title: COX-2 Inhibition ReducesBrucellaBacterial Burden in Draining Lymph Nodes.
abstract: Brucellais a Gram-negative facultative intracellular bacterium responsible for a chronic disease known as brucellosis, the most widespread re-emerging zoonosis worldwide. Establishment of a Th1-mediated immune response characterized by the production of IL-12 and IFNγ is essential to control the disease. Leukotrienes derived from arachidonic acid (AA) metabolism are known to negatively regulate a protective Th1 immune response against bacterial infections. Here, using genomics approaches we demonstrate thatBrucella abortusstrongly stimulates the prostaglandin (PG) pathway in dendritic cells (DC). We also show an induction of AA production by infected cells. This correlates with the expression ofPtgs2, a gene encoding the downstream cyclooxygenase-2 (COX-2) enzyme in infected DC. By comparing different infection routes (oral, intradermal, intranasal and conjunctival), we identified the intradermal inoculation route as the more potent in inducingPtgs2expression but also in inducing a local inflammatory response in the draining cervical lymph nodes (CLN). NS-398, a specific inhibitor of COX-2 enzymatic activity decreasedB. melitensisburden in the CLN after intradermal infection. This effect was accompanied by a decrease ofIl10and a concomitant increase ofIfngexpression. Altogether, these results suggest thatBrucellahas evolved to take advantage of the PG pathway in the harsh environment of the CLN in order to persist and subvert immune responses. This work also proposes that novel strategies to control brucellosis may include the use of COX-2 inhibitors.
authors.affiliation: Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy Marseille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Gagnaire
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis MO, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gorvel
authors.affiliation: Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy Marseille, France.
authors.forename: Alexia
authors.initials: A
authors.lastname: Papadopoulos
authors.affiliation: Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy Marseille, France.
authors.forename: Kristine
authors.initials: K
authors.lastname: Von Bargen
authors.affiliation: Aix Marseille Univ, INSERM, CNRS, IRD, URMITE Marseille, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mège
authors.affiliation: Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy Marseille, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gorvel
keywords: Brucella; COX-2; dendritic cells; intradermal infection; prostaglandins