Abstract
Several mechanisms have been proposed to account for the marked increase in severity of human infections with avian compared to human influenza strains, including increased cytokine expression, poor immune response, and differences in target cell receptor affinity. Here, the potential effect of target cell tropism on disease severity is studied using a mathematical model for in-host influenza viral infection in a cell population consisting of two different cell types. The two cell types differ only in their susceptibility to infection and rate of virus production. We show the existence of a parameter regime which is characterized by high viral loads sustained long after the onset of infection. This finding suggests that differences in cell tropism between influenza strains could be sufficient to cause significant differences in viral titer profiles, similar to those observed in infections with certain strains of influenza A virus. The two target cell mathematical model offers good agreement with experimental data from severe influenza infections, as does the usual, single target cell model albeit with biologically unrealistic parameters. Both models predict that while neuraminidase inhibitors and adamantanes are only effective when administered early to treat an uncomplicated seasonal infection, they can be effective against more severe influenza infections even when administered late.
Highlights
The potential spread of a severe pandemic influenza is a worldwide cause for concern
The aim of this paper is two-fold: (1) to theoretically explore the parameter space of an infection model consisting in two target cell populations to understand what role, if any, cell tropism could play in modulating an influenza infection’s dynamics; and (2) to consider what implications such an effect would have on treatment with antivirals
Mathematical model The proposed two target cell model, which consists of two cell populations both susceptible to influenza virus infection, is an extension of the differential equation model consisting of a single susceptible cell population and delayed viral production proposed in [28], and fitted therein to match the dynamics of a primary influenza A/HK/123/77 (H1N1) infection in human volunteers
Summary
The potential spread of a severe pandemic influenza is a worldwide cause for concern. Recent work has focused on the binding affinity of different strains of influenza virus for specific cell receptors within the respiratory tract [18,19,20,21] and it is believed that this difference in affinity between human and avian strains may in part be responsible for the difference in severity between the two strains, though the reasons for this are currently not well understood. A similar trend has developed for in vivo influenza infection assays which are preferably performed in ferrets rather than mice because the former has lung cells which predominantly express (human lung-like) SAa2,6 Gal receptors, while the latter mostly has lung cells expressing SAa2,3 Gal receptors [25,26,27]. A better understanding of the infection parameter differences between the mouse and ferret models could ease the translation of results obtained in mice into predictions for the course and outcome of infection in ferrets and humans
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