An essential role for the antiviral endoribonuclease, RNase-L, in antibacterial immunity
An essential role for the antiviral endoribonuclease, RNase-L, in antibacterial immunity
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DOI：
10.1073/pnas.0807265105
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发表时间：
2008-12-30
影响因子：
11.1
通讯作者：
Hassel, Bret A.
中科院分区：
文献类型：
--
作者：
Li, Xiao-Ling;Ezelle, Heather J.;Hassel, Bret A.
I型IFN被发现为主要的抗病毒细胞因子，并且现在已知在宿主防御细菌病原体中起关键作用。因此，IFN抗病毒活性的确定介质可能介导以前未被认识到的抗菌功能。RNase-L是RNA衰变途径的末端组分，是IFN诱导的抗病毒活性的重要介质。在这里，我们确定了RNase-L在宿主抗菌反应中的作用。RNase-L（-/-）小鼠在用炭疽杆菌和大肠杆菌攻击后死亡率急剧增加;这种易感性增加是由于免疫应答受损导致细菌负荷增加。RNase-L抗菌活性机制的研究表明，RNase-L是最佳诱导促炎细胞因子所必需的，所述促炎细胞因子在宿主防御细菌病原体中起重要作用。RNase-L还调节内溶酶体蛋白酶、组织蛋白酶-E和内体相关活性的表达，其功能是消除内化的细菌，并可能有助于RNase-L的抗微生物作用。我们的研究结果揭示了RNase-L在通过多种机制介导的抗菌反应中的独特作用。作为先天免疫应答的基本组分的调节剂，RNase-L代表了增强宿主对多种微生物病原体的防御的可行的治疗靶标。
Type I IFNs were discovered as the primary antiviral cytokines and are now known to serve critical functions in host defense against bacterial pathogens. Accordingly, established mediators of IFN antiviral activity may mediate previously unrecognized antibacterial functions. RNase-L is the terminal component of an RNA decay pathway that is an important mediator of IFN-induced antiviral activity. Here, we identify a role for RNase-L in the host antibacterial response. RNase-L(-/-)mice exhibited a dramatic increase in mortality after challenge with Bacillus anthracis and Escherichia coli; this increased susceptibility was due to a compromised immune response resulting in increased bacterial load. Investigation of the mechanisms of RNase-L antibacterial activity indicated that RNase-L is required for the optimal induction of proinflammatory cytokines that play essential roles in host defense from bacterial pathogens. RNase-L also regulated the expression of the endolysosomal protease, cathepsin-E, and endosome-associated activities, that function to eliminate internalized bacteria and may contribute to RNase-L antimicrobial action. Our results reveal a unique role for RNase-L in the antibacterial response that is mediated through multiple mechanisms. As a regulator of fundamental components of the innate immune response, RNase-L represents a viable therapeutic target to augment host defense against diverse microbial pathogens.