Polarized type 1 cytokine response and cell-mediated immunity determine genetic resistance to mousepox
Polarized type 1 cytokine response and cell-mediated immunity determine genetic resistance to mousepox
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DOI：
10.1073/pnas.0402949101
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发表时间：
2004-06-15
影响因子：
11.1
通讯作者：
Karupiah, G
中科院分区：
文献类型：
--
作者：
Chaudhri, G;Panchanathan, V;Karupiah, G
鼠痘病毒（ECTV）是一种天然的小鼠病原体和正痘病毒，已被用于通过使用明确定义的抗性和易感小鼠品系来研究在痘病毒感染中极化的1型或2型免疫应答与疾病抗性之间的相关性。我们的数据表明，在感染ECTV的抗性和易感小鼠中表达的细胞因子谱存在明显差异。耐药C57 BL/6小鼠在感染的最初几天内产生1型细胞因子应答[IFN-γ、IL-2和肿瘤坏死因子（TNF）]，这与强烈的细胞毒性T淋巴细胞应答（CTL）和从ECTV感染中恢复有关。另一方面，小鼠的易感品系（BALB/c和A/J）产生2型细胞因子应答（IL-4但很少或没有IFN-γ和IL-2），其与弱的或不存在的CTL应答相关，导致不受控制的病毒复制和死亡。尽管单独缺失IL-4功能并不改变易感小鼠中感染的结果，但抗性小鼠中IFN-γ功能的丧失废除了自然杀伤（NK）细胞和CTL效应子功能，导致暴发性疾病和100%死亡率。因此，在该病毒模型中，特异性1型细胞因子（特别是IFN-γ）的早期产生、细胞免疫应答的性质和疾病结果之间存在明确的联系。在鼠痘模型中的这一发现提出了不适当的细胞因子反应可能导致人类对天花易感性增加的可能性。
Ectromelia virus (ECTV), a natural mouse pathogen and an orthopoxvirus, has been used to investigate the correlation between polarized type 1 or type 2 immune responses and resistance to disease in poxvirus infections by using well defined resistant and susceptible mouse strains. Our data show that distinct differences exist in the cytokine profiles expressed in resistant and susceptible mice infected with ECTV. Resistant C57BL/6 mice generate a type 1 cytokine response [IFN-gamma, IL-2, and tumor necrosis factor (TNF)], within the first few days of infection, which is associated with strong cytotoxic T lymphocyte response (CTL) and recovery from ECTV infection. Susceptible strains of mice (BALB/c and A/J) on the other hand generate a type 2 cytokine response (IL-4 but little or no IFN-gamma and IL-2), which is associated with a weak or an absent CTL response, resulting in uncontrolled virus replication and death. Although deletion of IL-4 function alone did not change the outcome of infection in susceptible mice, the loss of IFN-gamma function in resistant mice abrogated natural killer (NK) cell and CTL effector functions resulting in fulminant disease and 100% mortality. Therefore, a clear link exists between the early production of specific type 1 cytokines, in particular, IFN-,y, the nature of the cellular immune response, and disease outcome in this virus model. This finding in the mousepox model raises the possibility that inappropriate cytokine responses may result in increased susceptibility to smallpox in humans.