Enhanced viral infectivity and reduced interferon production are associated with high pathogenicity for influenza viruses

Abstract

AbstractEpidemiological and clinical evidence indicates that humans infected with the 1918 pandemic influenza virus and highly pathogenic avian H5N1 influenza viruses often displayed severe lung pathology. High viral load and extensive infiltration of macrophages are the hallmarks of highly pathogenic (HP) influenza viral infections. However, it remains unclear what biological mechanisms primarily determine the observed difference in the kinetics of viral load and macrophages between HP and low pathogenic (LP) viral infections, and how the mechanistic differences are associated with viral pathogenicity. In this study, we develop a mathematical model of viral dynamics that includes the dynamics of different macrophage populations and interferon. We fit the model to in vivo kinetic data of viral load and macrophage level from BALB/c mice infected with an HP or LP strain of H1N1/H5N1 virus using Bayesian inference. Our primary finding is that HP viruses has a higher viral infection rate, a lower interferon production rate and a lower macrophage recruitment rate compared to LP viruses, which are strongly associated with more severe tissue damage (quantified by a higher percentage of epithelial cell loss). We also quantify the relative contribution of macrophages to viral clearance and find that macrophages do not play a dominant role in direct clearance of free virus although their role in mediating immune responses such as interferon production is crucial. Our work provides new insight into the mechanisms that convey the observed difference in viral and macrophage kinetics between HP and LP infections and establishes an improved model fitting framework to enhance the analysis of new data on viral pathogenicity.Author SummaryInfections with highly pathogenic (HP) influenza virus (e.g., the 1918 pandemic virus) often lead to serious morbidity and mortality. HP influenza virus infection is characterised by rapid viral growth rate, high viral load and excessive infiltration of macrophages to the lungs. Despite extensive study, we do not yet fully understand what biological processes leading to the observed viral and macrophage dynamics and therefore viral pathogenicity. Experimental studies have previously suggested that bot viral factors (e.g., viral proteins) and host factors (e.g., the host immune response) play a role to enhance viral pathogenicity. Here, we utilise in vivo kinetic data of viral load and macrophages and fit a viral dynamic model the data. Our model allow us to explore the biological mechanisms that contribute to the difference viral and macrophage dynamics between HP and LP infections. This study improves our understanding of the role of interferon on distinguishing immunodynamics between HP and LP infections. Our findings may contribute to the development of next-generation treatment which rely upon an understanding of the host different immunological response to HP influenza viruses.