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.
Highlights
Respiratory pathogens, which enter the body through the mucosal surfaces of the respiratory tract, are responsible for local inflammation and tissue damages [1,2]
In the preliminary sensitivity analysis, with all 30 parameters but no interactions between parameters, the variance explained by the parameters retained for the main sensitivity analysis on each output was 89% for the viral titer, 89% for the cumulative number of phagocyting macrophages and 70% for the percentage of infected macrophages
We used the model to explore the influence of macrophage permissiveness and cytokine synthesis capacities on the infection duration and immune dynamics
Summary
Respiratory pathogens, which enter the body through the mucosal surfaces of the respiratory tract, are responsible for local inflammation and tissue damages [1,2]. They initiate the infection and the immune response. The first interaction between the pathogen and the immune system involves the innate immune system This first line of defence, which includes epithelial surfaces, inflammation process, complement system and innate cells, provides an immediate but non-specific response. Macrophages and dendritic cells phagocyte the pathogens, whereas the natural killers destroy the host infected cells. The adaptive immune system mainly involves the cellular, the humoral and the regulatory responses. Innate and adaptive immune cells synthesise cytokines, small proteins which regulate the immune mechanisms in complex ways
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