RNA sensor-induced type I IFN prevents diabetes caused by a β cell-tropic virus in mice
RNA sensor-induced type I IFN prevents diabetes caused by a β cell-tropic virus in mice
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DOI：
10.1172/jci44005
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发表时间：
2011-04-01
影响因子：
15.9
通讯作者：
Colonna, Marco
中科院分区：
文献类型：
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作者：
McCartney, Stephen A.;Vermi, William;Colonna, Marco
病毒感染与I型糖尿病（T1 D）的发病有关，病毒被认为通过引起β细胞损伤和随后的自身抗原释放直接诱导疾病，并通过病毒触发的宿主I型干扰素（IFN-I）反应间接诱导疾病。与此一致，对T1 D的抗性与损害黑素瘤分化相关基因-5（MDA 5）功能的多态性相关，所述基因5是激发IFN-1应答的病毒RNA的传感器。在动物模型中，另一种病毒传感器TLR 3的触发与糖尿病有关。在这里，我们发现MDA 5和TLR 3都是预防脑心肌炎病毒株D（EMCV-D）感染的小鼠糖尿病所必需的，该病毒株D对胰腺产生胰岛素的β细胞具有嗜性。Tlr 3（-/-）小鼠感染引起糖尿病是由于IFN-I应答受损和病毒诱导的β细胞损伤，而不是T细胞介导的自身免疫。当感染EMCV-D时，仅缺乏1个Mda 5拷贝的小鼠出现短暂的高血糖症，而纯合Mda 5（-/-）小鼠出现严重的心脏病理学。TLR 3和MDA 5分别通过作用于造血细胞和基质细胞，在动力学不同的时间点诱导IFN-1应答，从而控制EMCV-D感染和糖尿病。因此，我们得出结论，当由感染和损害胰腺β细胞的病毒引起糖尿病时，需要病毒传感器的最佳功能和及时的IFN-I反应来预防糖尿病。
Viral infections have been linked to the onset of type I diabetes (T1D), with viruses postulated to induce disease directly by causing beta cell injury and subsequent release of autoantigens and indirectly via the host type I interferon (IFN-I) response triggered by the virus. Consistent with this, resistance to T1D is associated with polymorphisms that impair the function of melanoma differentiation associated gene-5 (MDA5), a sensor of viral RNA that elicits IFN-I responses. In animal models, triggering of another viral sensor, TLR3, has been implicated in diabetes. Here, we found that MDA5 and TLR3 are both required to prevent diabetes in mice infected with encephalomyocarditis virus strain D (EMCV-D), which has tropism for the insulin-producing beta cells of the pancreas. Infection of Tlr3(-/-) mice caused diabetes due to impaired IFN-I responses and virus-induced beta cell damage rather than T cell-mediated autoimmunity. Mice lacking just 1 copy of Mda5 developed transient hyperglycemia when infected with EMCV-D, whereas homozygous Mda5(-/-) mice developed severe cardiac pathology. TLR3 and MDA5 controlled EMCV-D infection and diabetes by acting in hematopoietic and stromal cells, respectively, inducing IFN-I responses at kinetically distinct time points. We therefore conclude that optimal functioning of viral sensors and prompt IFN-I responses are required to prevent diabetes when caused by a virus that infects and damages the beta cells of the pancreas.