Characterization of Yellow Fever Virus Infection of Human and Non-human Primate Antigen Presenting Cells and Their Interaction with CD4+ T Cells.
Characterization of Yellow Fever Virus Infection of Human and Non-human Primate Antigen Presenting Cells and Their Interaction with CD4+ T Cells.
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DOI：
10.1371/journal.pntd.0004709
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发表时间：
2016-05
影响因子：
3.8
通讯作者：
Holbrook MR
中科院分区：
文献类型：
--
作者：
Cong Y;McArthur MA;Cohen M;Jahrling PB;Janosko KB;Josleyn N;Kang K;Zhang T;Holbrook MR
人类感染黄热病病毒（YFV），一种蚊媒黄病毒，可以发展为从轻度发热性疾病到出血热和死亡的疾病。YFV的17 D疫苗株是在20世纪30年代开发的，自开发以来一直在使用，并已被证明非常有效。疫苗和野生型病毒之间的遗传差异很少，但与保护或疾病相关的病毒或宿主机制尚未完全了解。在过去的20年中，在接种17 D疫苗后发现了许多疫苗相关疾病的病例;这些病例与接种时免疫状态降低有关。最近，有几项研究评估了人类和非人类灵长类动物对疫苗接种的T细胞应答，但没有一项研究评估了对野生型病毒感染的应答。在本文所述的研究中，评价了人和恒河猴的单核细胞源性巨噬细胞（MDM）和树突状细胞（MoDC）支持野生型Asibi病毒或17 D疫苗株感染的能力，并表征了宿主细胞因子和趋化因子反应。还评价了人MoDC和MDM刺激CD 4 + T细胞的能力。发现MoDC和MDM支持病毒复制，并且对野生型或疫苗病毒的感染有不同的细胞因子应答。此外，用活17 D病毒感染的MoDC能够刺激CD 4 + T细胞中IFN-γ和IL-2的产生，而用Asibi病毒感染的细胞则不能。这些数据表明野生型和疫苗YFV刺激靶抗原呈递细胞中的不同应答，并且野生型YFV可以抑制CD 4 + T细胞的MoDC活化，这是保护性免疫发展中的关键组分。这些数据为野生型YFV在疾病发展中的调控能力提供了初步但关键的见解。黄热病病毒（YFV）是一种蚊媒黄病毒，可引起感染者致命的出血热。一种有效的减毒活疫苗，17 D，于1937年开发出来，至今仍在使用。在过去的几年中，已经发现了一些疫苗相关疾病的病例，并将其与免疫状态受损联系起来。在这里介绍的研究中，我们评估了巨噬细胞和树突状细胞（DC）对YFV感染的易感性，它们对感染的细胞因子反应以及它们与CD 4 + T细胞相互作用和刺激CD 4 + T细胞的能力。这些研究发现，来自人和非人灵长类动物的巨噬细胞和DC对野生型Asibi YFV或17 D疫苗病毒的感染易感，这两种病毒在这些细胞中刺激不同的细胞因子应答，并且感染17 D病毒的人DC能够刺激CD 4 + T细胞，而感染Asibi病毒的人DC则不能。这些数据表明野生型和疫苗病毒之间存在明显差异，这可能与17 D疫苗的成功有关。这些数据还表明，野生型YFV可能能够抑制免疫应答的关键组分，从而允许病毒繁殖和传播。
Humans infected with yellow fever virus (YFV), a mosquito-borne flavivirus, can develop illness ranging from a mild febrile disease to hemorrhagic fever and death. The 17D vaccine strain of YFV was developed in the 1930s, has been used continuously since development and has proven very effective. Genetic differences between vaccine and wild-type viruses are few, yet viral or host mechanisms associated with protection or disease are not fully understood. Over the past 20 years, a number of cases of vaccine-associated disease have been identified following vaccination with 17D; these cases have been correlated with reduced immune status at the time of vaccination. Recently, several studies have evaluated T cell responses to vaccination in both humans and non-human primates, but none have evaluated the response to wild-type virus infection. In the studies described here, monocyte-derived macrophages (MDM) and dendritic cells (MoDC) from both humans and rhesus macaques were evaluated for their ability to support infection with either wild-type Asibi virus or the 17D vaccine strain and the host cytokine and chemokine response characterized. Human MoDC and MDM were also evaluated for their ability to stimulate CD4+ T cells. It was found that MoDC and MDM supported viral replication and that there were differential cytokine responses to infection with either wild-type or vaccine viruses. Additionally, MoDCs infected with live 17D virus were able to stimulate IFN-γ and IL-2 production in CD4+ T cells, while cells infected with Asibi virus were not. These data demonstrate that wild-type and vaccine YFV stimulate different responses in target antigen presenting cells and that wild-type YFV can inhibit MoDC activation of CD4+ T cells, a critical component in development of protective immunity. These data provide initial, but critical insight into regulatory capabilities of wild-type YFV in development of disease. Yellow fever virus (YFV) is a mosquito-borne flavivirus that can cause lethal hemorrhagic fever in infected humans. An effective live-attenuated vaccine, 17D, was developed in 1937 and continues to be used today. Over the past several years, a number of cases of vaccine-associated disease have been identified and linked to a compromised immune status. In the studies presented here we evaluated the susceptibility of macrophages and dendritic cells (DCs) to YFV infection, their cytokine response to infection and their ability to interact with and stimulate CD4+ T cells. These studies found that macrophages and DCs derived from both humans and non-human primates were susceptible to infection with either a wild-type Asibi YFV or the 17D vaccine virus, that the two viruses stimulated different cytokine responses in these cells and that human DCs infected with the 17D virus were able to stimulate CD4+ T cells while those infected with Asibi virus did not. These data demonstrate clear differences between the wild-type and vaccine viruses that may be related to the success of the 17D vaccine. These data also suggest that wild-type YFV may be able to inhibit critical components of the immune response to allow virus propagation and dissemination.