title: Mucosal pre-exposure to Th17-inducing adjuvants exacerbates pathology after influenza infection.
abstract: Mucosal vaccines are thought to confer superior protection against mucosal infectious diseases. In addition, mucosal routes of vaccine delivery preferentially induce the generation of T helper 17 (Th17) cells, which produce the cytokine IL-17. Th17 cells are critical in mediating vaccine-induced immunity against several mucosal infectious diseases. However, IL-17 is also a potent proinflammatory cytokine, and we recently showed that IL-17 mediates immunopathology and lung injury after influenza infection in mice. In the present study, we tested the hypothesis that mucosal pre-exposure to Th17-inducing adjuvants can promote disease exacerbation upon subsequent infection with influenza virus. Mice mucosally pre-exposed to Th17-inducing adjuvants, such as type II heat-labile enterotoxin or cholera toxin, resulted in increased morbidity and exacerbated lung inflammation upon subsequent infection with influenza virus. Furthermore, the increased morbidity was accompanied by increased expression of inflammatory chemokines and increased accumulation of neutrophils. Importantly, blockade of the IL-17 pathway in mice pre-exposed to Th17-inducing adjuvants resulted in attenuation of the inflammatory phenotype seen in influenza-infected mice. Our findings indicate that, before mucosal Th17-inducing adjuvants can be used in vaccine strategies, the short- and long-term detrimental effects of such adjuvants on disease exacerbation and lung injury in response to infections, such as influenza, should be carefully studied.
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Radha
authors.initials: R
authors.lastname: Gopal
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, New York.
authors.forename: Javier
authors.initials: J
authors.lastname: Rangel-Moreno
authors.affiliation: Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fallert Junecko
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Mallon
authors.affiliation: Department of Pediatrics and Immunology, the Richard King Mellon Institute for Pediatric Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Kong
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pediatrics and Immunology, the Richard King Mellon Institute for Pediatric Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Pociask
authors.affiliation: Witebsky Center for Microbial Pathogenesis and Immunology and Department of Microbiology and Immunology, University at Buffalo, Buffalo, New York.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Connell
authors.affiliation: Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Reinhart
authors.affiliation: Division of Pulmonary Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Ross
authors.affiliation: Department of Pediatrics and Immunology, the Richard King Mellon Institute for Pediatric Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Electronic address: khader@borcim.wustl.edu.
authors.forename: Shabaana A
authors.initials: SA
authors.lastname: Khader
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009980:Influenza A virus; D007252:Influenza Vaccines / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000473:pathology; D016133:Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D007252:Influenza Vaccines; D020381:Interleukin-17