Immunoepidemiological Modeling of Dengue Viral Infection

Dengue viral infection is a mosquito-borne disease prevalent in tropical areas, resulting in over 300 million cases each year, a quarter of which are symptomatic. Dengue virus has four distinct serotypes, where the interactions between these strains have implications on the severity of the disease outcomes. During primary infections with one strain, dengue infection is largely asymptomatic, sometimes resulting in mild dengue fever. However, patients that develop a secondary infection with a different strain are at an increased risk of more severe disease, such as dengue hemorrhagic fever or dengue shock syndrome. The two competing hypotheses for the increased severity during secondary infections are antibody dependent enhancement and original antigenic sin. Antibody dependent enhancement suggests that long-lived antibodies from primary infection dominate antibody responses to secondary virus strains. The pre-existing antibody does not remove virus; instead, it signals phagocytes to migrate to the site of infection and ingest antibody-virus particles. Once inside the cell, virus unbinds and infects the phagocyte, which leads to enhanced infection and more severe disease. Original antigenic sin proposes that T lymphocytes specific to primary infection dominate cellular immune responses during secondary infections, but are inefficient at clearing cells infected with non-specific strains. Thus, the infected cells are not cleared quickly enough, leading to the immune cells remaining for longer periods, producing more cytokines, and leading to more severe disease. To analyze these hypotheses, we developed and analyzed within-host mathematical models. In previous work, we developed models of neutralizing and non-neutralizing antibody response. We found that in order to fit the secondary infection model to data, we must predict a decreased non-neutralizing antibody effect during secondary infection. Since this effect accounts for decreased viral clearance and the virus is in quasi-equilibrium with infected cells, we could be accounting for reduced cell killing and the original antigenic sin hypothesis. To further understand these interactions, we then develop a model of T cell responses to primary and secondary dengue virus infections that considers the effect of T cell crossreactivity in disease enhancement. We fit the models to published patient data and show that the overall infected cell killing is similar in dengue heterologous infections, resulting in dengue fever and dengue hemorrhagic fever. The contribution to overall killing, however, is dominated by non-specific T cell responses during the majority of secondary dengue hemorrhagic fever cases. By contrast, more than half of secondary dengue fever cases have predominant strain-specific T cell responses with high avidity. These results support the hypothesis that cross-reactive T cell responses occur mainly during severe disease cases of heterologous dengue virus infections. Finally, using the results from our within-host models and making certain simplifying assumptions, we develop an immunoepidemiological model of dengue viral infection which couples the within-host virus dynamics to the population level through a system of partial differential equations. The resulting multiscale model examines the dynamics of betweenhost infections in the presence of two circulating virus strains that involves feedback from the within-host and between-host interactions. We analytically determine the relationship between the model parameters and the characteristics of the solutions to the model, and find analytical thresholds under which infections persist in the population. Furthermore, we develop and implement a full numerical scheme for our immunoepidemiological model, allowing the simulation of population dynamics under variable parameter conditions. Immunoepidemiological Modeling of Dengue Viral Infection