This Article Full Text Full Text (PDF) Other Versions of this Article: IAI.01762-06v1 75/10/4942    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Karaolis, D. K. R. Articles by Standiford, T. J. Search for Related Content PubMed PubMed Citation Articles by Karaolis, D. K. R. Articles by Standiford, T. J.

Cyclic Di-GMP Stimulates Protective Innate Immunity in Bacterial Pneumonia

Intragenics Research Institute, Havre de Grace, Maryland 21078,¹ Karagen Pharmaceuticals, Baltimore, Maryland 21210,² Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109,³ Graduate School of Information Science/Human Informatics, Nagoya University, Nagoya, Japan⁴

Received 5 November 2006/ Returned for modification 18 December 2006/ Accepted 9 July 2007

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 ß T cells, as well as activated NK and ß 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.

Published ahead of print on 23 July 2007.

Editor: J. L. Flynn

This article has been cited by other articles:

• Clement, C. G., Evans, S. E., Evans, C. M., Hawke, D., Kobayashi, R., Reynolds, P. R., Moghaddam, S. J., Scott, B. L., Melicoff, E., Adachi, R., Dickey, B. F., Tuvim, M. J. (2008). Stimulation of Lung Innate Immunity Protects against Lethal Pneumococcal Pneumonia in Mice. Am. J. Respir. Crit. Care Med. 177: 1322-1330 [Abstract] [Full Text]