Transfusion-related immunomodulation influences infectious disease outcomes

项目摘要/摘要 在大流行期间通过输血传播急性病毒感染是一个严重的公共问题 健康问题，特别是对于新出现的感染，没有FDA批准的敏感测试 可用。虫媒病毒可以是严重的急性感染，导致严重的长期并发症，并且 以其大规模流行而闻名，最近的基孔肯雅病毒(CHIKV)和随后的寨卡病毒证明了这一点 病毒。尽管拥有输血传播(TT)所需的许多特征，例如 血液中的高传染性病毒载量和通过静脉接种感染的能力，从来没有过 有任何CHIKV TT事件的报告。尽管发生了大规模的流行病，高达2%的献血者 已经被发现是RNA反应性的。我们有初步数据支持这样一个事实，即CHIKV可以 小鼠输血传播，输注RBC可减轻CHIKV致病作用。中环 这项研究背后的假设是TT确实会发生，但有许多因素会导致感染 倾向于无症状或温和的。此外，在传输期间的免疫调节，在这种情况下是通过 输血本身会导致疾病的减轻。具体地说，我们和其他人已经演示了 先天免疫因子的数量既受输血的调节，也能改变CHIKV的结局。这些 包括先天淋巴样细胞和调节性T细胞及其上游和下游的细胞因子 刺激。这项研究将使用CHIKV致病的小鼠模型来进一步研究这些发现。 此外，它还将模拟输血、CHIKV的TT，并研究免疫参数和疾病 结果。除了了解发病机制和输血之间的相互作用外，这些研究还将 对一般的急性病毒感染有更广泛的影响。类似的免疫因素很可能具有 对病毒复制和/或致病机制的戏剧性影响，从而加深对这些 机制的协调将允许更好地规划筛查工作，甚至可能进行干预 在严重的流行病期间。这将提高快速响应 对血液安全和可获得性的新病毒威胁。

Project Summary/Abstract Transmission of acute viral infections through blood transfusion during large epidemics is a serious public health issue, particularly for newly emerging infections for which no sensitive FDA-approved tests are available. Arboviruses can be serious acute infections leading to serious long-term complications, and are noted for their massive epidemic, as recently demonstrated with first chikungunya virus (CHIKV) and then Zika virus. Despite possessing many of the characteristics required for blood transfusion transmission (TT), such as high loads of infectious virus in blood and the ability to infect via intravenous inoculation, there have never been any CHIKV TT events reported. This is despite large-scale epidemics where up to 2% of blood donations have been found to be RNA reactive. We have preliminary data supporting the fact that CHIKV can be transfusion-transmitted in mice, and that transfusion of RBC attenuated CHIKV pathogenesis. The central hypothesis behind this study is that TT does occur, however a number of factors drive infection towards being asymptomatic or mild. Further, immune modulation during transmission, in this case via the blood transfusion itself, leads to an attenuation of disease. Specifically, we and others have demonstrated a number of innate immune factors are both modulated by transfusion and able to alter CHIKV outcomes. These include innate lymphoid cells and regulatory T cells and the cytokines both upstream and downstream of their stimulation. This study will use a murine model of CHIKV pathogenesis to investigate these findings further. Additionally, it will mimic blood transfusions, TT of CHIKV, and study immune parameters and disease outcomes. Beyond understanding the interplay between pathogenesis and blood transfusion, these studies will have a wider impact on acute viral infections in general. It is likely that similar immune factors can have dramatic effects on viral replication and/or pathogenesis, and thus a deeper understanding of how these mechanisms are mediated will allow better planning for screening efforts and potentially even interventions during serious epidemics. This will allow improved capabilities and decision making in responding rapidly to a new viral threat to blood safety and availability.