||抑制annexin A1 降低單純疱疹病毒感染引起的致死率
||Suppression of annexin A1 reduces the lethality induced by
herpes simplex virus
||Institute of Basic Medical Sciences
herpes simplex virus
疱疹病毒引起的腦炎是最常見的偶發致死性腦炎。在病人未接受抗病毒藥物治療的情況下，致死率高達百分之七十；即使給予病人抗疱疹病毒藥物的治療，只有百分之三的病人可恢復至正常的神經功能。此外，高達百分之九十的族群曾被疱疹病毒感染，但為何病毒只在少數人造成疾病的原因仍不明。病毒仰賴宿主的蛋白完成複製，但目前對於這些宿主蛋白以及其參與機制所知甚少。在我們的研究發現一種宿主蛋白，annexin A1 (Anx-A1) 表現在細胞的表面，疱疹病毒感染進一步增加Anx-A1在細胞表面的表現。疱疹病毒引起的Anx-A1外翻至細胞表面的現象，可在許多細胞及疱疹病毒種類觀察到。除此之外，細胞表面的Anx-A1與疱疹病毒在病毒貼附時有共位現象，且給予細胞抗Anx-A1的抗體可中和疱疹病毒的感染。我們利用培養自野生型或Anx-A1缺陷小鼠的胚胎纖維母細胞以及皮質神經元發現，Anx-A1藉由增加被感染細胞的數量以及與細胞結合的疱疹病毒數量，在細胞中增加疱疹病毒複製。我們進一步研究Anx-A1幫助疱疹病毒感染的機制並發現，Anx-A1與疱疹病毒的病毒顆粒結合，並且Anx-A1可與多於一種病毒結構蛋白結合。其中結合力最高的兩種蛋白經由matrix-assisted laser desorption inoization-time of flight (MALDI-TOF) mass spectrometry分析後，被辨認為病毒的醣蛋白D (gD) 和gE。利用共同免疫沉澱法，我們進一步發現Anx-A1與病毒的gE結合，但不與gD結合。這些結果顯示Anx-A1與表現在病毒顆粒上的gE結合，並藉此幫助病毒在細胞表面貼附。為了研究Anx-A1對疱疹病毒在活體感染的影響，我們利用由針刮過的角膜來感染小鼠疱疹病毒，此小鼠模式可以模仿病人的疱疹病毒感染。在模擬感染和疱疹病毒感染的小鼠中我們發現，Anx-A1表現在疱疹病毒的標的細胞 (表皮細胞和神經元) 及標的組織 (眼、三叉神經節及腦)中。疱疹病毒感染顯著的增加Anx-A1在小鼠腦中的表現。Anx-A1缺陷小鼠感染後比起野生型小鼠在組織中有較低病毒量、以及較高存活率，此結果指出Anx-A1缺陷小鼠更不易被疱疹病毒感染。除此之外，利用反股寡去氧核醣核酸抑制Anx-A1的表現，可減少小鼠在感染後的死亡率，並降低組織中的病毒量。總結上述結果，我們發現Anx-A1作為協助蛋白，利用與gE結合來幫助第一型疱疹病毒感染。在小鼠中剔除或抑制Anx-A1的表現，可減少第一型疱疹病毒腦炎的致死率。除此之外, 已知皮質類固醇可增加Anx-A1的外翻和細胞內的表現量，本篇實驗結果對皮質類固醇如何增加第一型疱疹病毒在細胞以及活體中的感染提出一個新的解釋，並建議Anx-A1是一個調控宿主對第一型疱疹病毒感受性的危險因子，尤其是在受到精神壓力以及皮質類固醇治療的宿主。
Herpes simplex virus (HSV)-induced encephalitis is the most common cause of sporadic, fatal encephalitis with a mortality rate as high as 70% in patients without treatment. Even treated with anti-herpetic drugs, only 3% survivors recover to normal neurological functions. Moreover, it remains elusive regarding why some individuals develop diseases in human population with more than 90% infected. Viruses rely on cellular proteins to complete their replication. However, little is known about these cellular factors and their mechanism. In our study, we found that annexin A1 (Anx-A1), a cellular protein, was expressed on cell surface. HSV-1 infection further enhanced Anx-A1 expression on cell surface. Enhanced surface Anx-A1 expression induced by HSV-1 infection is not specific to a particular virus strain or cell type. Furthermore, surface Anx-A1 co-localized with HSV-1 virion during virus attachment, and antiserum against Anx-A1 neutralized HSV-1 infection in cells. Using embryonic fibroblasts and cortical neurons cultured from wild-type or Anx-A1-deficient mice, we found that Anx-A1 increased HSV-1 replication in vitro via increasing the numbers of HSV-1-infected cells and virus binding on cells. To study the mechanism mediated by Anx-A1 to enhance HSV-1 infection, we found that Anx-A1 interacted with HSV-1 virions, and Anx-A1 interacted with more than one viral structural protiens. The strongest two interacting proteins were identified as viral glycoprotein (g) D and gE by matrix-assisted laser desorption inoization-time of flight (MALDI-TOF) mass spectrometry analysis. We further demonstrated that gE but not gD interacted with Anx-A1 via co-immunoprecipitation assay. These results indicate that Anx-A1 interacts with gE on HSV-1 virions to enhance virus binding on cells. To study the effect of Anx-A1 in HSV-1 infection in vivo, mice were infected with HSV-1 via scarified cornea which mimics virus infection in humans. Anx-A1 was detected in the HSV-1 target cells (epithelial cells and neurons) and tissues (eyes, trigeminal ganglia, and brains) of mock- and HSV-1-infecte mice. HSV-1 infection increased the expression of Anx-A1 in infected mouse brains. Mice deficient in Anx-A1 were significantly more resistant to HSV infection as demonstrated by lower tissue viral loads and a higher survival rate when compared with those of wild-type mice. Furthermore, knockdown of Anx-A1 expression in mice by an antisense oligodeoxynucleotide specific to Anx-A1 reduced the mortality in a dose dependent manner and inhibited viral replication in infected tissues. In conclusion, we found that Anx-A1 acts as an accessory protein that interacts with gE to enhance HSV-1 infection. Knockout or knockdown of Anx-A1 expression in mice reduces the lethality of HSV-1-infected mice. Furthermore, glucocorticoids enhance Anx-A1 externalization and expression. These results provide a new insight of how glucocorticoid treatment increases HSV-1 infection in vitro and in vivo and suggest that Anx-A1 is a risk factor that regulates the susceptibility of hosts to HSV-1 infection, especially in those who are under psychological stress or glucocorticoid treatment.
Figure list IX
1. Herpes simplex virus (HSV) 1
1.1 HSV Structure 1
1.2 HSV Entry and replication in host cells 1
1.3 HSV transmission in hosts 2
1.4 HSV-induced diseases and treatment 2
1.5 Cellular factors in enhancing HSV-1 replication 3
2. Annexin A1 (Anx-A1) 4
2.1 The annexin superfamily 4
2.2 Anx-A1 structure 4
2.3 Anx-A1 expression and its receptor 4
2.4 Multiple functions of Anx-A1 5
2.5 Anx-A1 in virus infection 10
Specific aims 11
Specific aim 1. To determine the effect of HSV-1 infection on Anx-A1 expression in vitro and in vivo 11
Specific aim 2. To determine the role of Anx-A1 on cell surface in HSV-1 infection 12
Specific aim 3. To identify the viral protein(s) interacting with Anx-A1 to enhance HSV-1 infection 12
Specific aim 4. To study whether Anx-A1 enhances HSV-1 titers in tissues and aggravates HSV-1-induced lethality in mice 12
Specific aim 5. To determine whether Anx-A1 knockdown protects mice from HSV-1-induced lethality 13
Materials and Methods 14
1. Cells and virus 14
2. Purification and fluorescent-label of HSV-1 virions 14
3. Generation of recombinant His-tag Anx-A1 and Anx-A1 specific antiserum and antibody 15
4. Neutralization assay 15
5. Infection of mice, tissue analysis, and antisense oligodeoxynucleotide treatment 15
6. Culture of mouse embryonic fibroblasts (MEFs) 16
7. Culture of mouse cortical neurons 17
8. Protein extraction and western blot analysis 17
9. Immunofluorescence staining 18
10. Virus binding assay 19
11. Plaque forming assay 19
12. Virus growth curve 20
13. Far western analysis 20
14. Co-immunoprecipitation 21
15. Statistics 21
1. Anx-A1 is expressed on cell surface, and HSV-1 infection increases Anx-A1 expression on cell surface. 22
2. Anx-A1 co-localizes with HSV-1 on cell surface, and blockage of Anx-A1 on cell surface by anti-Anx-A1 antiserum reduces HSV-1-infected cells. 23
3. Anx-A1 increases the levels of virus binding on cells, HSV-1-infected cells, and viral yields in infected cells. 24
4. Anx-A1 interacts with HSV-1 via gE. 25
5. Anx-A1 is expressed in the mouse tissues, which support viral replication. 27
6. Absence of Anx-A1 reduced the levels of mortality, tissue viral loads, and infected brain neurons of mice. 28
7. Treatment with the antisense oligodeoxynucleotide (ODN) specific to Anx-A1 reduced the lethality and tissue viral loads of HSV-1-infected mice. 29
1. The mechanism by which Anx-A1 is externalized 31
2. The role of externalized Anx-A1 in promoting HSV-1 infection 33
3. Other possibilities regarding how Anx-A1 promotes HSV-1 infection 33
4. Anx-A1 is incorporated in HSV-1 virions 35
5. The increase of Anx-A1 in the HSV-1-infected mouse brain 35
6. Glucocorticoid, Anx-A1, and HSV-1 36
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