title: The overlapping host responses to bacterial cyclic dinucleotides.
abstract: Macrophages respond to infection with Legionella pneumophila by the induction of inflammatory mediators, including type I Interferons (IFN-Is). To explore whether the bacterial second messenger cyclic 3'-5' diguanylate (c-diGMP) activates some of these mediators, macrophages were infected with L. pneumophila strains in which the levels of bacterial c-diGMP had been altered. Intriguingly, there was a positive correlation between c-diGMP levels and IFN-I expression. Subsequent studies with synthetic derivatives of c-diGMP, and newly described cyclic 3'-5' diadenylate (c-diAMP), determined that these molecules activate overlapping inflammatory responses in human and murine macrophages. Moreover, UV crosslinking studies determined that both dinucleotides physically associate with a shared set of host proteins. Fractionation of macrophage extracts on a biotin-c-diGMP affinity matrix led to the identification of a set of candidate host binding proteins. These studies suggest that mammalian macrophages can sense and mount a specific inflammatory response to bacterial dinucleotides.
authors.affiliation: Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Abdul-Sater
authors.forename: Andrzej
authors.initials: A
authors.lastname: Grajkowski
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.forename: Courtney
authors.initials: C
authors.lastname: Plumlee
authors.forename: Assaf
authors.initials: A
authors.lastname: Levi
authors.forename: Michael T
authors.initials: MT
authors.lastname: Schreiber
authors.forename: Carolyn
authors.initials: C
authors.lastname: Lee
authors.forename: Howard
authors.initials: H
authors.lastname: Shuman
authors.forename: Serge L
authors.initials: SL
authors.lastname: Beaucage
authors.forename: Christian
authors.initials: C
authors.lastname: Schindler
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015226:Dinucleoside Phosphates / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism; D016952:Legionella pneumophila / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction
chemical_list: D001426:Bacterial Proteins; D015226:Dinucleoside Phosphates; D007370:Interferon Type I; C528998:cyclic diadenosine phosphate; C062025:bis(3',5')-cyclic diguanylic acid; D016899:Interferon-beta; D006152:Cyclic GMP