title: c-di-GMP protects against intranasal Acinetobacter baumannii infection in mice by chemokine induction and enhanced neutrophil recruitment.
abstract: Acinetobacter baumannii has emerged as a major cause of both community-associated and nosocomial infections worldwide. A. baumannii rapidly develops resistance to multiple antibiotics; as a result, infections by this pathogen have become increasingly difficult to treat. In this study, we evaluated the effect of 3',5'-cyclic diguanylic acid (c-di-GMP), a bacterial second messenger and immunomodulator, in the host defense against A. baumannii infection in a mouse model of intranasal infection. Our results showed that 50 μg of c-di-GMP administered 18 h prior to infection provided the best protection against intranasal infection with A. baumannii. Mechanistically, administration of c-di-GMP induced the production of chemokines KC, MCP-1, MIP-1α, MIP-2 and RANTES, and enhanced neutrophil recruitment in the lung. Moreover, depletion of neutrophils abolished the protective role of c-di-GMP. Taken together, our data suggest that c-di-GMP confers resistance against intranasal A. baumannii infection in mice through a neutrophil-dependent mechanism and that c-di-GMP should be further explored as an immunomodulator for the treatment of A. baumannii infection.
authors.affiliation: Institute for Biological Sciences, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario, Canada K1A 0R6.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhao
authors.forename: Rhonda
authors.initials: R
authors.lastname: KuoLee
authors.forename: Greg
authors.initials: G
authors.lastname: Harris
authors.forename: Kha
authors.initials: K
authors.lastname: Tram
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yan
authors.forename: Wangxue
authors.initials: W
authors.lastname: Chen
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000281:Administration, Intranasal / Q000379:methods; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D054405:Chemokine CCL3 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects*; D013997:Time Factors
chemical_list: C491768:Ccl2 protein, mouse; C496534:Ccl3 protein, mouse; C503460:Ccl5 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D018946:Chemokine CCL5; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP