Saleh Maria-Carla, Tassetto Michel, van Rij Ronald P, Goic Bertsy, Gausson Valérie, Berry Bassam, Jacquier Caroline, Antoniewski Christophe, Andino Raul
Department of Microbiology and Immunology, University of California, San Francisco 94122-2280, USA.
Nature. 2009 Mar 19;458(7236):346-50. doi: 10.1038/nature07712. Epub 2009 Feb 8.
Multicellular organisms evolved sophisticated defence systems to confer protection against pathogens. An important characteristic of these immune systems is their ability to act both locally at the site of infection and at distal uninfected locations. In insects, such as Drosophila melanogaster, RNA interference (RNAi) mediates antiviral immunity. However, the antiviral RNAi defence in flies seems to be a local, cell-autonomous process, as flies are thought to be unable to generate a systemic RNAi response. Here we show that a recently defined double-stranded RNA (dsRNA) uptake pathway is essential for effective antiviral RNAi immunity in adult flies. Mutant flies defective in this dsRNA uptake pathway were hypersensitive to infection with Drosophila C virus and Sindbis virus. Mortality in dsRNA-uptake-defective flies was accompanied by 100-to 10(5)-fold increases in viral titres and higher levels of viral RNA. Furthermore, inoculating naked dsRNA into flies elicited a sequence-specific antiviral immune response that required an intact dsRNA uptake pathway. These findings suggest that spread of dsRNA to uninfected sites is essential for effective antiviral immunity. Notably, infection with green fluorescent protein (GFP)-tagged Sindbis virus suppressed expression of host-encoded GFP at a distal site. Thus, similar to protein-based immunity in vertebrates, the antiviral RNAi response in flies also relies on the systemic spread of a virus-specific immunity signal.
多细胞生物进化出了复杂的防御系统来抵御病原体。这些免疫系统的一个重要特征是它们能够在感染部位局部发挥作用，也能在未感染的远端部位发挥作用。在果蝇等昆虫中，RNA干扰（RNAi）介导抗病毒免疫。然而，果蝇中的抗病毒RNAi防御似乎是一个局部的、细胞自主的过程，因为人们认为果蝇无法产生系统性RNAi反应。在这里，我们表明，最近定义的双链RNA（dsRNA）摄取途径对于成年果蝇有效的抗病毒RNAi免疫至关重要。在该dsRNA摄取途径中存在缺陷的突变果蝇对果蝇C病毒和辛德毕斯病毒感染高度敏感。dsRNA摄取缺陷果蝇的死亡率伴随着病毒滴度增加100至10⁵倍以及病毒RNA水平升高。此外，将裸露的dsRNA接种到果蝇中引发了序列特异性抗病毒免疫反应，这需要完整的dsRNA摄取途径。这些发现表明，dsRNA扩散到未感染部位对于有效的抗病毒免疫至关重要。值得注意的是，用绿色荧光蛋白（GFP）标记的辛德毕斯病毒感染会抑制远端部位宿主编码的GFP表达。因此，与脊椎动物中基于蛋白质的免疫类似，果蝇中的抗病毒RNAi反应也依赖于病毒特异性免疫信号的系统性扩散。
