Pathogenicity of Ebola and Marburg Viruses Is Associated With Differential Activation of the Myeloid Compartment in Humanized Triple Knockout-Bone Marrow, Liver, and Thymus Mice
Pathogenicity of Ebola and Marburg Viruses Is Associated With Differential Activation of the Myeloid Compartment in Humanized Triple Knockout-Bone Marrow, Liver, and Thymus Mice
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DOI：
10.1093/infdis/jiy269
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发表时间：
2018-12-15
影响因子：
6.4
通讯作者：
Prescott, Joseph
中科院分区：
文献类型：
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作者：
Lavender, Kerry J.;Williamson, Brandi N.;Prescott, Joseph
埃博拉病毒（EBOV）和马尔堡病毒（MARV）的爆发具有高度致命性，感染后会导致具有复杂病原学的出血热。这些人畜共患病毒会使免疫系统失调而引起疾病，部分原因是通过在骨髓细胞内复制，而骨髓细胞通常会天生控制病毒感染并形成适应性免疫反应。我们使用三重敲除（TKO）-骨髓、肝脏、胸腺（BLT）人源化小鼠来重现对丝状病毒感染的早期体内人免疫应答。在TKO-BLT小鼠中，EBOV和MARV之间的疾病严重程度不同，在EBOV感染期间观察到更严重的疾病。与MARV感染小鼠相比，EBOV感染小鼠的疾病严重程度与肝脏枯否细胞感染增加、骨髓功能障碍水平升高以及巨噬细胞亚型倾斜有关。总的来说，TKO-BLT模型提供了一个实用的体内平台来研究人类对丝状病毒感染的免疫反应，并更好地了解这些病毒如何调节免疫系统的特定组分。
Ebola virus (EBOV) and Marburg virus (MARV) outbreaks are highly lethal, and infection results in a hemorrhagic fever with complex etiology. These zoonotic viruses dysregulate the immune system to cause disease, in part by replicating within myeloid cells that would normally innately control viral infection and shape the adaptive immune response. We used triple knockout (TKO)-bone marrow, liver, thymus (BLT) humanized mice to recapitulate the early in vivo human immune response to filovirus infection. Disease severity in TKO-BLT mice was dissimilar between EBOV and MARV with greater severity observed during EBOV infection. Disease severity was related to increased Kupffer cell infection in the liver, higher levels of myeloid dysfunction, and skewing of macrophage subtypes in EBOV compared with MARV-infected mice. Overall, the TKO-BLT model provided a practical in vivo platform to study the human immune response to filovirus infection and generated a better understanding of how these viruses modulate specific components of the immune system.