Gammaherpesvirus Alters Alveolar Macrophages According to the Host Genetic Background and Promotes Beneficial Inflammatory Control over Pneumovirus Infection

Abstract

Human respiratory syncytial virus (hRSV) infection brings a wide spectrum of clinical outcomes, from a mild cold to severe bronchiolitis or even acute interstitial pneumonia. Among the known factors influencing this clinical diversity, genetic background has often been mentioned. In parallel, recent evidence has also pointed out that an early infectious experience affects heterologous infections severity. Here, we analyzed the importance of these two host-related factors in shaping the immune response in pneumoviral disease. We show that a prior gammaherpesvirus infection improves, in a genetic background-dependent manner, the immune system response against a subsequent lethal dose of pneumovirus primary infection notably by inducing a systematic expansion of the CD8+ bystander cell pool and by modifying the resident alveolar macrophages (AMs) phenotype to induce immediate cyto/chemokinic responses upon pneumovirus exposure, thereby drastically attenuating the host inflammatory response without affecting viral replication. Moreover, we show that these AMs present similar rapid and increased production of neutrophil chemokines both in front of pneumoviral or bacterial challenge, confirming recent studies attributing a critical antibacterial role of primed AMs. These results corroborate other recent studies suggesting that the innate immunity cells are themselves capable of memory, a capacity hitherto reserved for acquired immunity.

Allergic Asthma Responses Are Dependent on Macrophage Ontogeny

“…Our observations are consistent with recent literature demonstrating that prior murine lung viral infection with murine herpesvirus 4 or murine adapted influenza A attenuates allergic airway inflammation or subsequent pneumovirus infection (56)(57)(58). Similar to our observation of AMØ turnover following LPS (Figure 2B), Machiels et al identified replacement of AMØs following murine herpesvirus 4 infections (56).…”

The impact of trained immunity in respiratory viral infections

“…After a prior intranasal infection of mice with murid herpesvirus 4, priming of memory resident AMs (MHC‐II hi ) was also shown to be mediated by infiltrating CD8 T cells which improved the immune response against a subsequent lethal challenge with a pneumonia virus of mice (closely related to human respiratory syncytial virus [RSV]) 28 days later 61 . The mechanisms involved changes in the phenotype of resident AMs, which were associated with a stronger but shorter cytokine/chemokine production resulting in a reduced host inflammatory response without affecting the replication of the second virus.…”

“…[RSV]) 28 days later. 61 The mechanisms involved changes in the phenotype of resident AMs, which were associated with a stronger but shorter cytokine/chemokine production resulting in a reduced host inflammatory response without affecting the replication of the second virus.…”