Division of Biology and Medicine, Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, USA.
PLoS One. 2012;7(6):e39161. doi: 10.1371/journal.pone.0039161. Epub 2012 Jun 18.
Antiviral defense in the liver during acute infection with the hepatotropic virus murine cytomegalovirus (MCMV) involves complex cytokine and cellular interactions. However, the mechanism of viral sensing in the liver that promotes these cytokine and cellular responses has remained unclear. Studies here were undertaken to investigate the role of nucleic acid-sensing Toll-like receptors (TLRs) in initiating antiviral immunity in the liver during infection with MCMV. We examined the host response of UNC93B1 mutant mice, which do not signal properly through TLR3, TLR7 and TLR9, to acute MCMV infection to determine whether liver antiviral defense depends on signaling through these molecules. Infection of UNC93B1 mutant mice revealed reduced production of systemic and liver proinflammatory cytokines including IFN-α, IFN-γ, IL-12 and TNF-α when compared to wild-type. UNC93B1 deficiency also contributed to a transient hepatitis later in acute infection, evidenced by augmented liver pathology and elevated systemic alanine aminotransferase levels. Moreover, viral clearance was impaired in UNC93B1 mutant mice, despite intact virus-specific CD8+ T cell responses in the liver. Altogether, these results suggest a combined role for nucleic acid-sensing TLRs in promoting early liver antiviral defense during MCMV infection.
在急性感染嗜肝病毒鼠巨细胞病毒 (MCMV) 期间，肝脏中的抗病毒防御涉及复杂的细胞因子和细胞相互作用。然而，促进这些细胞因子和细胞反应的肝脏病毒感应机制仍不清楚。本研究旨在探讨核酸感应 Toll 样受体 (TLR) 在 MCMV 感染期间启动肝脏抗病毒免疫中的作用。我们研究了 UNC93B1 突变小鼠的宿主反应，UNC93B1 突变小鼠不能通过 TLR3、TLR7 和 TLR9 正确信号转导，以确定肝脏抗病毒防御是否依赖于这些分子的信号转导。与野生型相比，UNC93B1 突变小鼠感染 MCMV 后，全身和肝脏促炎细胞因子（包括 IFN-α、IFN-γ、IL-12 和 TNF-α）的产生减少。UNC93B1 缺陷也导致急性感染后期的短暂肝炎，表现为肝病理学加重和系统丙氨酸氨基转移酶水平升高。此外，UNC93B1 突变小鼠的病毒清除受损，尽管肝脏中存在完整的病毒特异性 CD8+T 细胞反应。总之，这些结果表明核酸感应 TLR 在促进 MCMV 感染期间早期肝脏抗病毒防御中起共同作用。
