汉坦病毒（HV）感染抗病毒免疫机制尚未完全阐明。宿主限制因子组成的固有免疫是抗病毒感染的前沿防线。前期预实验结果显示新近发现的宿主限制因子SAMHD1在HV感染的HUVEC和THP-1细胞中高表达，过表达SAMHD1可抑制HV复制。我们提出在HV感染宿主细胞后诱导SAMHD1的表达，SAMHD1继而通过多种机制发挥抑制HV的作用，在HV感染免疫过程中扮演关键角色。. 本项申请拟进一步在不同靶细胞（HUVEC和THP-1）上明确SAMHD1抑制HV复制的关键环节，重点研究SAMHD1抑制HV是否依赖于dNTPase活性、Rnase活性、核定位及其磷酸化，深入探索SAMHD1表达调控机制，揭示HV蛋白与SAMHD1相互作用，并在动物模型和HFRS患者中验证。本课题将从限制因子的角度阐释汉坦病毒及宿主细胞之间的关系，为理解抗HV病毒免疫机制、新型抗病毒药物的研发提供新的思路。

Hemorrhagic fever with renal syndrome (HFRS) caused by hantavirus is a serious public health problem in China. Endothelial cells and macrophages are the main targets for hantavirus. The innate immune response constitutes the first cellular line of defense against initial virus infection and is characterized by IFN induction, the release of inflammatory cytokines that upregulate antiviral IFN-stimulated genes (ISGs), and genes encoding other proteins with antiviral potential (restriction factors). The role of cellular restriction factor during hantavirus infection remain poorly understood.. The sterile alpha motif and HD domain 1 (SAMHD1) protein is the deoxynucleoside triphosphate triphosphohydrolase and 3’→5’ exonuclease. Although identified as a potent restriction factor for HIV, other nonhuman retroviruses, and herpesviruses, the functional relevance of SAMHD1 in hantavirus infection and innate immune response are still unclear. We have found that HTNV infection upregulated endogenous SAMHD1 expression in HUVEC and THP-1 cells. Overexpression of SAMHD1 decreased the proliferation of HTNV in HUVEC and THP-1 cells. Thus, we speculate that during a course of hantavirus infection, SAMHD1 limits HTNV infection of endothelial cells and macrophages via multiple pathway and is an important immunoregulatory protein in innate immunity. . To distinguish the key link of SAMHD1 inhibiting HV replication，we will examine the dynamic expression and location of restriction factor SAMHD1 on HTNV-infected HUVEC and THP-1 cells and determine the anti-HV effect of SAMHD1 on these two cells. We will test whether this anti-HTNV ability of SAMHD1 is dependent on its dNTPase activity, RNase activity, nuclear location and phosphorylation by gene silencing, overexpression, mutation experiment, etc. We will also determine regulation factor/pathway involved in SAMHD1 function, including IFN-induced dephosphorylation, CDKs-regulated phosphorylation, ncRNA-modulated network, and so on. We will also dissect the direct interaction between hantavirus viral protein and SAMHD1. In addition, we will validate SAMHD1 function and these factors/pathway obtained from in vitro experiment in the animal model and in clinical HFRS patients.. This work will provide insight into the relationship of restriction factor SAMHD1, virus and host cells, which will be beneficial to expand understanding the mechanism of anti-hantavirus immune response as well as the development of novel treatment of HFRS.