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.

项目摘要/摘要 大型流行病期间通过输血传播急性病毒感染是一个严重的公众 健康问题，特别是对于新兴的感染，没有敏感的FDA批准测试是 可用的。刺病毒可能是严重的急性感染，导致严重的长期并发症，并且是 由于最近用第一个基孔肯雅病毒（Chikv）和Zika所证明的，他们的流行病很大 病毒。尽管拥有输血传播所需的许多特征（TT），例如 血液中的高负量传染病和通过静脉接种感染的能力，从来没有 一直报道的任何CHIKV TT事件。尽管大规模流行，但多达2％的血液捐赠 已发现RNA反应性。我们有初步数据支持Chikv可以是 输血传递在小鼠中，RBC的输血减弱了CHIKV发病机理。中央 这项研究背后的假设是TT确实发生了，但是许多因素引起了感染 致力于无症状或轻度。此外，在传播过程中的免疫调制，在这种情况下通过 输血本身会导致疾病的衰减。具体来说，我们和其他人证明了 先天免疫因子的数量均由输血调节，并且能够改变CHIKV结果。这些 包括先天淋巴样细胞和调节性T细胞以及其上游和下游的细胞因子 刺激。这项研究将使用CHIKV发病机理的鼠模型进一步研究这些发现。 此外，它将模仿输血，CHIKV的TT并研究免疫参数和疾病 结果。除了了解发病机理和输血之间的相互作用外，这些研究还将 一般来说，对急性病毒感染有更大的影响。可能具有类似的免疫因素 对病毒复制和/或发病机理的戏剧性影响，从而更深入地了解这些 介导的机制将允许更好地计划筛查工作，甚至有可能进行干预措施 在严重的流行期间。这将允许提高能力和决策，以迅速响应 对血液安全和可用性的新病毒威胁。