Collaborative Research: Modeling Immune Dynamics of RNA Viruses In Reservoir and Nonreservoir Species

合作研究：储存库和非储存库物种中 RNA 病毒的免疫动力学建模

• 批准号: 1517719
• 负责人: Linda Allen
• 金额: $ 34.98万
• 依托单位: Texas Tech University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1517719&HistoricalAwards=false
• 关键词: Collaborative; Research; Modeling; Immune; Dynamics

Over 50% of all human infectious diseases are zoonotic or originate through the cross-species transmission of viruses from wildlife to humans. Included among these are hantaviruses, which pose a significant threat to public health worldwide and are classified as emerging infectious diseases. Hantaviruses are transmitted to humans through contact with infected rodent excrement. Although hantaviruses cause little morbidity or mortality in their rodent reservoir, they establish a persistent infection that spills over into sympatric or human hosts. Spillover infection in nonreservoir rodents results in an asymptomatic acute infection without any apparent proinflammatory response or disease, whereas spillover in humans results in severe pathology (hantavirus cardiopulmonary syndrome) with mortality reaching 40-50%. Very little is known regarding the differences in the innate/adaptive immune response to hantavirus infection that characterize these three distinct responses: persistence, viral clearance, or severe pathology. The primary goals of this research are to formulate and to test new mathematical models based on carefully designed in vitro experiments for hantavirus infection and to identify key immune components at crucial time points that differentiate between natural versus nonnatural reservoirs (rodents and humans). This knowledge is essential for designing interventions and therapeutics for treatment of hantaviruses and other similar zoonotic viruses for which treatment is not currently available.The in vitro experiments are designed to clearly distinguish the pathways during hantavirus infection in natural reservoir (rodents) versus spillover into nonreservoir hosts (rodents and humans). Three different hantaviruses, endemic in North America, will be used to infect endothelial and immune cells: Sin Nombre virus, Black Creek Canal virus, and Prospect Hill virus in two different types of host cells, deer mice and human. Dependent on the combination of host and hantaviral species, three different outcomes can be observed in either reservoir or nonreservoir hosts: (i) persistence of infection with no disease, (ii) acute infection with viral clearance, and (iii) severe pathology and disease. In the lungs, endothelial cells and macrophages are the primary target cells of hantavirus. Based on the experimental outcomes, deterministic and stochastic mathematical models will be formulated and statistically validated for the dynamics of these and other cells important in the early phase of the immune response. Methods from ordinary and stochastic differential equations, Markov chains and branching processes will be used to model the virus-cell-immune dynamics that includes activation of proinflammatory and anti-inflammatory cytokines. Mathematical and statistical methods will be developed to identify thresholds that determine specific immunological pathways. In the broader context, this research will have educational and scientific impacts through cross-disciplinary training of students and a postdoc in mathematics and biology, through outreach and professional activities, and through development of new mathematical models and statistical methods. The mathematical models, methods, and data will be shared with other scientific groups to investigate questions and hypotheses regarding other zoonotic viruses important to public health such as avian influenza, Hendra, Ebola, and SARS Coronavirus.

超过50％的人类感染性疾病是人畜共患病或通过从野生动植物到人类的跨物种传播来引起的。 其中包括汉坦病毒，该病毒在全球范围内对公共卫生构成重大威胁，并被归类为新兴的传染病。汉坦病毒通过与感染的啮齿动物粪便接触传播给人类。尽管汉坦病毒在啮齿动物的储层中几乎没有发病或死亡率，但它们建立了一种持续的感染，会渗透到同胞或人类宿主中。非保存啮齿动物的溢出感染会导致无症状的急性感染，没有任何明显的促炎反应或疾病，而人类溢出会导致严重的病理（汉塔病毒心肺综合征），死亡率达到40-50％。关于对汉塔病毒感染的先天/适应性免疫反应的差异，这些差异表征了这三种不同的反应：持久性，病毒清除或严重的病理学。这项研究的主要目标是基于精心设计的汉坦病毒感染的体外实验制定和测试新的数学模型，并在重要的时间点上确定关键的免疫成分，这些时间点与自然储层（啮齿动物和人类）之间的区别相比，这些数学模型（啮齿动物和人类）区分了。该知识对于设计干预措施和治疗方法至关重要，以治疗汉坦病毒和其他类似的人畜共患病毒，目前尚无治疗的治疗。该体外实验旨在清楚地区分自然储层（啮齿动物）中hantavirus感染期间的途径，而不是溢流到非储库宿主（Rodents and odents and odents and andans）。在北美特有的三种不同的汉坦病毒将用于感染内皮和免疫细胞：Nombre病毒，Black Creek Canal Canal病毒以及两种不同类型的宿主细胞，鹿小鼠和人类中的前景山病毒。取决于宿主和汉坦病毒物种的组合，可以在储层或非保存宿主中观察到三种不同的结果：（i）没有疾病的持续性感染，（ii）病毒清除率以及（iii）严重病理学和疾病的急性感染。在肺中，内皮细胞和巨噬细胞是汉坦病毒的主要靶细胞。基于实验结果，将在免疫反应的早期阶段对这些和其他细胞的动力学进行制定和统计验证确定性和随机数学模型。来自普通和随机微分方程，马尔可夫链和分支过程的方法将用于模拟病毒 - 细胞免疫动力学，其中包括促炎和抗炎细胞因子的激活。将开发数学和统计方法，以识别确定特定免疫学途径的阈值。在更广泛的背景下，这项研究将通过对学生的跨学科培训以及数学和生物学博士后，通过外展和专业活动以及开发新的数学模型和统计方法的发展，从而产生教育和科学的影响。数学模型，方法和数据将与其他科学群体共享，以调查有关其他对公共卫生重要的人畜共患病病毒的问题和假设，例如禽流感，亨德拉，埃博拉病毒和SARS冠状病毒。