Gammaherpesvirus Colonization of the Spleen Requires Lytic Replication in B Cells.
Gammaherpesvirus Colonization of the Spleen Requires Lytic Replication in B Cells.
复制标题
伽玛疱疹病毒在脾脏的定植需要 B 细胞中的裂解性复制。
DOI：
10.1128/jvi.02199-17
复制
发表时间：
2018
影响因子：
5.4
通讯作者：
Lawler C
中科院分区：
文献类型：
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作者：
Lawler C
γ疱疹病毒感染淋巴细胞并引起淋巴细胞癌。鼠疱疹病毒-4（MuHV-4）、爱泼斯坦-巴尔病毒和卡波西肉瘤相关疱疹病毒都感染B细胞。潜伏性感染可通过B细胞再循环和增殖传播，但这是否单独实现全身感染尚不清楚。为了测试MuHV-4在B细胞中裂解性感染的需要，我们用loxP位点侧接其必需的ORF 50裂解性反式激活因子，然后感染表达B细胞特异性Cre（CD 19-Cre）的小鼠。floxed病毒在Cre−小鼠中正常复制。在CD 19-Cre小鼠中，鼻和淋巴结感染得以维持;但脾肿大很少，脾病毒载量仍然较低。Cre介导的其他必需裂解基因的去除得到了类似的表型。CD 19-Cre脾感染腹腔内病毒也受损。因此，MuHV-4必须从B细胞中裂解出来以定殖于脾脏。B细胞裂解性感染在宿主定植中的一个重要作用与传染性单核细胞增多症期间对γ疱疹病毒裂解性抗原产生的大的CD 8 +T细胞应答一致，并且表明能够抑制B细胞裂解性感染的疫苗诱导的免疫可能减少长期的病毒载量。大多数宿主定殖模型源自具有连续病毒驱动的B细胞增殖的细胞培养物。然而，基于这些模型的疫苗效果不佳。为了测试增殖的B细胞是否足以用于宿主定殖，我们灭活了小鼠γ疱疹病毒MuHV-4从B细胞重新出现的能力。修饰后的病毒能够在淋巴结中的第一波B细胞中定殖，但在次级部位（如脾脏）中难以扩散到B细胞。因此，病毒载量仍然很低。这些结果与利用正常宿主途径的病毒驱动的B细胞增殖一致，因此必须裂解转移到新的B细胞以进行新的增殖。我们的结论是，病毒裂解感染是一个潜在的目标，以减少B细胞增殖。
Gammaherpesviruses infect lymphocytes and cause lymphocytic cancers. Murid herpesvirus-4 (MuHV-4), Epstein-Barr virus, and Kaposi's sarcoma-associated herpesvirus all infect B cells. Latent infection can spread by B cell recirculation and proliferation, but whether this alone achieves systemic infection is unclear. To test the need of MuHV-4 for lytic infection in B cells, we flanked its essential ORF50 lytic transactivator withloxPsites and then infected mice expressing B cell-specific Cre (CD19-Cre). The floxed virus replicated normally in Cre−mice. In CD19-Cre mice, nasal and lymph node infections were maintained; but there was little splenomegaly, and splenic virus loads remained low. Cre-mediated removal of other essential lytic genes gave a similar phenotype. CD19-Cre spleen infection by intraperitoneal virus was also impaired. Therefore, MuHV-4 had to emerge lytically from B cells to colonize the spleen. An important role for B cell lytic infection in host colonization is consistent with the large CD8+T cell responses made to gammaherpesvirus lytic antigens during infectious mononucleosis and suggests that vaccine-induced immunity capable of suppressing B cell lytic infection might reduce long-term virus loads.IMPORTANCEGammaherpesviruses cause B cell cancers. Most models of host colonization derive from cell cultures with continuous, virus-driven B cell proliferation. However, vaccines based on these models have worked poorly. To test whether proliferating B cells suffice for host colonization, we inactivated the capacity of MuHV-4, a gammaherpesvirus of mice, to reemerge from B cells. The modified virus was able to colonize a first wave of B cells in lymph nodes but spread poorly to B cells in secondary sites such as the spleen. Consequently, viral loads remained low. These results were consistent with virus-driven B cell proliferation exploiting normal host pathways and thus having to transfer lytically to new B cells for new proliferation. We conclude that viral lytic infection is a potential target to reduce B cell proliferation.