Gp37 Regulates the Pathogenesis of Avian Leukosis Virus Subgroup J via Its C Terminus
Gp37 Regulates the Pathogenesis of Avian Leukosis Virus Subgroup J via Its C Terminus
复制标题
DOI：
10.1128/jvi.02180-19
复制
发表时间：
2020-06-01
影响因子：
5.4
通讯作者：
Ye, Jianqiang
中科院分区：
文献类型：
--
作者：
Li, Tuofan;Yao, Xiaohui;Ye, Jianqiang
与其它亚型的禽白血病病毒（ALV）不同，ALV-J具有高致病性。是引起鸡骨髓性白血病和血管瘤的罪魁祸首。J型ALV-env基因与其它ALV的同源性较低，其独特性与其独特的发病机制有关，但其潜在的机制尚不清楚。先前的研究表明，ALV-J的env可以根据Gp 37的胞质结构域（CTD）中的酪氨酸基序分为三种，即，抑制性基团、双功能基团和活性基团。为探讨Gp 37蛋白C末端或CTD中的酪氨酸基序是否影响ALV-J的致病性，对一组含有不同Gp 37蛋白C末端或酪氨酸基序突变体的ALV-J感染性克隆进行了体内外试验。病毒生长动力学研究表明，env活性的ALV-J复制最快，env抑制的ALV-J复制最慢，而且酪氨酸位点对ALV-J的复制有重要影响。体内试验表明，env活性或双功能的ALV-J感染鸡后，其病毒血症、泄殖腔病毒脱落和病毒组织载量均高于env抑制的ALV-J感染鸡。与对照鸡相比，感染了具有活性或双功能env的ALV-J的鸡表现出显著的体重下降。综上所述，这些研究结果表明，Gp 37的C末端在ALV-J的发病机制中起着至关重要的作用，从抑制性env到双功能或活性env的变化增加了ALV-J的发病机制。重要ALV-J可以引起严重的免疫抑制和感染鸡的髓系白血病。然而，没有针对ALV-J的疫苗或抗病毒药物，ALV-J的发病机制需要阐明。一般认为ALV的gp 85和LTR参与了ALV的致病过程。本研究发现，ALV-J的Gp 37的C端和CTD中的酪氨酸基序（YxxM、ITIM和ITAM-like）在体外和体内都能影响ALV-J的致病性。Gp 37仅含ITIM的ALV-J的致病性显著低于Gp 37既含YxxM又含ITIM的ALV-J和Gp 37既含YxxM又含ITAM-like的ALV-J。本研究揭示了Gp 37 C端在ALV-J发病机制中的重要作用，为阐明ALV-J与宿主的相互作用提供了新的视角，并为制定有效的抗ALV-J策略提供了分子基础。
Different from other subgroups of avian leukosis viruses (ALVs), ALV-J is highly pathogenic. It is the main culprit causing myeloid leukemia and hemangioma in chickens. The distinctiveness of the env gene of ALV-J, with low homology to those of other ALVs, is linked to its unique pathogenesis, but the underlying mechanism remains unclear. Previous studies show that env of ALV-J can be grouped into three species based on the tyrosine motifs in the cytoplasmic domain (CTD) of Gp37, i.e., the inhibitory, bifunctional, and active groups. To explore whether the C terminus or the tyrosine motifs in the CTD of Gp37 affect the pathogenicity of ALV-J, a set of ALV-J infectious clones containing different C termini of Gp37 or the mutants at the tyrosine sites were tested in vitro and in vivo. Viral growth kinetics indicated not only that ALV-J with active env is the fastest in replication and ALV-J with inhibitory env is the lowest but also that the tyrosine sites essentially affected the replication of ALV-J. Moreover, in vivo studies demonstrated that chickens infected by ALV-J with active or bifunctional env showed higher viremia, cloacal viral shedding, and viral tissue load than those infected by ALV-J with inhibitory env. Notably, the chickens infected by ALV-J with active or bifunctional env showed significant loss of body weight compared with the control chickens. Taken together, these findings reveal that the C terminus of Gp37 plays a vital role in ALV-J pathogenesis, and change from inhibitory env to bifunctional or active env increases the pathogenesis of ALV-J.IMPORTANCE ALV-J can cause severe immunosuppression and myeloid leukemia in infected chickens. However, no vaccine or antiviral drug is available against ALV-J, and the mechanism for ALV-J pathogenesis needs to be elucidated. It is generally believed that gp85 and LTR of ALV contribute to its pathogenesis. Here, we found that the C terminus and the tyrosine motifs (YxxM, ITIM, and ITAM-like) in the CTD of Gp37 of ALV-J could affect the pathogenicity of ALV-J in vitro and in vivo. The pathogenicity of ALV-J with Gp37 containing ITIM only was significantly less than ALV-J with Gp37 containing both YxxM and ITIM and ALV-J with Gp37 containing both YxxM and ITAM-like. This study highlights the vital role of the C terminus of Gp37 in the pathogenesis of ALV-J and thus provides a new perspective to elucidate the interaction between ALV-J and its host and a molecular basis to develop efficient strategies against ALV-J.