Pitré Emmanuelle, Bisht Karishma, Remick Kaleigh A, Ghorbani Amir, Yewdell Jonathan W, Elshina Elizaveta, Te Velthuis Aartjan J W
Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Department of Pathology, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QQ, UK.
Sci Adv. 2025 Aug 8;11(32):eadw8034. doi: 10.1126/sciadv.adw8034.
Influenza A virus (IAV) noncanonical RNAs are bound by retinoic acid-inducible gene I (RIG-I). However, innate immune activation is infrequent and it is not understood why noncanonical IAV RNAs activate RIG-I in a sequence- or RNA structure-dependent manner. We hypothesized that multiple events need to occur before IAV RNA synthesis activates RIG-I and investigated whether RIG-I activation is stimulated by the noncanonical or aberrant transcription of mini viral RNAs (mvRNA), an RNA that is overexpressed in highly pathogenic IAV infections. We find that mvRNAs can cause noncanonical transcription termination through a truncated 5' polyadenylation signal or a 5' transient RNA structure that interrupts polyadenylation. The resulting capped complementary RNAs stimulate the release of an mvRNA and complement RIG-I activation in trans. Overall, our findings indicate that sequential rounds of noncanonical or aberrant viral replication and transcription are needed for innate immune signaling by IAV RNA synthesis.
甲型流感病毒（IAV）的非规范RNA与视黄酸诱导基因I（RIG-I）结合。然而，先天免疫激活并不常见，并且尚不清楚为何非规范IAV RNA以序列或RNA结构依赖的方式激活RIG-I。我们推测在IAV RNA合成激活RIG-I之前需要发生多个事件，并研究了微型病毒RNA（mvRNA）的非规范或异常转录是否会刺激RIG-I激活，mvRNA是一种在高致病性IAV感染中过度表达的RNA。我们发现，mvRNA可通过截短的5'多聚腺苷酸化信号或中断多聚腺苷酸化的5'瞬时RNA结构导致非规范转录终止。由此产生的加帽互补RNA刺激mvRNA的释放，并在反式作用中补充RIG-I激活。总体而言，我们的研究结果表明，IAV RNA合成引发先天免疫信号需要连续几轮非规范或异常的病毒复制和转录。
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