Influenza A virus infection predisposes hosts to secondary infection with different Streptococcus pneumoniae serotypes with similar outcome but serotype-specific manifestation.

Abstract

Influenza A virus (IAV) and Streptococcus pneumoniae (S. pn.) are major causes of respiratory tract infections, particularly during co-infection. The synergism between these two pathogens is characterized by a complex network of dysregulated immune responses, some of which last until recovery post IAV infection. Despite the high serotype-diversity of S. pn. and the serotype-replacement observed since the introduction of conjugate vaccines, little is known about pneumococcal strain-dependency in the enhanced susceptibility to severe secondary S. pn. infection following IAV infection. Thus we studied how pre-infection with IAV alters host susceptibility to different S. pn. strains with varying degrees of invasiveness using a highly invasive serotype 4, an invasive serotype 7F and a carrier serotype 19F strain. A murine model of pneumococcal co-infection during the acute phase of IAV infection showed a significantly increased degree of pneumonia and mortality for all tested pneumococcal strains at otherwise sublethal doses. The incidence and kinetics of systemic dissemination however remained bacterial strain-dependent. Furthermore we observed strain-specific alterations in the pulmonary levels of alveolar macrophages, neutrophils and inflammatory mediators ultimately affecting immunopathology. During the recovery phase following IAV infection, bacterial growth in the lungs and systemic dissemination were enhanced in a strain-dependent manner. Altogether, this study shows that acute IAV infection predisposes the host to lethal S. pn. infection irrespective of the pneumococcal serotype, while the long lasting synergism between IAV and S. pn. is bacterial strain-dependent. These results hold implications for developing tailored therapeutic treatment regimens for dual infections during future IAV outbreaks.