Kinetics of Coinfection with Influenza A Virus and Streptococcus pneumoniae

Abstract

Secondary bacterial infections are a leading cause of illness and death during epidemic and pandemic influenza. Experimental studies suggest a lethal synergism between influenza and certain bacteria, particularly Streptococcus pneumoniae, but the precise processes involved are unclear. To address the mechanisms and determine the influences of pathogen dose and strain on disease, we infected groups of mice with either the H1N1 subtype influenza A virus A/Puerto Rico/8/34 (PR8) or a version expressing the 1918 PB1-F2 protein (PR8-PB1-F2(1918)), followed seven days later with one of two S. pneumoniae strains, type 2 D39 or type 3 A66.1. We determined that, following bacterial infection, viral titers initially rebound and then decline slowly. Bacterial titers rapidly rise to high levels and remain elevated. We used a kinetic model to explore the coupled interactions and study the dominant controlling mechanisms. We hypothesize that viral titers rebound in the presence of bacteria due to enhanced viral release from infected cells, and that bacterial titers increase due to alveolar macrophage impairment. Dynamics are affected by initial bacterial dose but not by the expression of the influenza 1918 PB1-F2 protein. Our model provides a framework to investigate pathogen interaction during coinfections and to uncover dynamical differences based on inoculum size and strain.

Author Summary

Influenza virus infected individuals often become coinfected with a bacterial pathogen and, consequently, morbidity and mortality are significantly increased. A better understanding of how these pathogens interact with each other and the host is of key importance. Here, we use data from infected mice together with mathematical modeling and quantitative analyses to understand how each pathogen influences the other, and how the 1918 influenza PB1-F2 protein and the bacterial strain and dose contribute to coinfection kinetics. We find that influenza viral titers increase when Streptococcus pneumoniae is present and that the bacteria establish and grow rapidly when influenza is present. Our model and analyses suggest that the influenza infection reduces the bacterial clearance ability of alveolar macrophages and that the subsequent S. pneumoniae infection enhances viral release from infected cells. These results provide new insights into the mechanisms of influenza coinfection and the differences in pathogenesis of influenza and S. pneumoniae strains.