title: c-di-GMP enhances protective innate immunity in a murine model of pertussis.
abstract: Innate immunity represents the first line of defense against invading pathogens in the respiratory tract. Innate immune cells such as monocytes, macrophages, dendritic cells, NK cells, and granulocytes contain specific pathogen-recognition molecules which induce the production of cytokines and subsequently activate the adaptive immune response. c-di-GMP is a ubiquitous second messenger that stimulates innate immunity and regulates biofilm formation, motility and virulence in a diverse range of bacterial species with potent immunomodulatory properties. In the present study, c-di-GMP was used to enhance the innate immune response against pertussis, a respiratory infection mainly caused by Bordetella pertussis. Intranasal treatment with c-di-GMP resulted in the induction of robust innate immune responses to infection with B. pertussis characterized by enhanced recruitment of neutrophils, macrophages, natural killer cells and dendritic cells. The immune responses were associated with an earlier and more vigorous expression of Th1-type cytokines, as well as an increase in the induction of nitric oxide in the lungs of treated animals, resulting in significant reduction of bacterial numbers in the lungs of infected mice. These results demonstrate that c-di-GMP is a potent innate immune stimulatory molecule that can be used to enhance protection against bacterial respiratory infections. In addition, our data suggest that priming of the innate immune system by c-di-GMP could further skew the immune response towards a Th1 type phenotype during subsequent infection. Thus, our data suggest that c-di-GMP might be useful as an adjuvant for the next generation of acellular pertussis vaccine to mount a more protective Th1 phenotype immune response, and also in other systems where a Th1 type immune response is required.
authors.affiliation: Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Shokrollah
authors.initials: S
authors.lastname: Elahi
authors.affiliation: Vaccine and Infectious Disease Organization, International Vaccine Centre, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Jill
authors.initials: J
authors.lastname: Van Kessel
authors.affiliation: Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Tedele G
authors.initials: TG
authors.lastname: Kiros
authors.affiliation: Vaccine and Infectious Disease Organization, International Vaccine Centre, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Stacy
authors.initials: S
authors.lastname: Strom
authors.affiliation: Faculty of Engineering, Department of Applied Chemistry, Aichi Institute of Technology, Toyota, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Faculty of Engineering, Department of Applied Chemistry, Aichi Institute of Technology, Toyota, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hyodo
authors.affiliation: Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Lorne A
authors.initials: LA
authors.lastname: Babiuk
authors.affiliation: Vaccine and Infectious Disease Organization, International Vaccine Centre, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Volker
authors.initials: V
authors.lastname: Gerdts
mesh_terms: D000818:Animals; D001886:Bordetella pertussis; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007107:Immune System / Q000187:drug effects / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D012137:Respiratory System / Q000187:drug effects / Q000276:immunology; D014917:Whooping Cough / Q000188:drug therapy* / Q000276:immunology
chemical_list: C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP