Faculty Collaboration Database

Francisella tularensis live vaccine strain folate metabolism and pseudouridine synthase gene mutants modulate macrophage caspase-1 activation. Infect Immun 2013 Jan;81(1):201-8

Date

11/02/2012

Pubmed ID

23115038

Pubmed Central ID

PMC3536133

DOI

10.1128/IAI.00991-12

Scopus ID

2-s2.0-84871886258 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

Francisella tularensis is a Gram-negative bacterium and the causative agent of the disease tularemia. Escape of F. tularensis from the phagosome into the cytosol of the macrophage triggers the activation of the AIM2 inflammasome through a mechanism that is not well understood. Activation of the AIM2 inflammasome results in autocatalytic cleavage of caspase-1, resulting in the processing and secretion of interleukin-1β (IL-1β) and IL-18, which play a crucial role in innate immune responses to F. tularensis. We have identified the 5-formyltetrahydrofolate cycloligase gene (FTL_0724) as being important for F. tularensis live vaccine strain (LVS) virulence. Infection of mice in vivo with a F. tularensis LVS FTL_0724 mutant resulted in diminished mortality compared to infection of mice with wild-type LVS. The FTL_0724 mutant also induced increased inflammasome-dependent IL-1β and IL-18 secretion and cytotoxicity in macrophages in vitro. In contrast, infection of macrophages with a F. tularensis LVS rluD pseudouridine synthase (FTL_0699) mutant resulted in diminished IL-1β and IL-18 secretion from macrophages in vitro compared to infection of macrophages with wild-type LVS. In addition, the FTL_0699 mutant was not attenuated in vivo. These findings further illustrate that F. tularensis LVS possesses numerous genes that influence its ability to activate the inflammasome, which is a key host strategy to control infection with this pathogen in vivo.

Author List

Ulland TK, Janowski AM, Buchan BW, Faron M, Cassel SL, Jones BD, Sutterwala FS

Author

Blake W. Buchan PhD Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Bacterial Vaccines
Carbon-Nitrogen Ligases
Caspase 1
Folic Acid
Francisella tularensis
Inflammasomes
Interleukin-18
Interleukin-1beta
Intramolecular Transferases
Macrophage Activation
Macrophages
Mice
Mice, Inbred C57BL
Mutation
Phagosomes
Tularemia
Vaccines, Attenuated
Virulence