Gibbert Kathrin, Francois Sandra, Sigmund Anna M, Harper Michael S, Barrett Bradley S, Kirchning Carsten J, Lu Mengji, Santiago Mario L, Dittmer Ulf
Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, Essen, Germany.
Institute for Medical Microbiology of the University Hospital in Essen, University of Duisburg-Essen, Essen, Germany.
Retrovirology. 2014 Dec 24;11:126. doi: 10.1186/s12977-014-0126-4.
Pathogen recognition drives host defense towards viral infections. Specific groups rather than single members of the protein family of pattern recognition receptors (PRRs) such as membrane spanning Toll-like receptors (TLRs) and cytosolic helicases might mediate sensing of replication intermediates of a specific virus species. TLR7 mediates host sensing of retroviruses and could significantly influence retrovirus-specific antibody responses. However, the origin of efficient cell-mediated immunity towards retroviruses is unknown. Double-stranded RNA intermediates produced during retroviral replication are good candidates for immune stimulatory viral products. Thus, we considered TLR3 as primer of cell-mediated immunity against retroviruses in vivo.
Infection of mice deficient in TLR3 (TLR3(-/-)) with Friend retrovirus (FV) complex revealed higher viral loads during acute retroviral infection compared to wild type mice. TLR3(-/-) mice exhibited significantly lower expression levels of type I interferons (IFNs) and IFN-stimulated genes like Pkr or Ifi44, as well as reduced numbers of activated myeloid dendritic cells (DCs) (CD86(+) and MHC-II(+)). DCs generated from FV-infected TLR3(-/-) mice were less capable of priming virus-specific CD8(+) T cell proliferation. Moreover, cytotoxicity of natural killer (NK) cells as well as CD8(+) T cells were reduced in vitro and in vivo, respectively, in FV-infected TLR3(-/-) mice.
TLR3 mediates antiretroviral cytotoxic NK cell and CD8(+) T cell activity in vivo. Our findings qualify TLR3 as target of immune therapy against retroviral infections.
病原体识别驱动宿主对病毒感染的防御。特定的蛋白质家族成员而非单个模式识别受体（PRR），如跨膜Toll样受体（TLR）和胞质解旋酶，可能介导对特定病毒种类复制中间体的感知。TLR7介导宿主对逆转录病毒的感知，并可能显著影响逆转录病毒特异性抗体反应。然而，针对逆转录病毒的有效细胞介导免疫的起源尚不清楚。逆转录病毒复制过程中产生的双链RNA中间体是免疫刺激病毒产物中的良好候选者。因此，我们认为TLR3是体内针对逆转录病毒的细胞介导免疫的启动因子。
用Friend逆转录病毒（FV）复合体感染TLR3缺陷小鼠（TLR3(-/-)），与野生型小鼠相比，急性逆转录病毒感染期间病毒载量更高。TLR3(-/-)小鼠I型干扰素（IFN）和IFN刺激基因如Pkr或Ifi44的表达水平显著降低，活化的髓样树突状细胞（DCs）（CD86(+)和MHC-II(+)）数量减少。从FV感染的TLR3(-/-)小鼠产生的DCs启动病毒特异性CD8(+) T细胞增殖的能力较弱。此外，FV感染的TLR3(-/-)小鼠体内，自然杀伤（NK）细胞以及CD8(+) T细胞的细胞毒性分别在体外和体内降低。
TLR3在体内介导抗逆转录病毒细胞毒性NK细胞和CD8(+) T细胞活性。我们的研究结果表明TLR3是抗逆转录病毒感染免疫治疗的靶点。
