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Genome-Wide Mouse Mutagenesis Reveals CD45-Mediated T Cell Function as Critical in Protective Immunity to HSV-1

机译:全基因组小鼠诱变揭示CD45介导的T细胞功能对HSV-1的保护性免疫至关重要

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摘要

Herpes simplex encephalitis (HSE) is a lethal neurological disease resulting from infection with Herpes Simplex Virus 1 (HSV-1). Loss-of-function mutations in the UNC93B1, TLR3, TRIF, TRAF3, and TBK1 genes have been associated with a human genetic predisposition to HSE, demonstrating the UNC93B-TLR3-type I IFN pathway as critical in protective immunity to HSV-1. However, the TLR3, UNC93B1, and TRIF mutations exhibit incomplete penetrance and represent only a minority of HSE cases, perhaps reflecting the effects of additional host genetic factors. In order to identify new host genes, proteins and signaling pathways involved in HSV-1 and HSE susceptibility, we have implemented the first genome-wide mutagenesis screen in an in vivo HSV-1 infectious model. One pedigree (named P43) segregated a susceptible trait with a fully penetrant phenotype. Genetic mapping and whole exome sequencing led to the identification of the causative nonsense mutation L3X in the Receptor-type tyrosine-protein phosphatase C gene (PtprcL3X), which encodes for the tyrosine phosphatase CD45. Expression of MCP1, IL-6, MMP3, MMP8, and the ICP4 viral gene were significantly increased in the brain stems of infected PtprcL3X mice accounting for hyper-inflammation and pathological damages caused by viral replication. PtprcL3X mutation drastically affects the early stages of thymocytes development but also the final stage of B cell maturation. Transfer of total splenocytes from heterozygous littermates into Ptprc L3X mice resulted in a complete HSV-1 protective effect. Furthermore, T cells were the only cell population to fully restore resistance to HSV-1 in the mutants, an effect that required both the CD4+ and CD8+ T cells and could be attributed to function of CD4+ T helper 1 (Th1) cells in CD8+ T cell recruitment to the site of infection. Altogether, these results revealed the CD45-mediated T cell function as potentially critical for infection and viral spread to the brain, and also for subsequent HSE development.
机译:单纯疱疹性脑炎(HSE)是由单纯疱疹病毒1(HSV-1)感染引起的致死性神经系统疾病。 UNC93B1,TLR3,TRIF,TRAF3和TBK1基因中的功能丧失突变与人类对HSE的遗传易感性相关,表明UNC93B-TLR3 I型IFN途径对于HSV-1的保护性免疫至关重要。但是,TLR3,UNC93B1和TRIF突变表现出不完全的外显率,仅代表少数HSE病例,可能反映了其他宿主遗传因素的影响。为了鉴定与HSV-1和HSE易感性有关的新宿主基因,蛋白质和信号传导途径,我们在体内HSV-1感染模型中实施了首个全基因组诱变筛选。一个家谱(命名为P43)分离出具有完全渗透性表型的易感性状。遗传作图和整个外显子组测序导致鉴定了编码酪氨酸磷酸酶CD45的受体型酪氨酸蛋白磷酸酶C基因(Ptprc L3X )的致病性无义突变L3X。在感染的 Ptprc L3X 小鼠脑干中MCP1,IL-6,MMP3,MMP8和 ICP4 病毒基因的表达显着增加解释由病毒复制引起的过度炎症和病理损害。 Ptprc L3X 突变会严重影响胸腺细胞发育的早期阶段,但也影响B细胞成熟的最后阶段。总杂脾细胞从杂合子同窝小鼠转移到 Ptprc L3X 小鼠中可产生完全的HSV-1保护作用。此外,T细胞是唯一能够完全恢复突变株对HSV-1耐药性的细胞群,这种作用需要CD4 + 和CD8 + T细胞,并且可以归因于CD8 + T细胞募集到感染部位的CD4 + T辅助1(Th1)细胞的功能。总而言之,这些结果表明,CD45介导的T细胞功能对于感染和病毒向大脑的扩散以及随后的HSE发育潜在至关重要。

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