title: Cyclic di-GMP stimulates protective innate immunity in bacterial pneumonia.
abstract: Innate immunity is the primary mechanism by which extracellular bacterial pathogens are effectively cleared from the lung. We have previously shown that cyclic di-GMP (c-di-GMP [c-diguanylate]) is a novel small molecule immunomodulator and immunostimulatory agent that triggers protective host innate immune responses. Using a murine model of bacterial pneumonia, we show that local intranasal (i.n.) or systemic subcutaneous (s.c.) administration of c-di-GMP prior to intratracheal (i.t.) challenge with Klebsiella pneumoniae stimulates protective immunity against infection. Specifically, i.n. or s.c. administration of c-di-GMP 48 and 24 h prior to i.t. K. pneumoniae challenge resulted in significantly increased survival. Pretreatment with c-di-GMP resulted in a 5-fold reduction in bacterial CFU in the lung (P < 0.05) and an impressive >1,000-fold decrease in CFU in the blood (P < 0.01). c-di-GMP administration stimulated a robust innate response to bacterial challenge, characterized by enhanced accumulation of neutrophils and alphabeta T cells, as well as activated NK and alphabeta T lymphocytes, which was associated with earlier and more vigorous expression of chemokines and type I cytokines. Moreover, lung macrophages recovered from Klebsiella-infected mice pretreated with c-di-GMP expressed greater quantities of inducible nitric oxide synthase and nitric oxide ex vivo than did macrophages isolated from infected mice pretreated with the control, c-GMP. These findings demonstrate that c-di-GMP delivered in either a compartmentalized or systemic fashion stimulates protective innate immunity in the lung and protects mice against bacterial invasion. We propose that the cyclic dinucleotide c-di-GMP may be used clinically as an effective immunomodulator, immune enhancer, and vaccine adjuvant to protect against respiratory infection and pneumonia in humans and animals.
authors.affiliation: Intragenics Research Institute, Havre de Grace, MD 21078, USA. dkaraolis@intragenics.org
authors.forename: David K R
authors.initials: DK
authors.lastname: Karaolis
authors.forename: Michael W
authors.initials: MW
authors.lastname: Newstead
authors.forename: Xianying
authors.initials: X
authors.lastname: Zeng
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hyodo
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Urvhashi
authors.initials: U
authors.lastname: Bhan
authors.forename: Hallie
authors.initials: H
authors.lastname: Liang
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001769:Blood / Q000382:microbiology; D018925:Chemokines / Q000276:immunology; D015169:Colony Count, Microbial; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects*; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007694:Killer Cells, Natural / Q000276:immunology; D007710:Klebsiella Infections / Q000276:immunology*; D007711:Klebsiella pneumoniae / Q000276:immunology*; D008168:Lung / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis; D018410:Pneumonia, Bacterial / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018925:Chemokines; D016207:Cytokines; D007155:Immunologic Factors; D009569:Nitric Oxide; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP