Abstract :
[en] Human respiratory syncytial virus (hRSV) infection in humans leads to a wide spectrum of clinical outcomes, ranging from mild (cough, runny nose, moderate fever) to severe (severe bronchiolitis, acute interstitial pneumonia). Among the host-related factors suspected of influencing this important clinical diversity, some research has put forward the genetic hypothesis. Let us cite, for example, the demonstration of certain SNPs that are overrepresented in patients hospitalized with hRSV compared to healthy controls or patients with a milder form of the disease. Over the last decade, experiments have also pointed out that a past infection can affect how a given host responds to a subsequent heterologous infection. Thus, we compared in a mouse model the respective importance of these two host-related factors (namely genetic make-up and trained innate immunity) in the overall shaping of the host’s immune response against a murine infectious model of hRSV. We analyzed in three murine strains with different genetic backgrounds (BALB/c, CD-1 and C57BL/6) the impact of a prior respiratory infection by a gammaherpesvirus (MuHV-4) on the course of a subsequent, theoretically lethal, murine pneumovirus (PVM) infection. Indeed, following PVM infection, a fatal outcome consistently occurs in naive mice due to an exaggerated inflammatory response with a significant increase in neutrophil and eosinophil recruitment alongside to an increased production of proinflammatory cytokines and chemokines. However, we show that a prior respiratory infection by a gammaherpesvirus significantly increases, with a strain-dependent efficacy, the resistance of the mouse to a subsequent PVM infection. Thus, the “conditioning” (or “priming”) induced by MuHV-4 limits the production of pro-inflammatory mediators and allows an increased recruitment of effector cytotoxic T cells. Furthermore, prior gammaherpesvirus infection also primes alveolar macrophages (AMs) to respond differently to subsequent pneumovirus exposure. Indeed, immune conditioning modifies the phenotype of AMs and induces in them an accelerated cyto/chemokine response but quickly controlled over time during exposure to PVM. These conditioned AMs thus ensure an improvement in the efficiency of the innate response by promoting a faster and controlled immune response over time, as well as the development of a controlled inflammatory response, thus ensuring sustained protection against the deadly inflammatory sequelae of PVM infection. Finally, the analysis of the AMs phenotype after MuHV-4- priming of C57BL/6 CCR2-/- mice disproved the hypothesis of a monocytic origin in the modification of the AM phenotype. However, in these same mice, the study of the cyto/chemokine response produced by AMs revealed the establishment of a less effective immune response after MuHV-4-priming. This result therefore suggests the need for a monocyte interaction with AMs for the establishment of an improved immune response. In summary, we have identified an effective innate immune protective mechanism, dependent of the host genetic background and AMs, that can serve as protection against pneumoviruses. We have also demonstrated a non-negligible role played by monocytes, following MuHV-4-priming, in the enhanced immune reaction of AMs against the fatal sequelae of pneumovirus infection.
