Sweeney Gibbons Joyce, Thakur Naveen, Komers Emma, Vogel Olivia A, Chakraborty Poushali, Tufariello JoAnn M, Basler Christopher F
Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Viruses. 2025 Aug 5;17(8):1082. doi: 10.3390/v17081082.
Měnglà virus (MLAV) is a member of the genus in the family which also includes Ebola virus (EBOV) and Marburg virus (MARV). Whether MLAV poses a threat to human health is uncertain. However, the MLAV VP35 and VP40 proteins can impair IFNα/β gene expression and block IFNα/β-induced Jak-STAT signaling, respectively, suggesting the capacity to counteract human innate immune defenses. In this study, MLAV VP40 is demonstrated to impair the Sendai virus (SeV)-induced activation of the IFNβ promoter. Inhibition is independent of the MLAV VP40 PPPY late-domain motif that interacts with host proteins possessing WW-domains to promote viral budding. Similar IFNβ promoter inhibition was not detected for EBOV or MARV VP40. MLAV VP40 exhibited lesser capacity to inhibit TNFα activation of an NF-κB reporter gene. MLAV VP40 impaired IFNβ promoter activation by an over-expressed, constitutively active form of RIG-I and by the over-expressed IRF3 kinases TBK1 and IKKε. However, MLAV VP40 did not inhibit IFNβ promoter activation by constitutively active IRF3 5D. Consistent with these findings, MLAV VP40 inhibited SeV-induced IRF3 phosphorylation. Although IRF3 phosphorylation occurs in the cytoplasm, MLAV VP40 exhibits substantial nuclear localization, accumulating in foci in HeLa cell nuclei. In contrast, the VP40 of EBOV and MARV exhibited lower degrees of nuclear localization and did not accumulate in foci. MLAV VP40 interacts with importin alpha-1 (IMPα1), suggesting entry via the IMPα/IMPβ nuclear import pathway. Cumulatively, these data identify novel features that distinguish MLAV VP40 from its homologues in EBOV and MARV.
勐腊病毒（MLAV）是该科属的成员之一，该科还包括埃博拉病毒（EBOV）和马尔堡病毒（MARV）。MLAV是否对人类健康构成威胁尚不确定。然而，MLAV的VP35和VP40蛋白可分别损害IFNα/β基因表达并阻断IFNα/β诱导的Jak-STAT信号传导，提示其具有对抗人类先天免疫防御的能力。在本研究中，证实MLAV VP40可损害仙台病毒（SeV）诱导的IFNβ启动子激活。抑制作用独立于MLAV VP40的PPPY晚期结构域基序，该基序与具有WW结构域的宿主蛋白相互作用以促进病毒出芽。未检测到EBOV或MARV VP40对IFNβ启动子有类似的抑制作用。MLAV VP40抑制NF-κB报告基因TNFα激活的能力较弱。MLAV VP40通过过表达的组成型活性形式的RIG-I以及过表达的IRF3激酶TBK1和IKKε损害IFNβ启动子激活。然而，MLAV VP40不抑制组成型活性IRF3 5D对IFNβ启动子的激活。与这些发现一致，MLAV VP40抑制SeV诱导的IRF3磷酸化。虽然IRF3磷酸化发生在细胞质中，但MLAV VP40表现出大量核定位，在HeLa细胞核中聚集成灶。相比之下，EBOV和MARV的VP40核定位程度较低，且不聚集成灶。MLAV VP40与输入蛋白α-1（IMPα1）相互作用，提示其通过IMPα/IMPβ核输入途径进入细胞核。总的来说，这些数据确定了区分MLAV VP40与其在EBOV和MARV中的同源物的新特征。
