title: A tolC mutant of Francisella tularensis is hypercytotoxic compared to the wild type and elicits increased proinflammatory responses from host cells.
abstract: The highly infectious bacterium Francisella tularensis is a facultative intracellular pathogen and the causative agent of tularemia. TolC, which is an outer membrane protein involved in drug efflux and type I protein secretion, is required for the virulence of the F. tularensis live vaccine strain (LVS) in mice. Here, we show that an LVS DeltatolC mutant colonizes livers, spleens, and lungs of mice infected intradermally or intranasally, but it is present at lower numbers in these organs than in those infected with the parental LVS. For both routes of infection, colonization by the DeltatolC mutant is most severely affected in the lungs, suggesting that TolC function is particularly important in this organ. The DeltatolC mutant is hypercytotoxic to murine and human macrophages compared to the wild-type LVS, and it elicits the increased secretion of proinflammatory chemokines from human macrophages and endothelial cells. Taken together, these data suggest that TolC function is required for F. tularensis to inhibit host cell death and dampen host immune responses. We propose that, in the absence of TolC, F. tularensis induces excessive host cell death, causing the bacterium to lose its intracellular replicative niche. This results in lower bacterial numbers, which then are cleared by the increased innate immune response of the host.
authors.affiliation: Center for Infectious Diseases, Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5120, USA.
authors.forename: Gabrielle J
authors.initials: GJ
authors.lastname: Platz
authors.forename: DeAnna C
authors.initials: DC
authors.lastname: Bublitz
authors.forename: Patricio
authors.initials: P
authors.lastname: Mena
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Benach
authors.forename: Martha B
authors.initials: MB
authors.lastname: Furie
authors.forename: David G
authors.initials: DG
authors.lastname: Thanassi
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D015169:Colony Count, Microbial; D042783:Endothelial Cells / Q000276:immunology / Q000382:microbiology; D005604:Francisella tularensis / Q000276:immunology* / Q000472:pathogenicity*; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D013154:Spleen / Q000382:microbiology; D014406:Tularemia / Q000382:microbiology* / Q000473:pathology*; D037521:Virulence Factors / Q000172:deficiency / Q000502:physiology*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D018836:Inflammation Mediators; D037521:Virulence Factors