Transfusion-related immunomodulation influences infectious disease outcomes

项目总结/摘要 在大规模流行期间，通过输血传播急性病毒感染是一个严重的公众问题。 健康问题，特别是对于新出现的感染，没有敏感的FDA批准的测试， available.虫媒病毒可以是严重的急性感染，导致严重的长期并发症， 以其大规模流行而闻名，最近首次出现基孔肯雅病毒（CHIKV），然后是寨卡病毒 病毒尽管具有输血传播（TT）所需的许多特征，如 血液中的高感染性病毒和通过静脉接种感染的能力， 报告了任何CHIKV TT事件。这是尽管大规模流行病，其中高达2%的献血 已经发现是RNA反应性的。我们有初步的数据支持CHIKV可以 在小鼠中输血传播，且输注RBC减弱了CHIKV发病机制。中央 这项研究背后的假设是，TT确实发生，但有许多因素驱动感染 无症状或轻微。此外，在传播期间的免疫调节，在这种情况下通过免疫调节， 输血本身会导致疾病的减弱。具体来说，我们和其他人已经证明了一个 许多先天免疫因子都通过输血调节，并且能够改变CHIKV结果。这些 包括先天性淋巴细胞和调节性T细胞以及它们的上游和下游的细胞因子。 刺激.本研究将使用CHIKV发病机制的小鼠模型来进一步研究这些发现。 此外，它将模拟输血，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，这些研究将 对一般急性病毒感染有更广泛的影响。类似的免疫因素很可能 对病毒复制和/或发病机制的巨大影响，从而更深入地了解这些 机制的调解将允许更好地规划筛选工作，甚至可能干预 在严重的流行病期间。这将提高快速应对突发事件的能力和决策能力， 新的病毒威胁血液安全和可用性。

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.