COX-2 Inhibition Reduces Brucella Bacterial Burden in Draining Lymph Nodes

Abstract

Brucella is 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 that Brucella abortus strongly 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 of Ptgs2, 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 inducing Ptgs2 expression 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 decreased B. melitensis burden in the CLN after intradermal infection. This effect was accompanied by a decrease of Il10 and a concomitant increase of Ifng expression. Altogether, these results suggest that Brucella has 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.

Loci Associated With Antibody Response in Feral Swine (Sus scrofa) Infected With Brucella suis

“…The Prostaglandin-Endoperoxide Synthase 2 (PTGS2) gene encodes the PTGS2 enzyme that catalyzes the breakdown of arachidonic acid from cell wall phospholipids to bioactive eicosanoid compounds (75,76). PTGS2 is expressed by a wide range of cells including macrophages, fibroblasts, vascular endothelial cells, and smooth muscle cells (77) and exposure of immune cells (dendritic or monocytes) to B. abortus or its LPS increases expression of prostaglandins (78,79). Previous studies suggest that increased prostaglandin concentrations favor prolonged survival of Brucella within host cells.…”

“…Previous studies suggest that increased prostaglandin concentrations favor prolonged survival of Brucella within host cells. Cyclooxygenase inhibition reduces Brucella colonization in a murine model (78) and has been shown to have suppressive effects on several other immune-modulating effectors. Prostaglandins are also potent immune modulators for T cells and can block T cell proliferation and promote cytokines associated with TH-2 responses (80,81).…”

Metabolomic analyses reveal lipid abnormalities and hepatic dysfunction in non-human primate model for Yersinia pestis

“…As early as 6 h post infection, the metabolites icosatetraenoic acid and myo-inositol three phosphate along with the gene prostaglandin-endoperoxide synthase 2 ( ptgs2 ) were observed as main nodes. The ptgs2 genes encodes a key enzyme in prostaglandin biosynthesis, and is highly inducible following pro-inflammatory stimuli such as cytokines or endotoxins (Gagnaire et al 2016 ). The metabolite linoleate showed up as a dominant node at 12 h post infection.…”

Rhoptry protein 5 (ROP5) Is a Key Virulence Factor in Neospora caninum

“…The resulting RNA concentrations were normalized using Ncactin ( Wang et al, 2017 ), and the relative expression levels of the target genes were analyzed using the ABI Prism 7500 software v2.0.5 (Biosystems Inc., USA). The RT-PCR conditions were as follows: 94°C for 5 s, 40 cycles of 94°C for 5 s and 60°C for 30 s. The relative expression of genes was calculated using the 2 -ΔΔCt method and standard deviation was calculated from three replicates ( Cárdenas-Mondragón et al, 2016 ; Gagnaire et al, 2016 ).…”