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Interferon Lambda Inhibits Bacterial Uptake during Influenza Superinfection.

ABSTRACT: Influenza kills 30,000 to 40,000 people each year in the United States and causes 10 times as many hospitalizations. A common complication of influenza is bacterial superinfection, which exacerbates morbidity and mortality from the viral illness. Recently, methicillin-resistant Staphylococcus aureus (MRSA) has emerged as the dominant pathogen found in bacterial superinfection, with Streptococcus pneumoniae a close second. However, clinicians have few tools to treat bacterial superinfection. Current therapy for influenza/bacterial superinfection consists of treating the underlying influenza infection and adding various antibiotics, which are increasingly rendered ineffective by rising bacterial multidrug resistance. Several groups have recently proposed the use of the antiviral cytokine interferon lambda (IFN-?) as a therapeutic for influenza, as administration of pegylated IFN-? improves lung function and survival during influenza by reducing the overabundance of neutrophils in the lung. However, our data suggest that therapeutic IFN-? impairs bacterial clearance during influenza superinfection. Specifically, mice treated with an adenoviral vector to overexpress IFN-? during influenza infection exhibited increased bacterial burdens upon superinfection with either MRSA or S. pneumoniae Surprisingly, adhesion molecule expression, antimicrobial peptide production, and reactive oxygen species activity were not altered by IFN-? treatment. However, neutrophil uptake of MRSA and S. pneumoniae was significantly reduced upon IFN-? treatment during influenza superinfection in vivo Together, these data support the theory that IFN-? decreases neutrophil motility and function in the influenza-infected lung, which increases the bacterial burden during superinfection. Thus, we believe that caution should be exercised in the possible future use of IFN-? as therapy for influenza.

SUBMITTER: Rich HE

PROVIDER: S-EPMC6479047 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Interferon Lambda Inhibits Bacterial Uptake during Influenza Superinfection.

Rich Helen E HE McCourt Collin C CC Zheng Wen Quan WQ McHugh Kevin J KJ Robinson Keven M KM Wang Jieru J Alcorn John F JF

Infection and immunity 20190301 5

Influenza kills 30,000 to 40,000 people each year in the United States and causes 10 times as many hospitalizations. A common complication of influenza is bacterial superinfection, which exacerbates morbidity and mortality from the viral illness. Recently, methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) has emerged as the dominant pathogen found in bacterial superinfection, with <i>Streptococcus pneumoniae</i> a close second. However, clinicians have few tools to treat bacterial superi ...[more]

PMID: 30804099

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Project description:UnlabelledMuch 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.ImportanceS. 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.

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Interferon Lambda Inhibits Bacterial Uptake during Influenza Superinfection.

Publications

Interferon Lambda Inhibits Bacterial Uptake during Influenza Superinfection.

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