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

Gautier Gilliaux,Daniel Desmecht

doi:10.3390/v14010098

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.

Highlights

Human respiratory syncytial virus infection leads to a wide spectrum of clinical outcomes, from a mild cold to severe bronchiolitis, pneumonia, or even asthma
To determine the resistance of each primed mouse strain and to address if the priming of the respiratory mucosa with living murid herpesvirus 4 (MuHV-4) would modify the outcome of a lethal pneumovirus infection, BALB/C, CD-1, and C57BL/6 mice were primed by living MuHV-4, Heat-inactivated MuHV-4, or PBS inoculation and subjected 28 days later to different infectious doses of pneumonia virus of mice (PVM) (25, 10 or 4 TCID50 units)
Following 10 TCID50 units of PVM inoculation, the CD-1 and C57BL/6 mice presented their first cases of survival following MuHV-4 priming while all the BALB/c mice succumbed to PVM infection

Summary

Introduction

Human respiratory syncytial virus (hRSV) infection leads to a wide spectrum of clinical outcomes, from a mild cold to severe bronchiolitis, pneumonia, or even asthma. 1–2% of them develop a disease that requires hospitalization, which makes it important to identify the key factors underlying the severe clinical forms [1,2,3] In this area, available studies have focused on socio-demographic and child-related risk factors. Studies of otherwise healthy infants and children have identified single nucleotide polymorphisms (SNPs) that are overrepresented in patients hospitalized with hRSV compared to either healthy controls or patients with milder hRSV disease Most of these severe bronchiolitis-associated SNPs bias the adaptive immunity Th1/Th2 balance toward a Th2-dominated response [5,6,7,8,9,10,11]. No decisive association has been demonstrated in a reproducible manner, and hRSV susceptibility/resistance is attributed to a large number of alleles acting in concert at multiple levels within the host [12]

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Conclusion