Integrative Model of the Immune Response to a Pulmonary Macrophage Infection: What Determines the Infection Duration?

Abstract

The immune mechanisms which determine the infection duration induced by pathogens targeting pulmonary macrophages are poorly known. To explore the impact of such pathogens, it is indispensable to integrate the various immune mechanisms and to take into account the variability in pathogen virulence and host susceptibility. In this context, mathematical models complement experimentation and are powerful tools to represent and explore the complex mechanisms involved in the infection and immune dynamics. We developed an original mathematical model in which we detailed the interactions between the macrophages and the pathogen, the orientation of the adaptive response and the cytokine regulations. We applied our model to the Porcine Respiratory and Reproductive Syndrome virus (PRRSv), a major concern for the swine industry. We extracted value ranges for the model parameters from modelling and experimental studies on respiratory pathogens. We identified the most influential parameters through a sensitivity analysis. We defined a parameter set, the reference scenario, resulting in a realistic and representative immune response to PRRSv infection. We then defined scenarios corresponding to graduated levels of strain virulence and host susceptibility around the reference scenario. We observed that high levels of antiviral cytokines and a dominant cellular response were associated with either short, the usual assumption, or long infection durations, depending on the immune mechanisms involved. To identify these mechanisms, we need to combine the levels of antiviral cytokines, including , and . The latter is a good indicator of the infected macrophage level, both combined provide the adaptive response orientation. Available PRRSv vaccines lack efficiency. By integrating the main interactions between the complex immune mechanisms, this modelling framework could be used to help designing more efficient vaccination strategies.

Modelling infectious viral diseases in swine populations: a state of the art

“…Doeschl-Wilson and Galina-Pantoja [ 23 ] presented models of increasing complexity to account specifically for host immunity. This work allowed building up an integrative approach to represent the interaction between viral replication and the immune response, to further understand the persistence of viremia and between-host variability of PRRS [ 24 – 26 ].…”

How to prevent viremia rebound? Evidence from a PRRSv data-supported model of immune response

“…A number of mechanistic models of virus infections in a variety of species aim at linking viremia profiles with the immune response, but only three for PRRSv [27, 31, 32]. Of particular relevance to our PRRSv modelling study are influenza models [2, 6, 10, 28–30, 33], as influenza is a respiratory virus that targets antigen presenting cells, among other cells.…”

“…Particularly for PRRSv, a large spectrum of immune mechanisms were found to influence the infection dynamics: target cell permissiveness, viral replication, adaptive response orientation, cytolysis, antibody neutralisation, all being modulated by various cytokines [reviews: 15–17, 25]. These mechanisms were only partly represented in the published models cited above, except in [27, 32] which provided a basis for this study but had a rougher representation of the adaptive response activation. Our study, based on an extension of these latter models, includes all relevant mechanisms and reflects the current understanding on PRRSv within-host dynamics.…”

“…The model represents the mechanisms at the between-cell scale and provides an integrative view of the immune response. It extends a previous model representing the dynamics in the main infection place, the lung, which allowed to identify the immune mechanisms that determine the infection duration [27]. This previous model focused on the interactions between the virus and its main target cells in the lung, the pulmonary macrophages, which are major cells of the innate immune system.…”

“…1, a sufficiently comprehensive representation of the multiplex immune response was required to avoid preliminary bias. This was achieved by extending an integrative model of the viral and immune component dynamics within the host representing immune mechanisms at the between-cell scale [27]. The resulting model, based on knowledge from in vitro and in vivo experimental studies on PRRSv, provides an explicit and detailed representation of: (i) the innate immune mechanisms, in particular the interactions between the virus and its target cells; (ii) the activation and orientation of the adaptive response towards the cellular, humoral or regulatory response; and (iii) the main cytokines and their complex regulations of the innate and adaptive immune mechanisms.…”