利用水流動式活體轉染(hydrodynamics-based in vivo transfection)方式將Hepatitis B virus (HBV)質體，pHBV3.6，以靜脈方式注入BALB/c小鼠，發現HBV在小鼠肝臟內能複製，血清中也能夠偵測到HBV抗原及HBV-DNA的存在，小鼠會產生特異性抗體反應，這樣的過程與人類急性HBV感染類似。透過應用此種急性HBV感染小鼠模式我們探討先天性免疫反應在急性HBV感染扮演重要角色。首先我們發現在TLR4正常C3H/HeN小鼠，HBV感染肝細胞周圍的肝臟浸潤白血球表現TLR4。在TLR4突變C3H/HeJ小鼠體內，HBV的複製高於TLR4正常C3H/HeN小鼠。C3H/HeJ小鼠肝臟內HBV特異性T反應、脾臟內Th1反應無法有效被誘發，將來自於TLR4正常C3H/HeN小鼠之脾臟細胞給予TLR4突變的C3H/HeJ小鼠，能夠使得C3H/HeJ小鼠體內HBV的複製被控制至與C3H/HeN小鼠相當的程度。另外，C3H/HeJ小鼠肝臟浸潤白血球無法有效表現iNOS，顯示iNOS可能參與在急性HBV感染的免疫反應。因此我們再比較iNOS缺失小鼠與正常小鼠HBV的感染情形，發現iNOS缺失小鼠肝臟內HBV的複製量、血清中HBV抗原及HBV-DNA的表現都要較正常小鼠高。HBV複製程度的增加可能是由於iNOS缺失小鼠無法有效誘使某些免疫細胞浸潤至肝臟有關，例如CD3+ T細胞、NKT細胞、B細胞及CD4+ T細胞。巨噬細胞及樹突細胞無法正常活化也可能是原因之一。此外，NO釋放化合物能夠透過抑制p38 MAPK磷酸化而抑制肝癌細胞株Huh7 HBV蛋白的分泌，顯示免疫細胞產生的NO能夠直接影響肝細胞內HBV的複製以及p38 MAPK可能參與HBV複製過程中。最後我們利用體外轉染pHBV3.6至Huh7細胞，發現細胞內p38 MAPK及其下游分子ATF2有磷酸化的現象。p38 MAPK特異性抑制劑SB203580可以有效抑制HBV的複製，包括HBV的RNA、細胞內核心蛋白相關DNA (intracellular core-assocaied DNA)及細胞外病毒顆粒相關DNA (extracellualr virion-associated DNA)。目前認為HBV複製重要指標的covantly closed circular DNA，也同樣能夠有效的被SB203580抑制，這顯示HBV感染肝細胞過程造成p38 MAPK的活化，並且p38 MAPK的活化可能是HBV複製所必需。

When pHBV3.6 plasmid containing whole HBV genome was intravenously injected into BALB/c mice by hydrodynamics-based in vivo transfection, HBV replication was observed in the liver, HBV antigens were detected in the circulation, and specific HBV antibody responses were induced post hydrodynamic injection of pHBV3.6. A murine model was established to mimic the human acute HBV infection. Using this murine model, we investigated the involvement of innate immunity during acute HBV infection. First, TLR4-expressing liver infiltrating leukocytes were observed nearby HBsAg-expressing hepatocytes. HBV replication in liver and HBV antigenemia were higher in TLR4 mutation C3H/HeJ than in TLR4 wild type C3H/HeN mice. Impaired HBV-induced IFN-g, TNF-a or IL-12 responses in liver or spleen were observed in C3H/HeJ mice. After adoptive transfer of splenocytes from C3H/HeN mice, the HBV replication in TLR4 mutant C3H/HeJ mice was reduced to the similar level of the C3H/HeN mice. Futhermore, iNOS expression on liver infiltrating leukocytes was impaired in C3H/HeJ mice. This suggested that iNOS might also involve in the immune responses during acute HBV infection. Therefore, the role of iNOS in acute HBV infection was further investigated using iNOS knockout mice. HBV replication in liver, as well as HBV antigenemia and serum HBV-DNA, was higher in iNOS knockout than in wild type mice. Increasing HBV replication might be due to the impaired infiltration of leukocytes, such as CD3+ T cells, CD3+NK1.1+ T cells, CD19+ B cells and CD4+ T cells. Impaired activation of macrophages and dendritic cells might also account for the increasing HBV replication in iNOS knockout mice. Furthermore, NO donor sodium nitroprusside could inhibit HBV secretion in the pHBV3.6-transfeted human hepatoma Huh7 cells through inhibition of the p38 MAPK phosphorylation. These results indicated that NO produced from immune cells could directly influence HBV replication in hepatocytes and p38 MAPK might involve in HBV replication. Finally, using a transient transfection of pHBV3.6 to Huh7 cells, p38 MAPK and its downstream molecule, ATF2, were found to be phosphorylated. SB203580, a selective p38 MAPK inhibitor, could inhibit HBV replication including its RNA, intracellular core-associated DNA and extracellular virion-associated DNA. The colvantly closed circular DNA, a most important index of HBV replication, was also inhibited by SB203580. This suggests that p38 MAPK was activated and might be essential for HBV replication in human hepatocytes.

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