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Infect. Immun. doi:10.1128/IAI.01762-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

c-di-GMP Stimulates Protective Innate Immunity in Bacterial Pneumonia

Intragenics Research Institute, Havre de Grace, MD 21078, Karagen Pharmaceuticals, Baltimore, MD 21210, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109 and Graduate School of Information Science, Nagoya University, Nagoya, Japan

^* To whom correspondence should be addressed. Email: dkaraolis{at}intragenics.org.

	Abstract

Innate immunity is the primary mechanism by which extracellular pathogens are effectively cleared from the lung. We have previously shown that c-di-GMP is a unique small molecule immunomodulator and immunostimulatory agent triggering protective host innate immune responses. Using a murine model of bacterial pneumonia, we show that local intranasal (i.n.) or systemic subcutaneous (s.q.) administration of c-di-GMP prior to intratracheal (i.t.) challenge with Klebsiella pneumoniae stimulates protective immunity against infection. Specifically, i.n. or s.q. 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 lung (p<0.05) and an impressive >1000-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 T cells, as well as activated NK and T lymphocytes, which was associated with earlier and more vigorous expression of chemokines and type-1 cytokines. Moreover, lung macrophages recovered from Klebsiella-infected mice pretreated with c-di-GMP expressed greater quantities of iNOS (inducible nitric oxide synthase) and nitric oxide ex-vivo than did macrophages isolated from infected mice pretreated with 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 can be used clinically as an effective immunomodulator, immune enhancer and vaccine adjuvant to protect against respiratory infection and pneumonia in humans and animals.

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