Hierarchical effects of pro-inflammatory cytokines on the post-influenza susceptibility to pneumococcal coinfection.

Stefanie Duvigneau,Van Kinh Nguyen,Sabine Stegemann-Koniszewski,Alessandro Boianelli,Esteban A Hernandez-Vargas,Dunja Bruder,Niharika Sharma-Chawla

doi:10.1038/srep37045

Abstract

In the course of influenza A virus (IAV) infections, a secondary bacterial infection frequently leads to serious respiratory conditions provoking high hospitalization and death tolls. Although abundant pro-inflammatory responses have been reported as key contributing factors for these severe dual infections, the relative contributions of cytokines remain largely unclear. In the current study, mathematical modelling based on murine experimental data dissects IFN-γ as a cytokine candidate responsible for impaired bacterial clearance, thereby promoting bacterial growth and systemic dissemination during acute IAV infection. We also found a time-dependent detrimental role of IL-6 in curtailing bacterial outgrowth which was not as distinct as for IFN-γ. Our numerical simulations suggested a detrimental effect of IFN-γ alone and in synergism with IL-6 but no conclusive pathogenic effect of IL-6 and TNF-α alone. This work provides a rationale to understand the potential impact of how to manipulate temporal immune components, facilitating the formulation of hypotheses about potential therapeutic strategies to treat coinfections.

Highlights

Mechanisms are the influenza A virus (IAV)-mediated immune modulations such as immune cell dysfunction and apoptosis causing an aberrant production of inflammatory mediators in the case of a secondary bacterial encounter
The dynamics of IAV and S. pneumoniae coinfection were investigated by establishing a murine model displaying disease upon subsequent infection with sub-lethal infection doses of both copathogens
Secondary infection with 1 × 106 colony forming units (CFU) of Streptococcus pneumoniae strain TIGR4 (T4) was performed on day 7 after IAV infection based on previous experimental observations that indicated peak susceptibility to pneumococcal disease at this time point during acute IAV infection[3,34]

Summary

Introduction

Mechanisms are the IAV-mediated immune modulations such as immune cell dysfunction and apoptosis causing an aberrant production of inflammatory mediators in the case of a secondary bacterial encounter. A number of studies describe a massive and overshooting inflammatory cell influx due to the hyper-production of pro-inflammatory cytokines such as type I Interferons (IFN-I), Interferon-γ (IFN-γ), Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α) during secondary bacterial infection These are often linked to pulmonary edema due to irreparable damage to the alveoli and immunopathology leading to mortality during coinfections[7,11,12,13,14]. Taken together, these studies strongly reflect an exacerbated cytokine and chemokine production that may significantly contribute to the detrimental changes in the lung microenvironment that favor secondary bacterial infections. By combining the results of murine in vivo experiments and mathematical modelling approaches, we aimed at clarifying the relative contributions of different underlying mechanisms of the IAV-S. pneumoniae synergism

Objectives

Results

Conclusion