克沙奇病毒B3型屬於人類腸病毒B群 (human enterovirus B, HEV-B)，在臨床上能感染新生兒並引起心肌炎、肝炎、腦膜炎、胰臟炎、腦炎等疾病，其中克沙奇病毒B3型的抗體依賴性增強現象也已經在動物實驗中證實會增加肝炎的嚴重度。為探討克沙奇病毒B3型在肝細胞中的抗體依賴性增強現象，以及抗體依賴性增強的可能機制，我們分別利用老鼠肝細胞株 (AML12) 及人類肝細胞株 (Huh7) 建立克沙奇病毒B3型的抗體依賴性增強細胞 (in vitro) 感染模式。結果發現，當以克沙奇病毒B3型感染AML12細胞時，小鼠抗克沙奇病毒B3免疫球蛋白G (immunoglobulin G, IgG) 之抗體濃度為0.02-0.18 μg/ml時可以使病毒量增加。以克沙奇病毒B3型感染Huh7細胞時，當人類靜脈注射免疫球蛋白濃度介於約3-7 μg/ml時，病毒濃度會有增高的現象；當人類免疫球蛋白G抗體濃度介於0.012-2 μg/ml時，病毒濃度也會有增高的現象。利用阻斷試驗阻斷病毒受體克沙奇病毒-腺病毒受體 (coxsackievirus and Adenovirus Receptor, CAR) 以及衰變促進因子 (Decay Accelerating Factor, DAF/CD55) 後，分別進行病毒感染及抗體依賴性增強感染。結果顯示，克沙奇病毒B3型在AML12以及Huh7細胞中所引發的抗體依賴性增強現象需要克沙奇病毒-腺病毒受體的參與。此外，將Huh7細胞阻斷克沙奇病毒-腺病毒受體後進行病毒單獨感染，可以看到病毒濃度會隨著阻斷性抗體的濃度增加而降低，顯示克沙奇病毒-腺病毒受體在克沙奇病毒B3/2630的感染中扮演了重要的角色。若是將衰變促進因子進行阻斷，病毒濃度下降的情況則不明顯，但若是同時阻斷克沙奇病毒-腺病毒以及衰變促進因子，則會有些微的協同抑制作用。進一步偵測Huh7細胞在抗體依賴性增強感染下的細胞激素變化，結果發現在感染後0-10小時內細胞激素與對照組並無差異。此外，利用酵素切除人類免疫球蛋白G之Fc片段並加入病毒感染Huh7細胞，發現當抗體失去Fc片段後並不能引起抗體依賴性增強現象，顯示克沙奇病毒B3在肝細胞中的抗體依賴性增強現象是需要克沙奇病毒-腺病毒受體以及抗體 Fc 片段的參與，並且不是由抗體前端F(ab’)2片段所引起。另一方面，為探討是否有其他克沙奇病毒B型受體參與抗體依賴性增強機制之可能性，我們將過去文獻所發現可以作為克沙奇病毒B3型病毒受體之硫酸乙醯肝素 (Heparan sulfate) 視為可能的目標，以流式細胞儀偵測硫酸乙醯肝素在肝細胞的表現情形，並以肝素酶 (Heparinase) 移除細胞表面的硫酸乙醯肝素，以病毒感染後再以流式細胞儀分析病毒對細胞之感染率。結果發現當AML12細胞表面移除硫酸乙醯肝素後，克沙奇病毒之感染率相較於未移除硫酸乙醯肝素之AML12細胞並無明顯差異，因此暫排除硫酸乙醯肝素作為非經由克沙奇病毒腺病毒受體參與抗體依賴性增強機制之可能性。總結實驗結果，在小鼠肝細胞AML12以及人類肝細胞Huh7的細胞模式中，克沙奇病毒B3型確實可以在肝細胞引起抗體依賴性增強現象，此抗體依賴性增強現象是需要病毒受體克沙奇病毒-腺病毒受體，而非透過抗體前端F(ab’)2片段所引起。而在Huh7的細胞模式中，抗體依賴性增強感染在感染後10小時內並不會引起細胞激素分泌的變化。

Coxsackievirus B3 is a member of the human enterovirus B. CVB3 infection can cause a series of severe diseases in neonates such as myocarditis, hepatitis, meningitis and encephalitis. Antibody-dependent enhancement (ADE) of CVB3 infection has been shown to associate with disease severity in myocarditis. A hepatotropic CVB3 strain, CVB3/2630, can increase liver inflammation and damage through ADE mechanism, which was reported previously. Both coxsackievirus and adenovirus receptor (CAR) and Fcγ receptors (FcγRs) on immune cells are involved in the homologous ADE mechanisms of CVB3 infection. To study the role of CAR or FcγRs in ADE of CVB3 infection in hepatocytes, diluted mouse anti-CVB3 IgG, human intravenous immunoglobulin (IVIG) and anti-CVB3 IgG from human IVIG each infected with CVB3 directly to hepatocytes or hepatocytes pretreated with anti-CAR and anti-DAF antibodies were conducted. We found that diluted mouse anti-CVB3 IgG enhanced CVB3 infection at the concentration 0.02-0.18 μg/ml in AML12 (mouse hepatocytes); IVIG and anti-CVB3 IgG from IVIG enhanced CVB3 infection at the concentration 3-7 μg/ml and 0.012-2 μg/ml respectively in Huh7 (human hepatocytes). Blocking CAR on AML12 and Huh7 before infection, the viral titer showed no difference between with and without mouse anti-CVB3 IgG. In addition, the cytokines expression pattern did not change significantly after infection for 10 hours in Huh7 via ADE. On the other hand, blocking CAR on Huh7 before CVB3 infection resulted in a dose-dependent inhibition of viral titer, while blocking DAF didn’t inhibit viral titer obviously. However, blocking both CAR and DAF showed synergistic inhibition on viral titer. To further investigate the F(ab’)2 portion in ADE mechanisms of CVB3 in Huh7, we remove the Fc fragment from human IVIG and then infected Huh7 with CVB3 and F(ab’)2 fragment. The viral titer didn’t enhance as IgG lost its Fc fragment, which indicated the CAR-dependent ADE of CVB3 infection in Huh7 is not via F(ab’)2 fragment. As heparan sulfate is a CAR-independent mediator of the CVB3 infection, we hypothesized that heparan sulfate might participate the ADE. The expression level of heparan sulfate on AML12 and Huh7 was analyzed, then removed the heparan sulfate by heparinase I on AML12. Flow cytometry analysis showed that the infection rate of CVB3 on AML12 cells have no difference with heparan sulfate-free AML12 cells. Heparan sulfate may not involve in ADE of CVB3 infection in AML12. In conclusion, we demonstrated that CVB3 can induce ADE via CAR in hepatocyte, and the ADE of CVB3 infection is not through F(ab’)2 fragment or the involvement of heparan sulfate.

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劉蓉燕 (中華民國九十五年) 克沙奇B3病毒引起肝炎之體外及體內模式的研究， 國立成功大學微生物暨免疫學研究所碩士論文。