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

Texas Tech University, Lubbock TX

Investigators

Abstract

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.