Type I interferon (IFN) signaling often involves the activation of an intracellular (endosomal or cytosolic) sensor that initiates the activation of IFN-b via several different interferon regulator factor (IRF) transcriptional activators, i.e. it senses organisms or PAMPs that have infiltrated the cell. Interaction of IFN-b with its heterodimeric receptors (interferon alpha/beta receptor, IFNAR) results in dimerisation and phosphorylation of STAT1/2 via Jak1 and Tyk2 leading to the downstream transcription of hundreds of genes. Type I IFN signaling has traditionally been associated with viral infection but it is now appreciated that bacteria and their products are also able to activate this pathway. Many bacterial pathogens, both intra- and extracellular are able to induce a type I IFN response via recognition of PAMPs and messengers such as DNA, RNA, peptidoglycan, LPS and cyclic diadenosine monophosphate (c-di-AMP). TLR2, 3, 4, 7, 8, 9, NOD, RNA polymerase III and stimulator of interferon genes (STING) are among the many sensors involved in activating the type I IFN response. Type I interferons exert their effect on a variety of cell types influencing cell function and antimicrobial production.

 

Type III IFN signaling (IFN-λ) utilizes many of the same receptors and triggers as type I IFN signaling. The IFN-λ members [IL-28A/B and IL-29 (only in humans)] signal through the IL-28 receptor (IL-28R or IFNLR) that is primarily located on epithelial cells in contrast to IFNAR that is ubiquitous. Although type I and III IFNs have distinct receptors they converge to phosphorylate STAT1/2 and thus activate similar transcripts. What differs in the transcriptome of type I and III IFN is the intensity and duration of the response. Type I is activated early and strongly and type III is induced over time at lower levels.

 

We have shown that both type I and type III IFN signaling contributes to the pathogenesis of S. aureus infection in the context of acute pneumonia. We have also demonstrated that the ability of S. aureus to activate the type I IFN response is correlated with virulence and damage to the lung. Different strains of S. aureus are also able to activate different levels of type I IFN and they each activate through different signaling pathways. Prior infection with influenza also significantly increases the susceptibility of mice to infection with S. aureus and both type I and III IFN are major contributors this increases in susceptibility.

 

Current studies focused on the interferons are aimed at examining the mechanism behind their role in the pathogenesis of S. aureus pneumonia. How they influence cellular influx, cytokine production and cell function and how this influences the outcome on infection. We have also begun studies examining the upper respiratory tract and the role the interferons play in the context of influenza superinfection and colonization of S. aureus.