Modelling the infection and immune dynamics induced by a pathogen targeting pulmonary macrophages : influence of strain virulence and host exposure

International audienceThe immune mechanisms which determine the infection severity and 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, host susceptibility, and host exposure to the pathogen. In this context, we developed an original ODE model representing the infection and immune dynamics induced by such a pathogen. Compared to previous modelling studies, we detailed the macrophage-pathogen interactions, the innate immune response, and the cytokine regulations. The adaptive immune response included the main functions of the cellular, humoral, and regulatory orientations. The model obtained has 14 state variables: the pathogen; four effectors of the innate response, consisting of three macrophage states (susceptible, phagocyting, and infected) and the natural killers; three effectors of the adaptive response, representing the cellular, humoral and regulatory responses; seven cytokine groups, consisting of the major pro-inflammatory, the innate antiviral and the immuno-regulatory (IFNg, IL12, IL10, TGFb) cytokines. The main processes integrated in the model are: the pathogen phagocytosis by the macrophages; the macrophage infection; the pathogen excretion by infected macrophages; the recruitment and decay/migration of the macrophages; the activation and decay/migration of the other effectors; the cytokine productions by the immune cells and their decay; the cytokine regulations.We calibrated our model for 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. A sensitivity analysis was used to identify the most influential parameters and to define a realistic reference scenario.We first used our model to explore the influence of strain virulence and host susceptibility on the infection duration and immune dynamics. We obtained contrasted results, suggesting hypotheses to explain the apparent contradictions between published results: high levels of antiviral cytokines and a dominant cellular response were associated with either short, the usual assumption, or long infection durations. In addition, we extracted some synthetic and original elements from our work to characterise immune mechanisms and their impact on the infection duration. We then used our model to explore the impact of host exposure on the infection duration and severity for various levels of strain virulence. We tested several exposure functions to account for experimental inoculations or natural infections. We found that: (i) high exposures induced high viral peaks; (ii) prolonged exposures and high virulences induced prolonged infections; and (iii) the viral peak determined the immune response activation and the adaptive response orientation, whereas the virulence determined the relative levels of adaptive antiviral and immuno-modulatory cytokines (IL10, TGFb).In conclusion, this integrative model provides a powerful framework to go beyond experimental constraints. It could be used to help designing efficient vaccination strategies. It could also provide a base for an immuno-epidemiological model, by identifying the key mechanisms (exposure x immune response) that are responsible for the infection severity and duration