Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA.
Viruses. 2020 Aug 19;12(9):907. doi: 10.3390/v12090907.
Mammarenaviruses include several known human pathogens, such as the prototypic lymphocytic choriomeningitis virus (LCMV) that can cause neurological diseases and Lassa virus (LASV) that causes endemic hemorrhagic fever infection. LASV-infected patients show diverse clinical manifestations ranging from asymptomatic infection to hemorrhage, multi-organ failures and death, the mechanisms of which have not been well characterized. We have previously shown that the matrix protein Z of pathogenic arenaviruses, including LASV and LCMV, can strongly inhibit the ability of the innate immune protein RIG-I to suppress type I interferon (IFN-I) expression, which serves as a mechanism of viral immune evasion and virulence. Here, we show that Z proteins of diverse LASV isolates derived from rodents and humans have a high degree of sequence variations at their N- and C-terminal regions and produce variable degrees of inhibition of human RIG-I (hRIG-I) function in an established IFN-β promoter-driven luciferase (LUC) reporter assay. Additionally, we show that Z proteins of four known LCMV strains can also inhibit hRIG-I at variable degrees of efficiency. Collectively, our results confirm that Z proteins of pathogenic LASV and LCMV can inhibit hRIG-I and suggest that strain variations of the Z proteins can influence their efficiency to suppress host innate immunity that might contribute to viral virulence and disease heterogeneity.
沙粒病毒包括几种已知的人类病原体，例如引起神经疾病的典型淋巴细胞性脉络丛脑膜炎病毒（Lymphocytic Choriomeningitis Virus，LCMV）和引起地方性出血热感染的拉萨病毒（Lassa Virus，LASV）。LASV 感染的患者表现出不同的临床表现，从无症状感染到出血、多器官衰竭和死亡，其机制尚未得到很好的描述。我们之前已经表明，包括 LASV 和 LCMV 在内的致病沙粒病毒的基质蛋白 Z 可以强烈抑制先天免疫蛋白 RIG-I 抑制 I 型干扰素（IFN-I）表达的能力，这是病毒免疫逃逸和毒力的一种机制。在这里，我们表明来自啮齿动物和人类的不同 LASV 分离株的 Z 蛋白在其 N 和 C 末端区域具有高度的序列变异，并在已建立的 IFN-β 启动子驱动的荧光素酶（LUC）报告基因测定中产生不同程度的抑制人 RIG-I（hRIG-I）功能的作用。此外，我们还表明，四种已知的 LCMV 株的 Z 蛋白也可以以不同的效率抑制 hRIG-I。总之，我们的结果证实了致病性 LASV 和 LCMV 的 Z 蛋白可以抑制 hRIG-I，并表明 Z 蛋白的株间变异可能影响其抑制宿主先天免疫的效率，这可能有助于病毒的毒力和疾病异质性。
