Molecular Virology Laboratory, Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, Leiden, The Netherlands.
Molecular Virology Laboratory, Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, Leiden, The Netherlands.
Virus Res. 2024 Sep;347:199431. doi: 10.1016/j.virusres.2024.199431. Epub 2024 Jul 9.
Usutu virus (USUV) is an emerging flavivirus that can infect birds and mammals. In humans, in severe cases, it may cause neuroinvasive disease. The innate immune system, and in particular the interferon response, functions as the important first line of defense against invading pathogens such as USUV. Many, if not all, viruses have developed mechanisms to suppress and/or evade the interferon response in order to facilitate their replication. The ability of USUV to antagonize the interferon response has so far remained largely unexplored. Using dual-luciferase reporter assays we observed that multiple of the USUV nonstructural (NS) proteins were involved in suppressing IFN-β production and signaling. In particular NS4A was very effective at suppressing IFN-β production. We found that NS4A interacted with the mitochondrial antiviral signaling protein (MAVS) and thereby blocked its interaction with melanoma differentiation-associated protein 5 (MDA5), resulting in reduced IFN-β production. The TM1 domain of NS4A was found to be essential for binding to MAVS. By screening a panel of flavivirus NS4A proteins we found that the interaction of NS4A with MAVS is conserved among flaviviruses. The increased understanding of the role of NS4A in flavivirus immune evasion could aid the development of vaccines and therapeutic strategies.
乌苏图病毒（USUV）是一种新兴的黄病毒，能够感染鸟类和哺乳动物。在人类中，严重情况下可能导致神经侵袭性疾病。先天免疫系统，特别是干扰素反应，是抵御诸如 USUV 等入侵病原体的重要第一道防线。许多（如果不是全部）病毒已经开发出抑制和/或逃避干扰素反应的机制，以促进其复制。迄今为止，USUV 拮抗干扰素反应的能力在很大程度上仍未得到探索。通过双荧光素酶报告基因检测，我们观察到 USUV 的多个非结构（NS）蛋白参与抑制 IFN-β 的产生和信号转导。特别是 NS4A 非常有效地抑制 IFN-β 的产生。我们发现 NS4A 与线粒体抗病毒信号蛋白（MAVS）相互作用，从而阻止其与黑色素瘤分化相关蛋白 5（MDA5）相互作用，导致 IFN-β 的产生减少。NS4A 的 TM1 结构域对于与 MAVS 的结合是必需的。通过筛选一组黄病毒 NS4A 蛋白，我们发现 NS4A 与 MAVS 的相互作用在黄病毒中是保守的。增加对 NS4A 在黄病毒免疫逃逸中的作用的理解可能有助于疫苗和治疗策略的开发。
