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

在所有人类传染病中，50%以上是人畜共患疾病，或源于病毒从野生动物向人类的跨物种传播。其中包括汉坦病毒，它对全世界的公共卫生构成重大威胁，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。虽然汉坦病毒在其啮齿动物宿主中很少引起发病率或死亡率，但它们建立了一种持续感染，并溢出到同域宿主或人类宿主中。在非蓄水池啮齿类动物中的外溢感染导致无症状急性感染，无任何明显的促炎反应或疾病，而在人类中的外溢导致严重病理（汉坦病毒心肺综合征），死亡率可达40-50%。关于汉坦病毒感染的先天/适应性免疫反应的差异，我们所知甚少，这三种不同反应的特征是：持续性、病毒清除或严重病理。本研究的主要目标是根据精心设计的汉坦病毒感染体外实验，制定和测试新的数学模型，并在关键时间点确定区分自然与非自然宿主（啮齿动物和人类）的关键免疫成分。这一知识对于设计治疗汉坦病毒和其他目前无法获得治疗的类似人畜共患病毒的干预措施和治疗方法至关重要。体外实验旨在明确区分汉坦病毒在自然宿主（啮齿动物）和外溢到非宿主（啮齿动物和人类）中的感染途径。三种不同的汉坦病毒，在北美的地方性，将被用来感染内皮细胞和免疫细胞：Sin Nombre病毒，黑溪运河病毒和前景山病毒在两种不同类型的宿主细胞，鹿小鼠和人类。根据宿主和汉坦病毒种类的组合，在宿主或非宿主中可以观察到三种不同的结果：(i)持续感染而无疾病，（ii）病毒清除的急性感染，以及（iii）严重的病理和疾病。在肺中，内皮细胞和巨噬细胞是汉坦病毒的主要靶细胞。基于实验结果，将制定确定性和随机数学模型，并对这些和其他在免疫反应早期重要的细胞的动力学进行统计验证。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，包括促炎和抗炎细胞因子的激活。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，通过推广和专业活动，以及通过开发新的数学模型和统计方法，对教育和科学产生影响。数学模型、方法和数据将与其他科学团体共享，以调查有关禽流感、亨德拉病毒、埃博拉病毒和SARS冠状病毒等对公共卫生重要的其他人畜共患病毒的问题和假设。

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.