Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation.
Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation.
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DOI：
10.1128/mbio.00682-18
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发表时间：
2018-04-24
期刊：
影响因子：
6.4
通讯作者：
Caposio P
中科院分区：
文献类型：
--
作者：
Crawford LB;Kim JH;Collins-McMillen D;Lee BJ;Landais I;Held C;Nelson JA;Yurochko AD;Caposio P
人巨细胞病毒(HCMV)从造血祖细胞(HPC)潜伏感染中重新激活的能力与细胞分化密切相关。我们的研究小组已经证明，HCMV编码UL7，它是由感染细胞分泌的，并诱导血管生成。在这项研究中，我们证明UL7是FMS样酪氨酸激酶3受体(Flt-3R)的配体，Flt-3R是HPC分化的一个众所周知的关键因素。我们观察到UL7直接与Flt-3R结合并诱导下游信号级联反应，包括磷脂酰肌醇3-激酶(PI3K)/Akt和丝裂原活化蛋白激酶(MAPK)/细胞外信号调节激酶(ERK)通路。重要的是，我们发现UL7蛋白可以诱导CD34+HPC和CD14+单核细胞分化。最后，我们发现缺乏UL7的人巨细胞病毒突变体在体外CD34+HPC和人源化小鼠中都不能重新激活。这些观察确定了第一个病毒编码的分化因子，不仅对HCMV的重新激活有重要意义，而且对移植患者的造血室的改变也有重要意义。人类巨细胞病毒(HCMV)仍然是异基因造血干细胞移植受者发病和死亡的重要原因。CD34+造血祖细胞(HPC)是移植人群中潜伏的HCMV的重要储存库，从而提供了传播到内脏器官的病毒源。人巨细胞病毒的重新激活与HPC/髓系细胞分化有关；然而，在分子水平上对这些事件涉及的机制知之甚少。在本研究中，我们证明了病毒蛋白是FMS样酪氨酸激酶3受体(Flt-3R)的配体，并且HCMV UL7与Flt-3R的结合触发了HPC和单核细胞的分化。此外，UL7的缺失在体外和人源化小鼠中阻止了HPC中的病毒重新激活。这些观察确定了第一个病毒编码的分化因子，不仅对HCMV的重新激活有重要意义，而且对移植患者的造血室的改变也有重要意义。
The ability of human cytomegalovirus (HCMV) to reactivate from latent infection of hematopoietic progenitor cells (HPCs) is intimately linked to cellular differentiation. HCMV encodes UL7 that our group has shown is secreted from infected cells and induces angiogenesis. In this study, we show that UL7 is a ligand for Fms-like tyrosine kinase 3 receptor (Flt-3R), a well-known critical factor in HPC differentiation. We observed that UL7 directly binds Flt-3R and induces downstream signaling cascades, including phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. Importantly, we show that UL7 protein induces differentiation of both CD34+ HPCs and CD14+ monocytes. Last, we show that an HCMV mutant lacking UL7 fails to reactivate in CD34+ HPCs in vitro as well as in humanized mice. These observations define the first virally encoded differentiation factor with significant implications not only for HCMV reactivation but also for alteration of the hematopoietic compartment in transplant patients. Human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant recipients. CD34+ hematopoietic progenitor cells (HPCs) represent a critical reservoir of latent HCMV in the transplant population, thereby providing a source of virus for dissemination to visceral organs. HCMV reactivation has been linked to HPC/myeloid cellular differentiation; however, the mechanisms involved in these events are poorly understood at the molecular level. In this study, we show that a viral protein is a ligand for Fms-like tyrosine kinase 3 receptor (Flt-3R) and that the binding of HCMV UL7 to the Flt-3R triggers HPC and monocyte differentiation. Moreover, the loss of UL7 prevents viral reactivation in HPCs in vitro as well as in humanized mice. These observations define the first virally encoded differentiation factor with significant implications not only for HCMV reactivation but also for alteration of the hematopoietic compartment in transplant patients.