Bats are reservoirs for many RNA viruses that are highly pathogenic in humans yet relatively apathogenic in the natural host. It has been suggested that differences in innate immunity are responsible. The antiviral OAS-RNase L pathway is well characterized in humans, but there is little known about its activation and antiviral activity in bats. During infection, OASs, upon sensing double-stranded RNA (dsRNA), produce 2'-5' oligoadenylates (2-5A), leading to activation of RNase L which degrades viral and host RNA, limiting viral replication. Humans encode three active OASs (OAS1 to -3). Analysis of the Egyptian Rousette bat genome combined with mRNA sequencing from bat RoNi/7 cells revealed three homologous OAS proteins. Interferon alpha treatment or viral infection induced all three OAS mRNAs, but RNase L mRNA is constitutively expressed. Sindbis virus (SINV) or vaccinia virus (VACVΔE3L) infection of wild-type (WT) or OAS1-KO (knockout), OAS2-KO, or MAVS-KO RoNi/7 cells, but not RNase L-KO or OAS3-KO cells, induces robust RNase L activation. SINV replication is 100- to 200-fold higher in the absence of RNase L or OAS3 than in WT cells. However, MAVS-KO had no detectable effect on RNA degradation or replication. Thus, in RoNi/7 bat cells, as in human cells, activation of RNase L during infection and its antiviral activity are dependent primarily on OAS3 while MAVS signaling is not required for the activation of RNase L and restriction of infection. Our findings indicate that OAS proteins serve as pattern recognition receptors (PRRs) to recognize viral dsRNA and that this pathway is a primary response to virus rather than a secondary effect of interferon signaling.IMPORTANCE Many RNA viruses that are highly pathogenic in humans are relatively apathogenic in their bat reservoirs, making it important to compare innate immune responses in bats to those well characterized in humans. One such antiviral response is the OAS-RNase L pathway. OASs, upon sensing dsRNA, produce 2-5A, leading to activation of RNase L which degrades viral and host RNA, limiting viral replication. Analysis of Egyptian Rousette bat sequences revealed three OAS genes expressing OAS1, OAS2, and OAS3 proteins. Interferon treatment or viral infection induces all three bat OAS mRNAs. In these bat cells as in human cells, RNase L activation and its antiviral activity are dependent primarily on OAS3 while MAVS signaling is not required. Importantly, our findings indicate the OAS-RNase L system is a primary response to virus rather than a secondary effect of interferon signaling and therefore can be activated early in infection or while interferon signaling is antagonized.

中文翻译：

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埃及卢塞特蝙蝠衍生的RoNi / 7细胞中RNase L的激活主要取决于OAS3，并且独立于MAVS信号传导。

蝙蝠是许多RNA病毒的储存库，这些RNA病毒在人类中具有高致病性，但在天然宿主中却相对无致病性。已经提出先天免疫的差异是造成的。抗病毒的OAS-RNase L途径在人类中已被很好地表征，但是对于蝙蝠的活化和抗病毒活性知之甚少。在感染过程中，OAS在检测到双链RNA（dsRNA）后会产生2'-5'寡腺苷酸（2-5A），导致RNase L活化，从而降解病毒和宿主RNA，从而限制了病毒的复制。人类编码三个活动的OAS（OAS1至-3）。对埃及Rousette蝙蝠基因组的分析与蝙蝠RoNi / 7细胞的mRNA测序相结合，揭示了三种同源的OAS蛋白。干扰素α治疗或病毒感染诱导了所有三个OAS mRNA，但RNase L mRNA组成型表达。Sindbis病毒（SINV）或牛痘病毒（VACVΔE3L）感染野生型（WT）或OAS1-KO（敲除），OAS2-KO或MAVS-KO RoNi / 7细胞，但不感染RNase L-KO或OAS3-KO细胞，诱导强大的RNase L激活。在不存在RNase L或OAS3的情况下，SINV复制比在WT细胞中高100到200倍。但是，MAVS-KO对RNA降解或复制没有可检测的影响。因此，在RoNi / 7 bat细胞中，就像在人类细胞中一样，感染期间RNase L的激活及其抗病毒活性主要取决于OAS3，而MAVS信号传导对于RNase L的激活和感染的限制并不是必需的。我们的发现表明，OAS蛋白可作为识别病毒dsRNA的模式识别受体（PRR），并且该途径是对病毒的主要反应，而不是干扰素信号传导的次要作用。重要说明：许多对人类有高致病性的RNA病毒在蝙蝠储藏室中具有相对的致病性，因此将蝙蝠的先天免疫应答与人类特征明确的那些进行比较非常重要。一种这样的抗病毒应答是OAS-RNase L途径。OAS在检测到dsRNA时会产生2-5A，从而导致RNase L活化，从而降解病毒和宿主RNA，限制病毒复制。分析埃及Rousette蝙蝠序列揭示了三个OAS基因，分别表达OAS1，OAS2和OAS3蛋白。干扰素治疗或病毒感染会诱导所有三个蝙蝠OAS mRNA。在这些蝙蝠细胞中，就像在人类细胞中一样，RNase L的激活及其抗病毒活性主要取决于OAS3，而不需要MAVS信号传导。重要的，