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

超过50%的人类传染病是人畜共患疾病，或源于野生动物向人类的跨物种病毒传播。 其中包括汉坦病毒，它对全世界的公共卫生构成重大威胁，并被列为新出现的传染病。汉坦病毒通过接触受感染的啮齿动物粪便传播给人类。虽然汉坦病毒在啮齿动物宿主中几乎不引起发病或死亡，但它们建立了一种持续感染，并蔓延到同域或人类宿主。非宿主啮齿动物的溢出感染导致无症状的急性感染，没有任何明显的促炎反应或疾病，而人类的溢出导致严重的病理学（汉坦病毒心肺综合征），死亡率达到40- 50%。关于先天性/适应性免疫反应对汉坦病毒感染的差异知之甚少，这三种不同的反应是：持久性，病毒清除或严重病理。这项研究的主要目标是制定和测试新的数学模型的基础上精心设计的体外实验汉坦病毒感染，并确定关键的免疫成分在关键的时间点，区分自然与非自然水库（啮齿动物和人类）。这些知识对于设计汉坦病毒和其他类似的人畜共患病病毒的干预和治疗方法是必不可少的，这些病毒目前还没有治疗方法。体外实验的目的是明确区分汉坦病毒感染天然宿主（啮齿动物）和溢出到非宿主宿主（啮齿动物和人类）的途径。三种不同的汉坦病毒，在北美流行，将被用来感染内皮细胞和免疫细胞：辛农布尔病毒，黑溪运河病毒，和前景希尔病毒在两种不同类型的宿主细胞，鹿，小鼠和人类。根据宿主和汉他病毒种属的组合，在储库或非储库宿主中可以观察到三种不同的结果：（i）持续感染，无疾病，（ii）急性感染，病毒清除，和（iii）严重病理和疾病。在肺中，内皮细胞和巨噬细胞是汉坦病毒的主要靶细胞。根据实验结果，将制定确定性和随机数学模型，并对这些和其他细胞在免疫反应早期阶段的重要动态进行统计验证。从普通和随机微分方程，马尔可夫链和分支过程的方法将被用来模拟病毒细胞免疫动力学，包括激活促炎和抗炎细胞因子。将开发数学和统计方法来确定确定特定免疫途径的阈值。在更广泛的背景下，这项研究将通过对学生和数学和生物学博士后的跨学科培训，通过外联和专业活动，以及通过开发新的数学模型和统计方法，产生教育和科学影响。数学模型，方法和数据将与其他科学团体共享，以调查有关对公共卫生重要的其他人畜共患病病毒的问题和假设，如禽流感，亨德拉，埃博拉和SARS冠状病毒。

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.