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 Streptococcus pneumoniae. Using an infant mouse model, we examined whether S. pneumoniae 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 S. pneumoniae were decreased in pups lacking the common IFN-I receptor (Ifnar1−/− mice). Additionally, providing exogenous recombinant IFN-I to S. pneumoniae-infected pups was sufficient to increase bacterial shedding. The expression of IFN-stimulated genes (ISGs) was upregulated in S. pneumoniae-infected wild-type (WT) but not Ifnar1−/− mice, including genes involved in mucin type O-glycan biosynthesis; this correlated with an increase in secretions in S. pneumoniae- and IAV-infected WT compared to Ifnar1−/− pups. S. pneumoniae stimulation of ISGs was largely dependent on its pore-forming toxin, pneumolysin, and coinfection with IAV and S. pneumoniae 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. IMPORTANCE Respiratory tract infections are a leading cause of childhood mortality and, globally, Streptococcus pneumoniae is the leading cause of mortality due to pneumonia. Transmission of S. pneumoniae primarily occurs through direct contact with respiratory secretions, although the host and bacterial factors underlying transmission are poorly understood. We examined transmission dynamics of S. pneumoniae in an infant mouse model and here show that S. pneumoniae 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 S. pneumoniae 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 S. pneumoniae contagion that is shared by viral infection.

Neuraminidase B controls neuraminidase A-dependent mucus production and evasion

“…However, during the period of stable colonization (>24hrs p.i. ), when Spn has migrated to the glycocalyx, we confirmed that the presence of Spn increases URT secretions, a result that recapitulates the correlation between rhinitis symptoms and Spn carriage in young children [40,41]. Adults, who have a lower density of colonizing Spn, have less pronounced secretions during episodes of carriage.…”

“…Since neuraminidases mediate both an effect on mucus production and evasion it is difficult to test conditions that could distinguish these effects. Interestingly, influenza virus, which contains a neuraminidase, induces copious mucus production in the URT [5,40]. In the setting of influenza A co-infection, the neuraminidase-deficient Spn mutant has been shown to exhibit decreased levels of colonization compared to controls without influenza A co-infection [5,42].…”

Streptococcus pneumoniae colonization associates with impaired adaptive immune responses against SARS-CoV-2

“…It has been shown that Spn stimulates IFN-I production and upregulates the expression of IFN-stimulated genes in both mouse and human studies ( 17 , 29 ). Therefore, it is possible that pneumococcal colonization interferes with the replication cycle of the virus ( 30 , 31 ) and contributes to host antiviral defenses by governing the production of IFNs ( 32 , 33 ).…”

Streptococcus pneumoniae colonisation associates with impaired adaptive immune responses against SARS-CoV-2

“…Recent reports demonstrated that SARS-CoV-2 virus is effective at avoiding or delaying the triggering of early innate immune responses, such as type I interferons (IFNs) in vitro 29 and in humans 30,31 . On the other hand, it has been shown that S. pneumoniae infection stimulates IFN-I production and upregulates the expression of IFN-stimulated genes in both mice and human studies 16,32 . Therefore, it is possible that pneumococcal colonisation interferes with the replication cycle of the virus 33,34 and contributes to host antiviral defences by governing the production of IFNs 35,36 .…”