Format

Send to

Choose Destination
Pathog Dis. 2015 Aug;73(6):ftv036. doi: 10.1093/femspd/ftv036. Epub 2015 May 17.

Characterization of Francisella tularensis Schu S4 defined mutants as live-attenuated vaccine candidates.

Author information

1
Departments of Pediatrics, University of Virginia Children's Hospital, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
2
Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
3
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
4
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
5
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA ebarry@medicine.umaryland.edu.

Abstract

Francisella tularensis (Ft), the etiological agent of tularemia and a Tier 1 select agent, has been previously weaponized and remains a high priority for vaccine development. Ft tularensis (type A) and Ft holarctica (type B) cause most human disease. We selected six attenuating genes from the live vaccine strain (LVS; type B), F. novicida and other intracellular bacteria: FTT0507, FTT0584, FTT0742, FTT1019c (guaA), FTT1043 (mip) and FTT1317c (guaB) and created unmarked deletion mutants of each in the highly human virulent Ft strain Schu S4 (Type A) background. FTT0507, FTT0584, FTT0742 and FTT1043 Schu S4 mutants were not attenuated for virulence in vitro or in vivo. In contrast, Schu S4 gua mutants were unable to replicate in murine macrophages and were attenuated in vivo, with an i.n. LD50 > 10(5) CFU in C57BL/6 mice. However, the gua mutants failed to protect mice against lethal challenge with WT Schu S4, despite demonstrating partial protection in rabbits in a previous study. These results contrast with the highly protective capacity of LVS gua mutants against a lethal LVS challenge in mice, and underscore differences between these strains and the animal models in which they are evaluated, and therefore have important implications for vaccine development.

KEYWORDS:

Francisella tularensis; Schu S4; live attenuated; mutants; tularemia; vaccines

PMID:
25986219
PMCID:
PMC4462183
DOI:
10.1093/femspd/ftv036
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center