Transfusion-related immunomodulation influences infectious disease outcomes

输血相关的免疫调节影响传染病的结果

• 批准号: 10249277
• 负责人: GRAHAM SIMMONS
• 金额: $ 61.24万
• 依托单位: VITALANT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249277
• 关键词: Acute; Adverse effects; Alphavirus; Animal Model; Arboviruses; Attenuated; Back; Blood; Blood Donations; Blood Transfusion; Characteristics; Chikungunya virus; Collection; Communicable Diseases; Data; Decision Making; Disease; Disease Outcome; Dose; Epidemic; Equilibrium; Event; FDA approved; Goals; Hand; Human; Immune; Immune response; Immune system; Immunocompetent; Immunologic Factors; Infection; Intervention; Intravenous; Knockout Mice; Knowledge; Lymphoid Cell; Mediating; Modeling; Molecular; Mus; Outcome; Packed Red Blood Cell Transfusion; Pathogenesis; Pathogenicity; Pathway interactions; Plasma; Platelet Transfusion; Public Health; Puerto Rico; RNA; Regulatory T-Lymphocyte; Reporting; Ross river virus; Safety; Symptoms; Testing; Therapeutic; Transfusion; Vascular blood supply; Viral; Viral Load result; Viral Pathogenesis; Viremia; Virus; Virus Diseases; Virus Replication; Zika Virus; acute infection; acute symptom; adverse outcome; arthropod-borne; attenuation; base; cell type; chikungunya; chikungunya infection; cost effectiveness; cytokine; human model; immunoregulation; improved; in vitro Assay; infection rate; mosquito-borne; mouse model; reduce symptoms; response; screening; tool; transmission process; viral RNA

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.

项目概要/摘要 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卫生问题 健康问题，特别是对于新出现的感染，FDA 批准的敏感测试无法针对这些感染 可用的。虫媒病毒可能是严重的急性感染，导致严重的长期并发症，并且 因其大规模流行而闻名，最近的第一个基孔肯雅病毒 (CHIKV) 和随后的寨卡病毒就证明了这一点 病毒。尽管拥有输血传播（TT）所需的许多特征，例如 血液中传染性病毒含量高，并且能够通过静脉注射进行感染，这是前所未有的。 是否报告过任何 CHIKV TT 事件。尽管发生大规模流行病，献血率高达 2% 已被发现具有RNA反应性。我们有初步数据支持 CHIKV 可以 小鼠中通过输血传播，输注红细胞可减弱 CHIKV 的发病机制。中央 这项研究背后的假设是 TT 确实发生，但有许多因素会导致感染 走向无症状或轻度。此外，传播过程中的免疫调节，在这种情况下通过 输血本身会导致疾病减弱。具体来说，我们和其他人已经证明了 许多先天免疫因子都可以通过输血调节并能够改变 CHIKV 结果。这些 包括先天性淋巴细胞和调节性T细胞及其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 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之外，这些研究还将 一般来说，对急性病毒感染有更广泛的影响。类似的免疫因子很可能具有 对病毒复制和/或发病机制产生巨大影响，从而更深入地了解这些 调解机制将有助于更好地规划筛查工作，甚至可能进行干预 在严重流行病期间。这将提高快速响应问题的能力和决策能力 新的病毒对血液安全和供应造成威胁。