccine (LAIV). However, the LAIV is not recommended for parts of the population, such as children under the age of two, immunocompromised individuals, the elderly, and pregnant adults. In order to improve the safety of the LAIV and make it available to more of the population, we sought to further attenuate the LAIV. In this study, we demonstrate that the influenza A virus (IAV) master donor virus (MDV) A/Ann Arbor/6/60 H2N2 LAIV can inhibit host gene expression using both the PA-X and NS1 proteins. Furthermore, we show that by removing PA-X, we can limit the replication of the MDV LAIV in a mouse model, while maintaining full protective efficacy. This work demonstrates a broadly applicable strategy of tuning the amount of host antiviral responses induced by the IAV MDV for the development of newer and safer LAIVs. Moreover, our results also demonstrate, for the first time, the feasibility of genetically manipulating the backbone of the IAV MDV to improve the efficacy of the current IAV LAIV.
季节性流感流行至今仍是最大的公共卫生负担之一。迄今为止，预防流感感染的最佳且最有效的策略是全球范围的疫苗接种运动。目前，有两种疫苗可供公众用于治疗流感感染，即化学灭活流感疫苗（IIV）和减毒活流感疫苗（LAIV）。然而，LAIV不推荐用于部分人群，如两岁以下儿童、免疫功能低下者、老年人以及怀孕的成年人。为了提高LAIV的安全性并使其能供更多人群使用，我们试图进一步减弱LAIV的毒性。在本研究中，我们证明甲型流感病毒（IAV）主供体病毒（MDV）A/Ann Arbor/6/60 H2N2 LAIV可利用PA-X和NS1蛋白抑制宿主基因表达。此外，我们表明通过去除PA-X，我们可以在小鼠模型中限制MDV LAIV的复制，同时保持完全的保护效力。这项工作展示了一种广泛适用的策略，即调节IAV MDV诱导的宿主抗病毒反应量，以开发更新、更安全的LAIV。此外，我们的结果还首次证明了对IAV MDV主干进行基因操作以提高当前IAV LAIV效力的可行性。
