Pig model mimicking chronic hepatitis E virus infection in immunocompromised patients to assess immune correlates during chronicity
Pig model mimicking chronic hepatitis E virus infection in immunocompromised patients to assess immune correlates during chronicity
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DOI：
10.1073/pnas.1705446114
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发表时间：
2017-07-03
影响因子：
11.1
通讯作者：
Meng, Xiang-Jin
中科院分区：
文献类型：
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作者：
Cao, Dianjun;Cao, Qian M.;Meng, Xiang-Jin
慢性戊型肝炎病毒（HEV）感染是一个重要的临床问题，在免疫功能低下的个人，如器官移植受体，虽然机制仍然未知，因为缺乏动物模型。我们成功地建立了慢性戊型肝炎病毒感染的猪模型，并检查了导致慢性化的免疫相关性。免疫功能低下的患者的条件是模仿治疗猪与免疫抑制方案，包括环孢素，硫唑嘌呤，和泼尼松龙。免疫功能低下的猪感染戊型肝炎病毒进展到慢性，因为8/10的药物治疗的戊型肝炎病毒感染的猪继续粪便病毒脱落超过感染的急性期，而大多数（7/10）的模拟治疗的戊型肝炎病毒感染的猪清除粪便病毒脱落在感染后8周。在慢性感染期间，血清中的肝酶水平。谷氨酰转移酶和粪便病毒脱落显着较高的免疫功能低下的HEV感染的猪。为了确定慢性感染的潜在免疫相关性，我们测定了猪的细胞因子和细胞介导的免疫应答的血清水平。结果表明，HEV感染免疫功能低下的猪的Th 1细胞因子IL-2和IL-12，和Th 2细胞因子IL-4和IL-10的血清水平降低，特别是在感染的急性期。此外，在感染的急性期，免疫功能低下的猪的IFN-γ特异性CD 4（+）T细胞应答降低，但在感染的慢性期，TNF-α特异性CD 8（+）T细胞应答增加。因此，在免疫功能低下的条件下主动抑制细胞介导的免疫应答可能有助于慢性HEV感染的建立。这种猪模型将有助于阐明慢性戊型肝炎病毒感染的机制，并开发有效的治疗慢性戊型肝炎的药物。
Chronic hepatitis E virus (HEV) infection is a significant clinical problem in immunocompromised individuals such as organ transplant recipients, although the mechanism remains unknown because of the lack of an animal model. We successfully developed a pig model of chronic HEV infection and examined immune correlates leading to chronicity. The conditions of immunocompromised patients were mimicked by treating pigs with an immunosuppressive regimen including cyclosporine, azathioprine, and prednisolone. Immunocompromised pigs infected with HEV progressed to chronicity, because 8/10 drug-treated HEV-infected pigs continued fecal virus shedding beyond the acute phase of infection, whereas the majority (7/10) of mock-treated HEV-infected pigs cleared fecal viral shedding at 8 wk postinfection. During chronic infection, serum levels of the liver enzyme.-glutamyl transferase and fecal virus shedding were significantly higher in immunocompromised HEV-infected pigs. To identify potential immune correlates of chronic infection, we determined serum levels of cytokines and cell-mediated immune responses in pigs. Results showed that HEV infection of immunocompromised pigs reduced the serum levels of Th1 cytokines IL-2 and IL-12, and Th2 cytokines IL-4 and IL-10, particularly during the acute phase of infection. Furthermore IFN-gamma-specific CD4(+) T-cell responses were reduced in immunocompromised pigs during the acute phase of infection, but TNF-alpha-specific CD8(+) T-cell responses increased during the chronic phase of infection. Thus, active suppression of cell-mediated immune responses under immunocompromised conditions may facilitate the establishment of chronic HEV infection. This pig model will aid in delineating the mechanisms of chronic HEV infection and in developing effective therapeutics against chronic hepatitis E.