UBXN3B Controls Immunopathogenesis of Arthritogenic Alphaviruses by Maintaining Hematopoietic Homeostasis.
UBXN3B Controls Immunopathogenesis of Arthritogenic Alphaviruses by Maintaining Hematopoietic Homeostasis.
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泛素调节性 X 结构域蛋白 (UBXN) 可能参与多种细胞过程。然而，它们的体内生理功能仍然很大程度上难以捉摸。我们最近表明，UBXN3B 正向调节干扰素基因刺激物 (STING) 介导的针对 DNA 病毒的先天免疫反应。在此，我们报道了 UBXN3B 在控制两种致关节炎 RNA 病毒基孔肯雅病毒 (CHIKV) 和 O’nyong’nyong (ONNV) 病毒的感染和免疫发病机制中的重要作用。与 Ubxn3b+/+ 同窝小鼠相比，Ubxn3b 缺陷 (Ubxn3b−/−) 小鼠表现出更高的病毒载量、更严重的足部肿胀和免疫浸润，以及更慢的病毒清除和炎症消退速度。虽然血清细胞因子水平完整，但 Ubxn3b−/− 小鼠的病毒特异性免疫球蛋白 G 和中和抗体水平较低。 Ubxn3b−/− 小鼠的同侧足部有更多的中性粒细胞和巨噬细胞，但 B 细胞却少得多。值得注意的是，在未感染的 Ubxn3b−/− 小鼠的脾脏和血液中也观察到了这种免疫失调。 UBXN3B 以细胞固有的方式限制 CHIKV 复制，但不依赖于 I 型 IFN 信号传导。这些结果证明了 UBXN3B 在维持免疫稳态和控制 RNA 病毒复制方面的双重作用。
Ubiquitin regulatory X domain-containing proteins (UBXN) might be involved in diverse cellular processes. However, their in vivo physiological functions remain largely elusive. We recently showed that UBXN3B positively regulated stimulator-of-interferon-genes (STING)-mediated innate immune responses to DNA viruses. Herein, we reported the essential role of UBXN3B in the control of infection and immunopathogenesis of two arthritogenic RNA viruses, Chikungunya (CHIKV) and O’nyong’nyong (ONNV) viruses. Ubxn3b deficient (Ubxn3b−/−) mice presented higher viral loads, more severe foot swelling and immune infiltrates, and slower clearance of viruses and resolution of inflammation than the Ubxn3b+/+ littermates. While the serum cytokine levels were intact, the virus-specific immunoglobulin G and neutralizing antibody levels were lower in the Ubxn3b−/− mice. The Ubxn3b−/− mice had more neutrophils and macrophages, but much fewer B cells in the ipsilateral feet. Of note, this immune dysregulation was also observed in the spleens and blood of uninfected Ubxn3b−/− mice. UBXN3B restricted CHIKV replication in a cell-intrinsic manner but independent of type I IFN signaling. These results demonstrated a dual role of UBXN3B in the maintenance of immune homeostasis and control of RNA virus replication.
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