Li Wen, Hofer Markus J, Jung So Ri, Lim Sue-Ling, Campbell Iain L
School of Molecular Bioscience and the Bosch Institute, University of Sydney, Sydney, NSW, Australia.
School of Molecular Bioscience and the Bosch Institute, University of Sydney, Sydney, NSW, Australia
J Virol. 2014 Jul;88(13):7578-88. doi: 10.1128/JVI.03117-13. Epub 2014 Apr 23.
Following systemic infection with lymphocytic choriomeningitis virus (LCMV), STAT1 knockout (KO) mice but not wild-type, STAT2 KO, IRF9 KO, or IFNAR KO mice develop lethal disease perpetrated by CD4(+) T cells. IRF7 is a key transcriptional activator of type I IFN (IFN-I) during LCMV infection. Here, the role of IRF7 in the lethal host response to LCMV infection in STAT1 KO mice was examined. In contrast to STAT1 KO mice, STAT1/IRF7 double KO (DKO) mice survived LCMV infection with a reduced immune pathology in key organs, such as the liver and spleen. However, similar to STAT1 KO mice, STAT1/IRF7 DKO mice failed to control LCMV replication and spread. LCMV infection in STAT1 KO mice was associated with a significant elevation in the levels of a number of cytokines in serum, including IFN-Is, but this was largely absent in STAT1/IRF7 DKO mice, which had a modest increase in the levels of gamma interferon and CCL2 only. Since IRF7 is known to be a key transcriptional regulator of IFN-I gene expression, the possible role of IFN-I in lethal disease was examined further. STAT1/IFNAR DKO mice, in contrast to STAT1 KO mice, all survived infection with LCMV and exhibited little tissue immune pathology. Additionally, STAT1 KO mice that were deficient for either of the two IFN-I signaling molecules, STAT2 or IRF9, also survived LCMV infection. We conclude that the lethal immune-mediated disease resulting from LCMV infection in STAT1 KO mice is (i) dependent on IRF7-induced IFN-I production and (ii) driven by noncanonical IFN-I signaling via STAT2 and IRF9.
Here we report on the basis for the novel, fatal immune-mediated disease of STAT1 KO mice infected with LCMV. Our findings show that, surprisingly, the pathogenesis of this disease is dependent on IRF7-mediated type I interferon production. Moreover, our study identifies noncanonical type I interferon signaling via STAT2 and IRF9 to be essential for the type I IFN-driven fatal disease in LCMV-infected STAT1 KO mice. These results further highlight the significance of noncanonical type I IFN signaling in the pathogenesis of host-mediated injury following viral infection.
感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）后，STAT1基因敲除（KO）小鼠而非野生型、STAT2 KO、IRF9 KO或IFNAR KO小鼠会发生由CD4(+) T细胞引发的致死性疾病。IRF7是LCMV感染期间I型干扰素（IFN-I）的关键转录激活因子。在此，研究了IRF7在STAT1 KO小鼠对LCMV感染的致死性宿主反应中的作用。与STAT1 KO小鼠不同，STAT1/IRF7双基因敲除（DKO）小鼠在LCMV感染后存活下来，关键器官（如肝脏和脾脏）中的免疫病理学损伤减轻。然而，与STAT1 KO小鼠相似，STAT1/IRF7 DKO小鼠无法控制LCMV的复制和传播。STAT1 KO小鼠感染LCMV后，血清中多种细胞因子水平显著升高，包括IFN-I，但STAT1/IRF7 DKO小鼠中基本不存在这种情况，其仅γ干扰素和CCL2水平有适度升高。由于已知IRF7是IFN-I基因表达的关键转录调节因子，因此进一步研究了IFN-I在致死性疾病中的可能作用。与STAT1 KO小鼠不同，STAT1/IFNAR DKO小鼠均在LCMV感染后存活，且几乎没有组织免疫病理学损伤。此外，缺乏两种IFN-I信号分子之一STAT2或IRF9的STAT1 KO小鼠也在LCMV感染后存活。我们得出结论，STAT1 KO小鼠因LCMV感染导致的致死性免疫介导疾病：（i）依赖于IRF7诱导的IFN-I产生；（ii）由通过STAT2和IRF9的非经典IFN-I信号驱动。
在此，我们报告了感染LCMV的STAT1 KO小鼠发生新型致命免疫介导疾病的基础。我们的研究结果表明，令人惊讶的是，这种疾病的发病机制依赖于IRF7介导的I型干扰素产生。此外，我们的研究确定通过STAT2和IRF9的非经典I型干扰素信号对于LCMV感染的STAT1 KO小鼠中I型干扰素驱动的致命疾病至关重要。这些结果进一步凸显了非经典I型干扰素信号在病毒感染后宿主介导损伤发病机制中的重要性。
