title: Reintroduction of two deleted virulence loci restores full virulence to the live vaccine strain of Francisella tularensis.
abstract: A disadvantage of several old vaccines is that the genetic events resulting in the attenuation are often largely unknown and reversion to virulence cannot be excluded. In the 1950s, a live vaccine strain, LVS, was developed from a type B strain of Francisella tularensis, the causative agent of tularemia. LVS, which is highly attenuated for humans but still virulent for mice by some infection routes, has been extensively studied and found to protect staff from laboratory-acquired tularemia. The efforts to improve biopreparedness have identified a demand for a vaccine against tularemia. Recently the rapid progress in genomics of different Francisella strains has led to identification of several regions of differences (RDs). Two genes carried within RDs, pilA, encoding a putative type IV pilin, and FTT0918, encoding an outer membrane protein, have been linked to virulence. Interestingly, LVS has lost these two genes via direct repeat-mediated deletions. Here we show that reintroduction of the two deleted regions restores virulence of LVS in a mouse infection model to a level indistinguishable from that of virulent type B strains. The identification of the two attenuating deletion events could facilitate the licensing of LVS for use in humans.
authors.affiliation: FOI Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
authors.forename: Emelie
authors.initials: E
authors.lastname: Salomonsson
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kuoppa
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Forslund
authors.forename: Carl
authors.initials: C
authors.lastname: Zingmark
authors.forename: Igor
authors.initials: I
authors.lastname: Golovliov
authors.forename: Anders
authors.initials: A
authors.lastname: Sjöstedt
authors.forename: Laila
authors.initials: L
authors.lastname: Noppa
authors.forename: Ake
authors.initials: A
authors.lastname: Forsberg
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000502:physiology; D001428:Bacterial Vaccines / Q000235:genetics*; D005260:Female; D036781:Fimbriae Proteins / Q000235:genetics / Q000502:physiology; D005604:Francisella tularensis / Q000235:genetics / Q000472:pathogenicity*; D005816:Genetic Complementation Test; D051379:Mice; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D014406:Tularemia / Q000382:microbiology*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001428:Bacterial Vaccines; D037521:Virulence Factors; D036781:Fimbriae Proteins