title: Mitogen-activated protein kinases (MAPKs) are modulated during Francisella tularensis infection, but inhibition of extracellular-signal-regulated kinases (ERKs) is of limited therapeutic benefit.
abstract: Francisella tularensis is a Gram-negative intracellular bacterium that causes the disease tularemia. The disease can be fatal if left untreated and there is currently no licenced vaccine available; the identification of new therapeutic targets is therefore required. Toll-like receptors represent an interesting target for therapeutic modulation due to their essential role in generating immune responses. In this study, we analysed the in vitro expression of the key mitogen-activated protein kinases (MAPKs) p38, JNK and ERK in murine alveolar macrophages during infection with F. tularensis. The phosphorylation profile of ERK highlighted its potential as a target for therapeutic modulation and subsequently the effect of ERK manipulation was measured in a lethal intranasal F. tularensis in vivo model of infection. The selective ERK1/2 inhibitor PD0325901 was administered orally to mice either pre- or post-challenge with F. tularensis strain LVS. Both treatment regimens selectively reduced ERK expression, but only the pre-exposure treatment produced decreased bacterial burden in the spleen and liver, which correlated with a significant reduction in the pro-inflammatory cytokines IFN-γ, MCP-1, IL-6, and TNF-α. However, no overall improvements in survival were observed for treated animals in this study. ERK may represent a useful therapeutic target where selective dampening of the immune response (to control the damaging pathology seen during infection) is combined with antibiotic treatment required to eradicate bacterial infection. This combination treatment strategy has been shown to be effective in other models of tularemia.
authors.affiliation: CBR Division, Defence Science and Technology Laboratory, Porton Down, Salisbury, SP4 0JQ, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Saint
authors.affiliation: CBR Division, Defence Science and Technology Laboratory, Porton Down, Salisbury, SP4 0JQ, UK. rvdelia@dstl.gov.uk.
authors.forename: R V
authors.initials: RV
authors.lastname: D'Elia
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES, UK.
authors.forename: C
authors.initials: C
authors.lastname: Bryant
authors.affiliation: CBR Division, Defence Science and Technology Laboratory, Porton Down, Salisbury, SP4 0JQ, UK.
authors.forename: G C
authors.initials: GC
authors.lastname: Clark
authors.affiliation: CBR Division, Defence Science and Technology Laboratory, Porton Down, Salisbury, SP4 0JQ, UK.|University of Exeter, Exeter, UK.
authors.forename: H S
authors.initials: HS
authors.lastname: Atkins
mesh_terms: D000818:Animals; D058491:Bacterial Load; D001549:Benzamides / Q000008:administration & dosage; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis*; D005260:Female; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D008099:Liver / Q000382:microbiology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000469:parasitology; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D016896:Treatment Outcome; D014406:Tularemia / Q000473:pathology*
chemical_list: D001549:Benzamides; D016207:Cytokines; D047428:Protein Kinase Inhibitors; C506614:mirdametinib; D004159:Diphenylamine; D048049:Extracellular Signal-Regulated MAP Kinases