Abstract
摘要:屬於黃質病毒屬的登革熱病毒及日本腦炎病毒,兩者皆可以引起多樣顯著的疾病症狀和致死率。登革熱病毒感染後會引起不同程度的疾病症狀,從輕微的急性熱症(或叫作登革熱),到嚴重的登革出血熱和登革休克。日本腦炎病毒則是會造成嚴重神經性功能缺失及神經性的破壞。在一些促發炎細胞素中介白素IL-1β和IL-18 已證明是發炎疾病的主要媒介物質。產生IL-1β和IL-18 需要活化caspase-1,其活性促使pro-IL-1β和pro-IL-18 分解成有活性的終產物,而分泌到細胞外作用。除此之外,caspase-1 也可以經由形成細胞孔洞誘發細胞死亡(pyroptosis),而此作用也對發炎疾病的病理機制有重要貢獻。研究顯示,IL-1β和IL-18 會參與登革出血熱,登革休克,及腦炎的發生。近期研究發現一個表現於myeloid lineage 細胞的先天免疫受體CLEC5A,在登革熱病毒的致病性有重要的角色。CLEC5A 因登革熱病毒感染而活化後會,引發caspase-1 活化,細胞死亡,發炎反應及動物死亡。另外caspase-1 的活化也參與類風濕性關節炎的病程。因此caspase-1 是一個合理的治療標靶,我們將在此計畫中發展小分子的caspase-1 抑制劑,並在細胞及動物模式確認對登革熱病毒、日本腦炎病毒感染及類風濕性關節炎的治療能力。我們預期caspase-1 抑制劑會比現有的IL-1R 拮抗劑有較好的抗發炎治療效果,因為抑制caspase-1 同時可以阻斷IL-18 產生及避免pyroptosis 細胞死亡。
Abstract: Dengue virus (DV) and Japanese encephalitis virus (JEV) belonging to Flavivirusgenus can cause pleomorphic diseases. DV infection causes a wide range of diseasesfrom the mild febrile illness dengue fever to the life-threatening dengue hemorrhagicfever (DHF) and dengue shock syndrome (DSS). On the other hand, JEV is a majorcontributor to the occurrence of viral neurotropic encephalitis worldwide, which ismanifested by the neuronal dysfunction and/or destruction. Interleukin-1β (IL-1β)and IL-18 are central orchestrators of immunity against various classes of pathogens,and key triggers of inflammatory diseases. For both cytokine actions, a signal thatactivates cysteine protease caspase-1 and triggers proteolytic pro-IL-1β andpro-IL-18 processing to produce bioactive cytokines is necessary. Besides producingIL-1β and IL-18, caspase-1 activation also induces cytokine-independent cell death(pyroptosis), which is featured by formation of membrane pores, and performs apathway to modulate disease pathogenesis. Recent studies have implicated IL-1β andIL-18 in the pathogenetic mechanisms (i.e. the increased permeability of the systemicvasculature and hemorrhagic syndrome, and the loss of integrity of the blood brainbarrier) that cause DHF, DSS and encephalitis. Most importantly, CLEC5A, an innateimmunity receptor expressing in myeloid lineage cells, is a new identified receptor tomediate DV-transmitted caspase-1 activation and infectious pathology. Converselyanti-CLEC5A antibody can abrogate CLEC5A-mediated signaling (includingcaspase-1 activation), systemic plasma leakage and animal lethality. In addition toinfectious diseases, caspase-1 activation contributes to the pathogenesis ofrheumatoid arthritis. Based on these information, caspase-1 is a rational candidate oftargeted therapy for a variety of infectious and autoinflammatory diseases. It ispredicted that caspase-1 inhibitors might have better therapeutic efficacy than IL-1Rantagonists which clinical used in inflammatory diseases, because abrogating IL-18production and preventing pyroptosis are two extra mechanisms not shared by IL-1Rantagonists. Therefore, in this study, we plan to develop small molecule caspase-1inhibitors and validate their therapeutic efficacies for DV and JEV infections, andrheumatoid arthritis. Four specific aims are included for this study: Aim 1: Usingreconstituted caspase-1 system in cells to screen small molecule chemicals withenzymatic inhibition. Aim 2: Confirm the efficacy of potential caspase-1 inhibitors inCLEC5A- and other pathogen recognition receptors (PRRs)-mediated inflammasomeactivation in immune cells. Aim 3: Validation of potential caspase-1 inhibitors for thetreatment of DV and JEV infections. Aim 4: Validation of potential caspase-1inhibitors capable of inhibiting collagen-induced arthritis (CIA) in animal RA model.
Keyword(s)
CLEC5A受體
caspase 1抑制劑
介白質-1beta
登革熱病毒
日本腦炎病毒
白色念珠菌
CLEC5A
caspase-1 inhibitor
IL-1beta
Dengue virus
JEV
Candida