Journal Article

Lambda Interferon Restructures the Nasal Microbiome and Increases Susceptibility to Staphylococcus aureus Superinfection

Parker, Dane, Leon, Justinne D., Planet, Paul J., Fierer, Noah, Chen, Emily I., Smith, Hannah, Hammer, Tobin J., Prince, Alice S., Cohen, Taylor S., Ryan, Chanelle

2016

Overview

Much of the morbidity and mortality associated with influenza virus respiratory infection is due to bacterial coinfection with pathogens that colonize the upper respiratory tract such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae . A major component of the immune response to influenza virus is the production of type I and III interferons. Here we show that the immune response to infection with influenza virus causes an increase and restructuring of the upper respiratory microbiota in wild-type (WT) mice but not in Il28r −/− mutant mice lacking the receptor for type III interferon. Mice lacking the IL-28 receptor fail to induce STAT1 phosphorylation and expression of its regulator, SOCS1. Il28r −/− mutant mice have increased expression of interleukin-22 (IL-22), as well as Ngal and RegIIIγ, in the nasal cavity, the source of organisms that would be aspirated to cause pneumonia. Proteomic analysis reveals changes in several cytoskeletal proteins that contribute to barrier function in the nasal epithelium that may contribute to the effects of IL-28 signaling on the microbiota. The importance of the effects of IL-28 signaling in the pathogenesis of MRSA pneumonia after influenza virus infection was confirmed by showing that WT mice nasally colonized before or after influenza virus infection had significantly higher levels of infection in the upper airways, as well as significantly greater susceptibility to MRSA pneumonia than Il28r −/− mutant mice did. Our results suggest that activation of the type III interferon in response to influenza virus infection has a major effect in expanding the upper airway microbiome and increasing susceptibility to lower respiratory tract infection. IMPORTANCE S. aureus and influenza virus are important respiratory pathogens, and coinfection with these organisms is associated with significant morbidity and mortality. The ability of influenza virus to increase susceptibility to S. aureus infection is less well understood. We show here that influenza virus leads to a change in the upper airway microbiome in a type III interferon-dependent manner. Mice lacking the type III interferon receptor have altered STAT1 and IL-22 signaling. In coinfection studies, mice without the type III interferon receptor had significantly less nasal S. aureus colonization and subsequent pneumonia than infected WT mice did. This work demonstrates that type III interferons induced by influenza virus contribute to nasal colonization and pneumonia due to S. aureus superinfection. S. aureus and influenza virus are important respiratory pathogens, and coinfection with these organisms is associated with significant morbidity and mortality. The ability of influenza virus to increase susceptibility to S. aureus infection is less well understood. We show here that influenza virus leads to a change in the upper airway microbiome in a type III interferon-dependent manner. Mice lacking the type III interferon receptor have altered STAT1 and IL-22 signaling. In coinfection studies, mice without the type III interferon receptor had significantly less nasal S. aureus colonization and subsequent pneumonia than infected WT mice did. This work demonstrates that type III interferons induced by influenza virus contribute to nasal colonization and pneumonia due to S. aureus superinfection.

• Publisher: American Society for Microbiology,American Society of Microbiology
• Subject: Animals / Bacteria / Colonization / Cytokines - metabolism / Cytoskeleton / Drug resistance / Epithelium / Immune response / Influenza / Interferon / Interleukin 22 / Methicillin / Mice / Mice, Knockout / Microbiomes / Microbiota / Microbiota - immunology / Morbidity / Mortality / Mutants / Nasal Cavity - microbiology / Nose / Orthomyxoviridae Infections - immunology / Pathogens / Phosphorylation / Pneumonia / Pneumonia, Staphylococcal - immunology / Pneumonia, Staphylococcal - microbiology / Proteomics / Respiratory diseases / Respiratory tract infection / Staphylococcus aureus / Staphylococcus aureus - drug effects / Staphylococcus aureus - growth & development / Staphylococcus infections / Stat1 protein / Streptococcus infections / Superinfection / Susceptibility / Viruses