Abstract
In recent years, the within-host viral dynamics of dengue infections have been increasingly characterized, and the relationship between aspects of these dynamics and the manifestation of severe disease has been increasingly probed. Despite this progress, there are few mathematical models of within-host dengue dynamics, and the ones that exist focus primarily on the general role of immune cells in the clearance of infected cells, while neglecting other components of the immune response in limiting viraemia. Here, by considering a suite of mathematical within-host dengue models of increasing complexity, we aim to isolate the critical components of the innate and the adaptive immune response that suffice in the reproduction of several well-characterized features of primary and secondary dengue infections. By building up from a simple target cell limited model, we show that only the innate immune response is needed to recover the characteristic features of a primary symptomatic dengue infection, while a higher rate of viral infectivity (indicative of antibody-dependent enhancement) and infected cell clearance by T cells are further needed to recover the characteristic features of a secondary dengue infection. We show that these minimal models can reproduce the increased risk of disease associated with secondary heterologous infections that arises as a result of a cytokine storm, and, further, that they are consistent with virological indicators that predict the onset of severe disease, such as the magnitude of peak viraemia, time to peak viral load, and viral clearance rate. Finally, we show that the effectiveness of these virological indicators to predict the onset of severe disease depends on the contribution of T cells in fuelling the cytokine storm.
Highlights
Dengue is estimated to infect 390 million individuals annually [1], making it the most prevalent arthropod-borne viral disease in the world
Further studies have shown that memory T-cells established during a primary infection may act to increase the risk of developing severe disease in a heterologous secondary infection through increased pro-inflammatory cytokine production [7,8]. Complementing these experimental studies, epidemiological studies have successfully isolated host and viral risk factors associated with severe disease [9,10,11,12]. These studies have indicated that excessive activation of the immune response during a dengue infection may lead to a cascade of cytokine production, known as a cytokine storm, that results in direct damage to vascular endothelial cells and increased capillary permeability [7,13,14]
We find that higher viral infectivity rates along with infected cell clearance by T cells are necessary to reproduce these characteristic features of a secondary dengue infection, underscoring the contribution of the adaptive immune response in these infections
Summary
Dengue is estimated to infect 390 million individuals annually [1], making it the most prevalent arthropod-borne viral disease in the world. Complementing these experimental studies, epidemiological studies have successfully isolated host and viral risk factors associated with severe disease [9,10,11,12] Taken together, these studies have indicated that excessive activation of the immune response during a dengue infection may lead to a cascade of cytokine production, known as a cytokine storm, that results in direct damage to vascular endothelial cells and increased capillary permeability [7,13,14]. It assumes that disease severity is positively correlated with the level of antibodies in a heterologous secondary infection None of these existing dengue models consider the role that the innate immune response plays in controlling the viral infection or how infec- 2 tion dynamics explicitly impact disease severity. Our analysis highlights how the effectiveness of virological indicators in predicting dengue disease severity critically depends on the contribution of T cells to disease severity
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