Type I Interferon Signaling Is a Common Factor Driving Streptococcus pneumoniae and Influenza A Virus Shedding and Transmission

Abstract

The dynamics underlying respiratory contagion (the transmission of infectious agents from the airways) are poorly understood. We investigated host factors involved in the transmission of the leading respiratory pathogen <i>Streptococcus pneumoniae</i> Using an infant mouse model, we examined whether <i>S. pneumoniae</i> triggers inflammatory pathways shared by influenza A virus (IAV) to promote nasal secretions and shedding from the upper respiratory tract to facilitate transit to new hosts. Here, we show that amplification of the type I interferon (IFN-I) response is a critical host factor in this process, as shedding and transmission by both IAV and <i>S. pneumoniae</i> were decreased in pups lacking the common IFN-I receptor (<i>Ifnar1</i>^-/- mice). Additionally, providing exogenous recombinant IFN-I to <i>S. pneumoniae</i>-infected pups was sufficient to increase bacterial shedding. The expression of IFN-stimulated genes (ISGs) was upregulated in <i>S. pneumoniae</i>-infected wild-type (WT) but not <i>Ifnar1</i>^-/- mice, including genes involved in mucin type O-glycan biosynthesis; this correlated with an increase in secretions in <i>S. pneumoniae</i>- and IAV-infected WT compared to <i>Ifnar1</i>^-/- pups. <i>S. pneumoniae</i> stimulation of ISGs was largely dependent on its pore-forming toxin, pneumolysin, and coinfection with IAV and <i>S. pneumoniae</i> resulted in synergistic increases in ISG expression. We conclude that the induction of IFN-I signaling appears to be a common factor driving viral and bacterial respiratory contagion.<b>IMPORTANCE</b> Respiratory tract infections are a leading cause of childhood mortality and, globally, <i>Streptococcus pneumoniae</i> is the leading cause of mortality due to pneumonia. Transmission of <i>S. pneumoniae</i> primarily occurs through direct contact with respiratory secretions, although the host and bacterial factors underlying transmission are poorly understood. We examined transmission dynamics of <i>S. pneumoniae</i> in an infant mouse model and here show that <i>S. pneumoniae</i> colonization of the upper respiratory tract stimulates host inflammatory pathways commonly associated with viral infections. Amplification of this response was shown to be a critical host factor driving shedding and transmission of both <i>S. pneumoniae</i> and influenza A virus, with infection stimulating expression of a wide variety of genes, including those involved in the biosynthesis of mucin, a major component of respiratory secretions. Our findings suggest a mechanism facilitating <i>S. pneumoniae</i> contagion that is shared by viral infection.