title: A conserved and immunodominant lipoprotein of Francisella tularensis is proinflammatory but not essential for virulence.
abstract: Francisella tularensis is a highly virulent bacterium that causes tularemia, a disease that is often fatal if untreated. A live vaccine strain (LVS) of this bacterium is attenuated for virulence in humans but produces lethal disease in mice. F. tularensis has been classified as a Category A agent of bioterrorism. Despite this categorization, little is known about the components of the organism that are responsible for causing disease in its hosts. Here, we report the deletion of a well-characterized lipoprotein of F. tularensis, designated LpnA (also known as Tul4), in the LVS. An LpnA deletion mutant was comparable to the wild-type strain in its ability to grow intracellularly and cause lethal disease in mice. Additionally, mice inoculated with a sublethal dose of the mutant strain were afforded the same protection against a subsequent lethal challenge with the LVS as were mice initially administered a sublethal dose of the wild-type bacterium. The LpnA-deficient strain showed an equivalent ability to promote secretion of chemokines by human monocyte-derived macrophages as its wild-type counterpart. However, recombinant LpnA potently stimulated primary cultures of human macrophages in a Toll-like receptor 2-dependent manner. Although human endothelial cells were also activated by recombinant LpnA, their response was relatively modest. LpnA is clearly unnecessary for multiple functions of the LVS, but its inflammatory capacity implicates it and other Francisella lipoproteins as potentially important to the pathogenesis of tularemia.
authors.affiliation: Center for Infectious Diseases, School of Medicine, Stony Brook University, Stony Brook, NY 11794-5120, USA.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Forestal
authors.forename: Horacio
authors.initials: H
authors.lastname: Gil
authors.forename: Michael
authors.initials: M
authors.lastname: Monfett
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Noah
authors.forename: Gabrielle J
authors.initials: GJ
authors.lastname: Platz
authors.forename: David G
authors.initials: DG
authors.lastname: Thanassi
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Benach
authors.forename: Martha B
authors.initials: MB
authors.lastname: Furie
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D001428:Bacterial Vaccines / Q000235:genetics / Q000276:immunology*; D018925:Chemokines / Q000276:immunology; D003227:Conjugation, Genetic; D042783:Endothelial Cells / Q000276:immunology / Q000382:microbiology; D005260:Female; D005604:Francisella tularensis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology*; D008074:Lipoproteins / Q000235:genetics / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D017384:Sequence Deletion; D014406:Tularemia / Q000276:immunology* / Q000382:microbiology; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D018925:Chemokines; D018836:Inflammation Mediators; D008074:Lipoproteins; D014613:Vaccines, Attenuated; C075214:TUL4 protein, Francisella tularensis