title: Haemophilus influenzae responds to glucocorticoids used in asthma therapy by modulation of biofilm formation and antibiotic resistance.
abstract: Glucocorticosteroids are used as a main treatment to reduce airway inflammation in people with asthma who suffer from neutrophilic airway inflammation, a condition frequently associated with Haemophilus influenzae colonization. Here we show that glucocorticosteroids have a direct influence on the behavior of H. influenzae that may account for associated difficulties with therapy. Using a mouse model of infection, we show that corticosteroid treatment promotes H. influenzae persistence. Transcriptomic analysis of bacteria either isolated from infected mouse airway or grown in laboratory medium identified a number of genes encoding regulatory factors whose expression responded to the presence of glucocorticosteroids. Importantly, a number of these corticosteroid-responsive genes also showed elevated expression in H. influenzae within sputum from asthma patients undergoing steroid treatment. Addition of corticosteroid to H. influenzae led to alteration in biofilm formation and enhanced resistance to azithromycin, and promoted azithromycin resistance in an animal model of respiratory infection. Taken together, these data strongly suggest that H. influenzae can respond directly to corticosteroid treatment in the airway potentially influencing biofilm formation, persistence and the efficacy of antibiotic treatment.
authors.affiliation: Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: Chris S
authors.initials: CS
authors.lastname: Earl
authors.affiliation: Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore.
authors.forename: Teh Wooi
authors.initials: TW
authors.lastname: Keong
authors.affiliation: Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: Shi-qi
authors.initials: SQ
authors.lastname: An
authors.affiliation: Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Murdoch
authors.affiliation: School of Microbiology, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: McCarthy
authors.affiliation: Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
authors.forename: Junkal
authors.initials: J
authors.lastname: Garmendia
authors.affiliation: Division of Molecular Medicine, College of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Ward
authors.affiliation: School of Microbiology, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: J Maxwell
authors.initials: JM
authors.lastname: Dow
authors.affiliation: Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore.
authors.forename: Liang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: O'Toole
authors.affiliation: Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee, UK rpryan@dundee.ac.uk.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Ryan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001249:Asthma / Q000150:complications / Q000188:drug therapy; D017963:Azithromycin / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000378:metabolism* / Q000627:therapeutic use; D006192:Haemophilus Infections / Q000382:microbiology*; D006193:Haemophilus influenzae / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D051379:Mice; D013183:Sputum / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D005938:Glucocorticoids; D017963:Azithromycin
keywords: Haemophilus influenzae; antibiotic resistance; asthma; biofilm; steroids