title: Generation of protection against Francisella novicida in mice depends on the pathogenicity protein PdpA, but not PdpC or PdpD.
abstract: Previous results suggest that mutations in most genes in the Francisella pathogenicity island (FPI) attenuate the bacterium. Using a mouse model, here we determined the impact of mutations in pdpA, pdpC, and pdpD in Francisella novicida on in vitro replication in macrophages, and in vivo immunogenicity. In contrast to most FPI genes, deletion of pdpC (FnΔpdpC) and pdpD (FnΔpdpD) from F. novicida did not impact growth in mouse bone-marrow derived macrophages. Nonetheless, both FnΔpdpC and FnΔpdpD were highly attenuated when administered intradermally. Infected mice produced relatively normal anti-F. novicida serum antibodies. Further, splenocytes from infected mice controlled intramacrophage Francisella replication, indicating T cell priming, and mice immunized by infection with FnΔpdpC or FnΔpdpD survived secondary lethal parenteral challenge with either F. novicida or Francisella tularensis LVS. In contrast, deletion of pdpA (FnΔpdpA) ablated growth in macrophages in vitro. FnΔpdpA disseminated and replicated poorly in infected mice, accompanied by development of some anti-F. novicida serum antibodies. However, primed Th1 cells were not detected, and vaccinated mice did not survive even low dose challenge with either F. novicida or LVS. Taken together, these results suggest that successful priming of Th1 cells, and protection against lethal challenge, depends on expression of PdpA.
authors.affiliation: Laboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, 1401 Rockville Pike, HFM-431, Rockville, MD 20852, USA.
authors.forename: Alicia Y
authors.initials: AY
authors.lastname: Chou
authors.forename: Nikki J
authors.initials: NJ
authors.lastname: Kennett
authors.forename: Eli B
authors.initials: EB
authors.lastname: Nix
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Schmerk
authors.forename: Francis E
authors.initials: FE
authors.lastname: Nano
authors.forename: Karen L
authors.initials: KL
authors.lastname: Elkins
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005603:Francisella / Q000235:genetics / Q000254:growth & development* / Q000276:immunology*; D017353:Gene Deletion; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008264:Macrophages / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D014406:Tularemia / Q000517:prevention & control*; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D037521:Virulence Factors
keywords: Francisella; Mice; Pathogenicity island; Protective immunity; T lymphocytes