Estep Ryan D, Govindan Aparna N, Fitzpatrick Kristin, Blair Tiffany C, Rezaee S A Rahim, Blackbourn David J, Wong Scott W
Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, United States of America
Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, United States of America.
J Virol. 2021 Mar 1;95(5). doi: 10.1128/JVI.01654-20. Epub 2020 Dec 16.
The CD200-CD200R pathway is involved in inhibition of immune responses, and the importance of this pathway to infectious disease is highlighted by the fact that viral CD200 (vCD200) molecules have been found to be encoded by several DNA viruses, including the human gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV), and the closely related rhesus macaque rhadinovirus (RRV). KSHV vCD200 is the most extensively studied vCD200 molecule, however, the only herpesvirus vCD200 molecule to be examined is that encoded by RRV. Our prior studies have demonstrated that RRV vCD200 is a functional CD200 homologue that is capable of affecting immune responses , and further, that RRV can express a secreted form of vCD200 (vCD200-Sec) during infection. Despite this information, RRV vCD200 has not been examined specifically for effects on RM CD200R signaling, and the functionality of vCD200-Sec has not been examined in any context. Thus, we developed an model system in which B cells expressing vCD200 were utilized to assess the effects of this molecule on the regulation of myeloid cells expressing RM CD200R, mimicking interactions that are predicted to occur Our findings suggest that RRV vCD200 can bind and induce functional signals through RM CD200R, while vCD200-Sec represents a non-functional protein incapable of affecting CD200R signaling. We also provide the first demonstration of the function of RM CD200, which appears to possess more robust signaling capabilities than RRV vCD200, and also show that KSHV vCD200 does not efficiently induce signaling via RM CD200R. Viral CD200 homologues are encoded by KSHV and the closely related RRV. Though RRV vCD200 has been examined, questions still exist in regard to the ability of this molecule to induce signaling via rhesus macaque CD200R, as well as the potential function of a secreted form of vCD200. Further, all previous studies of RRV vCD200 have utilized an Fc fusion protein to examine functionality, which does not replicate the structural properties of the membrane-associated form of vCD200 that is naturally produced during RRV infection. In this study, we demonstrate for the first time that membrane-expressed RRV vCD200 is capable of inducing signal transduction via RM CD200R, while the secreted form of vCD200 appears to be non-functional. Further, we also demonstrate that RM CD200 induces signaling via RM CD200R, and is more robust than RRV vCD200, while KSHV vCD200 does not appear to induce efficient signaling via RM CD200R.
CD200-CD200R通路参与免疫反应的抑制，几种DNA病毒已被发现编码病毒CD200（vCD200）分子，包括人类γ疱疹病毒卡波西肉瘤相关疱疹病毒（KSHV）以及密切相关的恒河猴嗜淋巴细胞病毒（RRV），这一事实凸显了该通路对传染病的重要性。KSHV vCD200是研究最广泛的vCD200分子，然而，唯一被检测的疱疹病毒vCD200分子是RRV编码的。我们之前的研究表明，RRV vCD200是一种功能性CD200同源物，能够影响免疫反应，此外，RRV在感染期间可表达一种分泌形式的vCD200（vCD200-Sec）。尽管有这些信息，但RRV vCD200对恒河猴CD200R信号传导的影响尚未被专门研究，vCD200-Sec的功能在任何情况下都未被研究过。因此，我们开发了一个模型系统，利用表达vCD200的B细胞来评估该分子对表达恒河猴CD200R的髓样细胞调节的影响，模拟预计会发生的相互作用。我们的研究结果表明，RRV vCD200可以通过恒河猴CD200R结合并诱导功能性信号，而vCD200-Sec是一种无功能的蛋白质，无法影响CD200R信号传导。我们还首次证明了恒河猴CD200的功能，它似乎比RRV vCD200具有更强的信号传导能力，并且还表明KSHV vCD200不能有效地通过恒河猴CD200R诱导信号传导。病毒CD200同源物由KSHV和密切相关的RRV编码。尽管RRV vCD200已被研究，但关于该分子通过恒河猴CD200R诱导信号传导的能力以及vCD200分泌形式的潜在功能仍存在疑问。此外，之前所有关于RRV vCD200的研究都使用Fc融合蛋白来检测功能，这无法复制RRV感染期间自然产生的膜相关形式vCD200的结构特性。在本研究中，我们首次证明膜表达的RRV vCD200能够通过恒河猴CD200R诱导信号转导，而vCD200的分泌形式似乎无功能。此外，我们还证明恒河猴CD200通过恒河猴CD200R诱导信号传导，并且比RRV vCD200更强，而KSHV vCD200似乎不能通过恒河猴CD200R诱导有效信号传导。
