Abstract
Influenza is an infectious disease that primarily attacks the respiratory system. Innate immunity provides both a very early defense to influenza virus invasion and an effective control of viral growth. Previous modelling studies of virus–innate immune response interactions have focused on infection with a single virus and, while improving our understanding of viral and immune dynamics, have been unable to effectively evaluate the relative feasibility of different hypothesised mechanisms of antiviral immunity. In recent experiments, we have applied consecutive exposures to different virus strains in a ferret model, and demonstrated that viruses differed in their ability to induce a state of temporary immunity or viral interference capable of modifying the infection kinetics of the subsequent exposure. These results imply that virus-induced early immune responses may be responsible for the observed viral hierarchy. Here we introduce and analyse a family of within-host models of re-infection viral kinetics which allow for different viruses to stimulate the innate immune response to different degrees. The proposed models differ in their hypothesised mechanisms of action of the non-specific innate immune response. We compare these alternative models in terms of their abilities to reproduce the re-exposure data. Our results show that 1) a model with viral control mediated solely by a virus-resistant state, as commonly considered in the literature, is not able to reproduce the observed viral hierarchy; 2) the synchronised and desynchronised behaviour of consecutive virus infections is highly dependent upon the interval between primary virus and challenge virus exposures and is consistent with virus-dependent stimulation of the innate immune response. Our study provides the first mechanistic explanation for the recently observed influenza viral hierarchies and demonstrates the importance of understanding the host response to multi-strain viral infections. Re-exposure experiments provide a new paradigm in which to study the immune response to influenza and its role in viral control.
Highlights
Influenza is an infectious respiratory disease affecting and threatening millions of people worldwide [1]
We introduce a family of mathematical models of the within-host dynamics of influenza infection which allow for re-infection
This study improves our understanding of the innate immune response to influenza and demonstrates that re-exposure studies provide a new paradigm for further experimental research
Summary
Influenza is an infectious respiratory disease affecting and threatening millions of people worldwide [1]. The invasion of the influenza virus into a host’s upper respiratory tract (URT) starts from a sufficient number of virions (single viral particles) entering the URT and infecting healthy epithelial cells ( referred to as target cells) [2]. Immune responses are activated during influenza virus infection, and contribute to the control of infection and viral clearance from the host [3]. Of particular importance is the cytokine interferon (IFN, type 1), whose protective functions include inducing a virus-resistant state in target cells, reducing viral replication, and activating natural killer (NK) cells to induce apoptosis in infected cells [6,7,8,9]. A portion of those B cells and T cells become long-lived memory cells which can be activated rapidly to form a defense upon re-exposure to the same or an antigenically related virus
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