The Gammaherpesviruses Kaposi's Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus 68 Modulate the Toll-Like Receptor-Induced Proinflammatory Cytokine Response
The Gammaherpesviruses Kaposi's Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus 68 Modulate the Toll-Like Receptor-Induced Proinflammatory Cytokine Response
复制标题
DOI：
10.1128/jvi.00841-14
复制
发表时间：
2014-08-01
影响因子：
5.4
通讯作者：
Brinkmann, Melanie M.
中科院分区：
文献类型：
--
作者：
Bussey, Kendra A.;Reimer, Elisa;Brinkmann, Melanie M.
人类病原体卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤、原发性渗出性淋巴瘤和多中心Castleman病的病原体，在感染后会产生终生潜伏期。鼠γ疱疹病毒68（MHV 68）是KSHV的一种成熟模型。Toll样受体（TLR）在机体对病原体的天然免疫应答中起着重要作用。尽管KSHV和MHV 68可通过TLR检测到，但研究表明它们分别调节TLR 4和TLR 9信号传导。在这项研究中，我们表明，在骨髓来源的巨噬细胞（BMDM），MHV 68没有诱导可检测的促炎细胞因子反应。此外，MHV 68消除了BMDM中对TLR 2、TLR 4、TLR 7和TLR 9激动剂的应答。与MHV 68的观察结果类似，KSHV感染有效抑制THP-1单核细胞中的TLR 2信号传导。使用KSHV开放阅读框（ORF）文库，我们发现K4.2、ORF 21、ORF 31和复制和转录激活蛋白（RTA）/ORF 50抑制HEK 293 TLR 2-黄色荧光蛋白（YFP）-和Flag-TLR 2-转染的HEK 293 T细胞中TLR 2依赖性核因子κ B（NF-κ B）活化。在所鉴定的ORF中，RTA/ORF 50通过降低TLR 2和TLR 4蛋白表达而强烈下调TLR 2和TLR 4信号传导。共聚焦显微镜显示，TLR 2和TLR 4不再定位于细胞表达RTA/ORF 50的质膜。在这项研究中，我们已经表明，γ疱疹病毒MHV 68和KSHV有效地下调TLR信号在巨噬细胞，并确定了一种新的功能RTA/ORF 50的先天免疫反应的调制。
The human pathogen Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease, establishes lifelong latency upon infection. Murine gammaherpesvirus 68 (MHV68) is a well-established model for KSHV. Toll-like receptors (TLRs) play a crucial role for the innate immune response to pathogens. Although KSHV and MHV68 are detected by TLRs, studies suggest they modulate TLR4 and TLR9 signaling, respectively. In this study, we show that in bone marrow-derived macrophages (BMDMs), MHV68 did not induce a detectable proinflammatory cytokine response. Furthermore, MHV68 abrogated the response to TLR2, -4, -7, and -9 agonists in BMDMs. Similarly to observations with MHV68, infection with KSHV efficiently inhibited TLR2 signaling in THP-1 monocytes. Using a KSHV open reading frame (ORF) library, we found that K4.2, ORF21, ORF31, and the replication and transcription activator protein (RTA)/ORF50 inhibited TLR2-dependent nuclear factor kappa B (NF-kappa B) activation in HEK293 TLR2-yellow fluorescent protein (YFP)- and Flag-TLR2-transfected HEK293T cells. Of the identified ORFs, RTA/ORF50 strongly downregulated TLR2 and TLR4 signaling by reducing TLR2 and TLR4 protein expression. Confocal microscopy revealed that TLR2 and TLR4 were no longer localized to the plasma membrane in cells expressing RTA/ORF50. In this study, we have shown that the gammaherpesviruses MHV68 and KSHV efficiently downmodulate TLR signaling in macrophages and have identified a novel function of RTA/ORF50 in modulation of the innate immune response.