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.

Protection against Streptococcus pneumoniae Invasive Pathogenesis by a Protein-Based Vaccine Is Achieved by Suppression of Nasopharyngeal Bacterial Density during Influenza A Virus Coinfection

“…S. pneumoniae colonization is usually cleared from the NP without progressing to disease (22,23). Perturbations in the upper respiratory tract colonization niche, driven by viral coinfection, help S. pneumoniae to grow and are essential for progression from an asymptomatic to a pathogenic inoculum (18,24).…”

“…FITC, fluorescein isothiocyanate. (18)(19)(20). Therefore, the invasive-coinfection (S. pneumoniae plus PR8) model provides an ideal tool to evaluate the efficacy of vaccination in circumventing the progression of S. pneumoniae pathogenesis during influenza virus coinfection.…”

Emergence of Highly Pathogenic Avian Influenza A(H5N1) Virus PB1-F2 Variants and Their Virulence in BALB/c Mice

“…Several possible mechanisms have been suggested, including mitochondrial targeting and proapoptotic activity (8,9,19), enhancing PB1 function (20), and inhibition (21)(22)(23)(24)(25)(26)(27) or enhancement (28) of the IFN-␤ response. PB1-F2 has also been linked to bacterial infections following IAV infection (29)(30)(31)(32). However, most of these phenotypes have been difficult to generalize to all strains of virus and across host models tested.…”

Viral/bacterial respiratory tract co-infections in children

“…Subsequent S. pneumoniae challenge after IAV infection has been found to cause an increase in viral titres (163). A mathematical model established that the increase was likely due to bacterial enhancement of virion production and release from infected cells (163).…”

“…Subsequent S. pneumoniae challenge after IAV infection has been found to cause an increase in viral titres (163). A mathematical model established that the increase was likely due to bacterial enhancement of virion production and release from infected cells (163). S. aureus proteases have been found to cleave and thereby activate IAV haemagglutinin in a viral and bacterial strain-dependent manner, increasing viral replication in the lungs of mice (164).…”