p53-responsive TLR8 SNP enhances human innate immune response to respiratory syncytial virus.
p53-responsive TLR8 SNP enhances human innate immune response to respiratory syncytial virus.
复制标题
p53 响应性 TLR8 SNP 增强人类对呼吸道合胞病毒的先天免疫反应。
DOI：
10.1172/jci128626
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Resnick,MichaelA
中科院分区：
文献类型：
--
作者：
Menendez,Daniel;Snipe,Joyce;Marzec,Jacqui;Innes,CynthiaL;Polack,FernandoP;Caballero,MauricioT;Schurman,ShepherdH;Kleeberger,StevenR;Resnick,MichaelA
Toll样受体8（TLR 8）在对RNA病毒感染（包括呼吸道合胞病毒（RSV））的先天免疫应答中具有重要作用。我们以前报道过肿瘤抑制因子和转录因子p53通过TLR 8启动子中的单核苷酸多态性（SNP）（rs3761624）直接增加TLR 8的表达，从而将TLR 8置于p53/免疫轴。由于该SNP与其他与几种感染性疾病相关的SNP处于连锁不平衡，我们研究了p53和SNP对下游炎症信号传导的联合影响，以响应TLR 8同源ssRNA配体。使用人原代淋巴细胞，在与ssRNA配体孵育后，通过化学治疗剂如电离辐射的p53诱导引起IL-6的SNP依赖性协同增加，以及TLR 8 RNA和蛋白质表达沿着p53在TLR-p53 SNP位点的结合。由于TLR 8是X连锁的，杂合子女性的增加通常减少。我们发现，在因RSV感染住院的婴儿中，p53应答等位基因与RSV疾病严重程度存在相应的相关性。我们的结论是，p53可以强烈影响TLR 8介导的免疫反应，并且对p53反应性SNP的了解可以为RSV疾病和可能具有TLR 8组分的其他疾病（包括癌症）的诊断和预后提供信息。
The Toll-like receptor 8 (TLR8) has an important role in innate immune responses to RNA viral infections, including respiratory syncytial virus (RSV). We previously reported thatTLR8expression was increased directly by the tumor suppressor and transcription factor p53 via a single nucleotide polymorphism (SNP) (rs3761624) in theTLR8promoter, thereby placing TLR8 in the p53/immune axis. Because this SNP is in linkage disequilibrium with other SNPs associated with several infectious diseases, we addressed the combined influence of p53 and the SNP on downstream inflammatory signaling in response to a TLR8 cognate ssRNA ligand. Using human primary lymphocytes, p53 induction by chemotherapeutic agents such as ionizing radiation caused SNP-dependent synergistic increases in IL-6 following incubation with an ssRNA ligand, as well as TLR8 RNA and protein expression along with p53 binding at the TLR-p53 SNP site. BecauseTLR8is X-linked, the increases were generally reduced in heterozygous females. We found a corresponding association of the p53-responsive allele with RSV disease severity in infants hospitalized with RSV infection. We conclude that p53 can strongly influence TLR8-mediated immune responses and that knowledge of the p53-responsive SNP can inform diagnosis and prognosis of RSV disease and other diseases that might have a TLR8 component, including cancer.