Abstract
摘要:第一簡單型疱疹病毒 (簡稱HSV-1)是常見的人類病原體。經過在皮膚組織的感染複製後,可以進入感覺神經節而造成潛伏性感染。這樣的特性因此使得該病毒成為探討病毒與宿主的免疫系統之間的交互關係的重要研究模式之一。小鼠是常用來研究HSV-1 致病機轉的動物模式。經表皮感染HSV-1 後,可以在皮膚表面形成痂傷甚至沿著感覺神經節的末梢神經束造成帶狀疱疹的臨床症狀。IL-15 是一種具有多功能的細胞激素,主要能活化並促進自然殺手細胞以及CD8 T 細胞的活化與作用。雖然其他的非淋巴性組織例如皮膚、肌肉、關節骨膜等都能分泌IL-15,它在局部組織的作用以及調控機理尚不清楚。在胚胎時期,表現V5 的 T 細胞即進入皮膚的表皮層並且進行自我更新的發育與增殖。過去的研究結果證實皮層細胞所分泌的IL-15對於該群表現V5 的 T 細胞 (又稱為樹突狀表皮T 細胞)的發育、壽命與活化十分重要。缺乏 T 細胞的小鼠雖然對於大多數的病原感具有免疫抵禦的能力,但是對於某些特定的感染或是環境暴露也有較高的皮發發炎反應。已知 T 細胞具有多重免疫調節功能,然而它與IL-15 的交互影響對於皮膚組織中的抗病毒免疫反應的作用尚未被探討。利用IL-15 基因突變與 T 細胞剔除鼠感染HSV-1 後,我們初步的結果發現:HSV-1 誘發的皮膚發炎反應包括產生細胞激素的種類、免疫細胞的組織浸潤程度與細胞組成成分、病毒在皮膚中的複製能力甚至帶狀疱疹的痂傷嚴重程度都會因為IL-15 或是 T 細胞的缺失而受到影響; 顯示IL-15 與表皮 T 細胞對於調控皮膚組織的先天性免疫反應有重要的角色。另外,IL-15 突變鼠所表現的IL-15 異構體極有可能負向地調控皮膚中IL-15 的相關功能。本研究為一四年期計畫,將繼續利用現行經皮感染HSV-1 的動物模式探討IL-15與表皮 T 細胞二者在皮膚的抗病毒免疫反應的功能,並探討當IL-15 與表皮 T 細胞的抵禦機制不完備的情況下,HSV-1 將可能利用哪些感覺神經細胞受器進出神經節造成皮層區的帶狀疱疹。實驗將從以下四方面進行: (一) 利用小鼠感染HSV-1 的模式,了解表皮 T 細胞的移行與發炎反應是否會受到IL-15 表現量高低的影響; (二) 探討IL-15 異構體是否會負向調控表皮 T 細胞的活化而影響抗原特異性T 細胞的移行與皮膚浸潤; (三)區辨 T 細胞各次群細胞的功能以及影響HSV-1 神經侵入性; 最後,(四)找出皮膚週邊神經束與HSV-1 作用的細胞受器,以進一步地了解皮膚中的先天性免疫反應機制如何調控HSV-1 進入神經節。本研究的結果將能發現IL-15 與表皮皮層中 T 細胞的新功能,並且深入地了解皮膚週邊的先天性抗病毒免疫反應的機制。對於未來發展相關的治療方法有重要的貢獻。
Abstract: Herpes Simplex Virus-1 (HSV-1) is a ubiquitous human pathogen. Its capability in theestablishment of latent infection within the host after primary cutaneous replication has made it asa valuable tool to delineate the virus-host interactions within the immune system. Inoculation ofHSV-1 on abraded mouse flank skin represents a well established model which mimics the timingand the steps involved in the histopathological development of HSV-1 zosteriform and hostimmune responses. The model has been successfully established in our laboratory and we willcontinue to use it in the proposed study.IL-15 is a pleiotropic cytokine which supports NK and CD8 T cell function within thelymphoid compartment. Its expression and regulation in non-lymphoid tissues largely remainunclear. The development and proliferation of skin resident T cells known as dendriticepidermal T cells depend on IL-15 and reportedly have multifaceted immune-regulatory functionbecause T cells deficient mice are shown to have increased susceptibilities to certain types ofskin infection and dermatitis. Our preliminary observations using mice lacking of sufficientIL-15 and functional epithelial T cells have found that HSV-1 induced inflammatory cytokineproduction, inflammatory cell infiltrations, virus replication, zosteriform spread and lesionseverity in mouse skin were all modulated, implicating IL-15 and T cells are important innatecomponents in the control of HSV-1 cutaneous replication and neural invasion. How IL-15 andDETCs work together to orchestrate innate antiviral mechanisms and how HSV-1 enters andtravels back to skin from the dorsal root ganglia are the central questions addressed in the study.Experiments in this 4-year study are designed to: Aim 1. Characterize the effect of IL-15 on therecruitment of DETCs and proinflammatory responses in response to cutaneous HSV-1 infectionunder the differential expression levels of IL-15 in vivo; Aim 2. Investigate the effects of IL-15alternative splice variant on DETC activation and recruitment of skin-homing T cells to HSV-1lesional skin both in vitro and in vivo; Aim 3. Identify the role and the subset of epithelial Tcells in the control of HSV-1 neuroinvasion; and Aim 4. Identify the sensory receptor or receptorstargeted by HSV-1 for neuroinvasion. Proposed studies will define the undisclosed functions ofIL-15 and T cells in skin and lead to better understandings of epidermal innate antiviralmechanisms. Results from these experiments will generate useful information for thedevelopment of novel strategies to treat human herpesviral infection.
Keyword(s)
Capacitive deionization
Energy efficient water reclamation technology
Energy storage system