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

Abstract

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.

Viral strategies predisposing to respiratory bacterial superinfections

“…In a mouse model of influenza virus infection, upregulation of the IFN‐λ signaling in the upper airway was associated with a reduction of antimicrobial peptides that control the abundance of commensal flora 107 . The upregulation of the IFN‐λ signaling was associated with a significant increase in the total numbers of bacteria recovered from the upper airway, with specific changes in the relative abundance of certain bacterial species, including staphylococci 108 . In these animals, a reduction in the expression of cytoskeletal components that regulate the mucosal barrier function was also detected, and associated with a significantly greater susceptibility to methicillin‐resistant Staphylococcus aureus superinfection, both in upper and lower airways 108 .…”

“…The upregulation of the IFN‐λ signaling was associated with a significant increase in the total numbers of bacteria recovered from the upper airway, with specific changes in the relative abundance of certain bacterial species, including staphylococci 108 . In these animals, a reduction in the expression of cytoskeletal components that regulate the mucosal barrier function was also detected, and associated with a significantly greater susceptibility to methicillin‐resistant Staphylococcus aureus superinfection, both in upper and lower airways 108 . Therefore, activation of the type III IFNs in response to influenza virus infection can have a major effect in modifying the upper airway microbiome and increasing susceptibility to lower respiratory tract infection.…”

Staphylococcus aureus and Influenza A Virus: Partners in Coinfection

“…Interestingly, these effects were attributable to IAV-driven activation of type III IFN signaling, as opposed to type I IFN responses (13). IAV-infected mice harbored significantly more upper-respiratory commensal bacteria than healthy mice, in combination with an increase in the relative abundance of murine commensal staphylococci.…”

Interactions of Respiratory Viruses and the Nasal Microbiota during the First Year of Life in Healthy Infants

“…Furthermore, respiratory viral infections play an important role in morbidity and early immune development during the first year of life in otherwise healthy infants (12)(13)(14)(15)(16). Despite recent data on the association between viral infections and changes in the microbiota in adults, data for young children are scarce (17)(18)(19)(20)(21)(22). Due to several risk factors triggering both viral and bacterial infections, it is difficult to draw causal associations between those early infections and later disease development.…”