<i>Francisella tularensis</i>as a potential agent of bioterrorism?

Maurin, Max

doi:10.1586/14787210.2015.986463

Cited by 52 publications

(50 citation statements)

References 28 publications

(42 reference statements)

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“…No effective vaccine is currently licenced for human or animal use, and a few antibiotic compounds are used as first-line drugs in tularaemia patients. Alternative treatments are urgently needed both to improve the prognosis of patients with severe diseases, and also to improve our preparedness to the intentional release of resistant strains of this pathogen in the context of bioterrorism 4,5 . Although numerous genes have been shown to be important for the pathogenesis and virulence of F. tularensis , there is still a blatant lack of knowledge about central biological functions such as iron homeostasis 6,7 and metalloregulators 8,9 .…”

Section: Introductionmentioning

confidence: 99%

Structural and functional studies of the metalloregulator Fur identify a promoter-binding mechanism and its role in Francisella tularensis virulence

et al. 2018

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Francisella tularensis is a Gram-negative bacterium causing tularaemia. Classified as possible bioterrorism agent, it may be transmitted to humans via animal infection or inhalation leading to severe pneumonia. Its virulence is related to iron homeostasis involving siderophore biosynthesis directly controlled at the transcription level by the ferric uptake regulator Fur, as presented here together with the first crystal structure of the tetrameric F. tularensis Fur in the presence of its physiological cofactor, Fe2+. Through structural, biophysical, biochemical and modelling studies, we show that promoter sequences of F. tularensis containing Fur boxes enable this tetrameric protein to bind them by splitting it into two dimers. Furthermore, the critical role of F. tularensis Fur in virulence and pathogenesis is demonstrated with a fur-deleted mutant showing an attenuated virulence in macrophage-like cells and mice. Together, our study suggests that Fur is an attractive target of new antibiotics that attenuate the virulence of F. tularensis.

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Section: Introductionmentioning

confidence: 99%

Structural and functional studies of the metalloregulator Fur identify a promoter-binding mechanism and its role in Francisella tularensis virulence

et al. 2018

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“…The virulent strains ( F. tularensis tularensis ) can cause disease in humans with inhalation of as few as 10 organisms. In addition, this organism is easily aerosolized and has historically been developed as a bioweapon [1–3]. The United States government has classified F. tularensis as a Tier 1 and Category A Select Agent.…”

Section: Introductionmentioning

confidence: 99%

Intraperitoneal treatment with antimicrobial peptide rescues mice from a pulmonaryFrancisellainfection

Hoek

Kaushal

Bishop

et al. 2019

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7Our long-term goal is to identify new antimicrobial peptides that might be effective 8 against pneumonic Francisella infection in mice. Previously, our group searched the peptidome 9 of the American alligator for novel cationic antimicrobial peptides and identified a naturally-10 occurring C-terminal fragment of apolipoprotein C-1, which we called Apo6. This peptide was 11 found to have antibacterial activity against the ESKAPE pathogens, including those exhibiting 12 multi-drug resistance. In this work, we tested Apo6 and synthetic derivatives for antibacterial 13 activity against Francisella tularensis including the virulent strain F. tularensis SchuS4.14 Francisella is inherently highly resistant to the cyclic peptide polymyxin antibiotics and beta-15 lactam antibiotics. We found that our synthetic peptide derivatives (called GATR peptides), 16 designed with increased hydrophobicity and charge, had generally stronger in vitro antimicrobial 17 activity against Francisella than the parent peptide Apo6. The GATR peptides had a greater 18 effect on the bacterial membrane than the Apo6 peptide and were able to bind Francisella LPS, 19 suggesting their mechanism of action against Francisella. Cytotoxicity experiments showed low 20 cytotoxicity for most of the GATR peptides, and whole organism toxicity studies in the 21 waxworm allowed us to down-select to two our lead peptides, GATR-3 and GATR-6. These 22 peptides were tested in a murine pulmonary tularemia model. We found that the GATR-3 peptide 23 rescued 50-60% of mice from lethal tularemia infection when administered systemically through 24 2 the intraperitoneal route. This peptide is a candidate for further pre-clinical studies for a potential 25 peptide-based approach to tularemia. 26

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“…Francisella tularensis subsp. tularensis (F. tularensis) is a gramnegative, facultative intracellular bacterium that causes the zoonotic disease tularemia (Decors et al, 2011;Ellis, Oyston, Green, & Titball, 2002), and it is classified as a category A bioterrorism agent (Maurin, 2015). The vector-borne transmission of F. tularensis to mammalian hosts precedes the development of tularemia (Petersen, Mead, & Schriefer, 2009;Suzuki, Uda, Watanabe, Shimizu, & Watarai, 2016;Suzuki, Hashino, et al, 2016).…”

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confidence: 99%

Expression of Francisella pathogenicity island protein intracellular growth locus E (IglE) in mammalian cells is involved in intracellular trafficking, possibly through microtubule organizing center

et al. 2018

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Francisella tularensis is the causative agent of the infectious disease tularemia and is designated a category A bioterrorism agent. The type VI secretion system encoded by the Francisella pathogenicity island (FPI) is necessary for intracellular growth; however, the functions of FPI proteins are largely unknown. In this study, we found that the FPI protein intracellular growth locus E (IglE) showed a unique localization pattern compared to other FPI proteins. Deleting iglE from Francisella tularensis subsp. novicida (F. novicida) decreased intracellular growth. Immunoprecipitation and pull-down assays revealed that IglE was associated with β-tubulin. Additionally, GFP-fused IglE colocalized with microtubule organizing centers (MTOCs) in 293T cells. The iglE deletion mutant was transferred with dynein toward MTOCs and packed into lysosome-localizing areas. Conversely, the wild-type F. novicida exhibited intracellular growth distant from MTOCs. In addition, IglE expressed in 293T cells colocalized with dynein. These results suggest that IglE helps to prevent dynein- and MTOC-mediated intracellular trafficking in host cells to inhibit the transport of F. novicida toward lysosomes.

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Francisella tularensisas a potential agent of bioterrorism?

Cited by 52 publications

References 28 publications

Structural and functional studies of the metalloregulator Fur identify a promoter-binding mechanism and its role in Francisella tularensis virulence

Structural and functional studies of the metalloregulator Fur identify a promoter-binding mechanism and its role in Francisella tularensis virulence

Intraperitoneal treatment with antimicrobial peptide rescues mice from a pulmonaryFrancisellainfection

Expression of Francisella pathogenicity island protein intracellular growth locus E (IglE) in mammalian cells is involved in intracellular trafficking, possibly through microtubule organizing center

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