title: MicroRNA-155 regulates host immune response to postviral bacterial pneumonia via IL-23/IL-17 pathway.
abstract: Postinfluenza bacterial pneumonia is associated with significant mortality and morbidity. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. miR-155 has recently emerged as a crucial regulator of innate immunity and inflammatory responses and is induced in macrophages during infection. We hypothesized upregulation of miR-155 inhibits IL-17 and increases susceptibility to secondary bacterial pneumonia. Mice were challenged with 100 plaque-forming units H1N1 intranasally and were infected with 10(7) colony-forming units of MRSA intratracheally at day 5 postviral challenge. Lungs were harvested 24 h later, and expression of miR-155, IL-17, and IL-23 was measured by real-time RT-PCR. Induction of miR-155 was 3.6-fold higher in dual-infected lungs compared with single infection. miR-155(-/-) mice were protected with significantly lower (4-fold) bacterial burden and no differences in viral load, associated with robust induction of IL-23 and IL-17 (2.2- and 4.8-fold, respectively) postsequential challenge with virus and bacteria, compared with WT mice. Treatment with miR-155 antagomir improved lung bacterial clearance by 4.2-fold compared with control antagomir postsequential infection with virus and bacteria. Moreover, lung macrophages collected from patients with postviral bacterial pneumonia also had upregulation of miR-155 expression compared with healthy controls, consistent with observations in our murine model. This is the first demonstration that cellular miRNAs regulate postinfluenza immune response to subsequent bacterial challenge by suppressing the IL-17 pathway in the lung. Our findings suggest that antagonizing certain microRNA might serve as a potential therapeutic strategy against secondary bacterial infection.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan;
authors.forename: Amy
authors.initials: A
authors.lastname: Podsiad
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan;
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Ohio State University, Columbus, Ohio; and.
authors.forename: Megan N
authors.initials: MN
authors.lastname: Ballinger
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan;
authors.forename: Richard
authors.initials: R
authors.lastname: Eakin
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan;
authors.forename: Pauline
authors.initials: P
authors.lastname: Park
authors.affiliation: Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan;
authors.forename: Bethany B
authors.identifier: http://orcid.org/0000-0003-3051-745X
authors.initials: BB
authors.lastname: Moore
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan; ubhan@umich.edu.
authors.forename: Urvashi
authors.initials: U
authors.lastname: Bhan
mesh_terms: D000818:Animals; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology; D008168:Lung / Q000276:immunology; D016676:Macrophages, Alveolar / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009976:Orthomyxoviridae Infections / Q000382:microbiology / Q000821:virology; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000382:microbiology*
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse
keywords: IL-17; miR-155; postviral bacterial pneumonia