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: David K R Karaolis, Michael W Newstead, Xianying Zeng, Mamoru Hyodo, Yoshihiro Hayakawa, Urvhashi Bhan, Hallie Liang, Theodore J Standiford
• Journal: Infection and immunity (Infect Immun) Vol. 75 Issue 10 Pg. 4942-50 (Oct 2007) ISSN: 0019-9567 [Print] United States
• PMID: 17646358 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Chemokines
• Cytokines
• Immunologic Factors
• Nitric Oxide
• bis(3',5')-cyclic diguanylic acid
• Cyclic GMP

Topics

• Administration, Intranasal
• Animals
• Blood (microbiology)
• Chemokines (immunology)
• Colony Count, Microbial
• Cyclic GMP (analogs & derivatives, immunology)
• Cytokines (biosynthesis)
• Female
• Immunity, Innate (drug effects)
• Immunologic Factors (administration & dosage, pharmacology)
• Injections, Subcutaneous
• Killer Cells, Natural (immunology)
• Klebsiella Infections (immunology)
• Klebsiella pneumoniae (immunology)
• Lung (microbiology)
• Macrophages, Alveolar (immunology)
• Mice
• Mice, Inbred BALB C
• Neutrophils (immunology)
• Nitric Oxide (biosynthesis)
• Pneumonia, Bacterial (immunology)
• Specific Pathogen-Free Organisms
• Survival Analysis
• T-Lymphocytes (immunology)