Francisella tularensis live vaccine strain folate metabolism and pseudouridine synthase gene mutants modulate macrophage caspase-1 activation

Tyler K Ulland; Ann M Janowski; Blake W Buchan; Matthew Faron; Suzanne L Cassel; Bradley D Jones; Fayyaz S Sutterwala

doi:10.1128/IAI.00991-12

Back

Francisella tularensis live vaccine strain folate metabolism and pseudouridine synthase gene mutants modulate macrophage caspase-1 activation

Journal article

Open access

Peer reviewed

Francisella tularensis live vaccine strain folate metabolism and pseudouridine synthase gene mutants modulate macrophage caspase-1 activation

Tyler K Ulland, Ann M Janowski, Blake W Buchan, Matthew Faron, Suzanne L Cassel, Bradley D Jones and Fayyaz S Sutterwala

Infection and immunity, Vol.81(1), pp.201-208

01/2013

DOI: 10.1128/IAI.00991-12

PMCID: PMC3536133

PMID: 23115038

Files and links (1)

url

https://doi.org/10.1128/IAI.00991-12View

Published (Version of record) Open Access

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.

Phagosomes - microbiology

Interleukin-18 - immunology

Tularemia - metabolism

Inflammasomes - metabolism

Macrophage Activation - genetics

Folic Acid - immunology

Tularemia - genetics

Caspase 1 - metabolism

Caspase 1 - immunology

Vaccines, Attenuated - metabolism

Mutation - immunology

Carbon-Nitrogen Ligases - genetics

Phagosomes - immunology

Tularemia - microbiology

Francisella tularensis - metabolism

Interleukin-1beta - metabolism

Tularemia - immunology

Bacterial Vaccines - metabolism

Francisella tularensis - genetics

Intramolecular Transferases - immunology

Macrophages - immunology

Macrophages - microbiology

Francisella tularensis - immunology

Intramolecular Transferases - genetics

Carbon-Nitrogen Ligases - metabolism

Macrophage Activation - immunology

Mice, Inbred C57BL

Phagosomes - metabolism

Interleukin-1beta - immunology

Mutation - genetics

Inflammasomes - genetics

Intramolecular Transferases - metabolism

Macrophages - metabolism

Vaccines, Attenuated - immunology

Animals

Bacterial Vaccines - immunology

Inflammasomes - immunology

Virulence - immunology

Carbon-Nitrogen Ligases - immunology

Folic Acid - metabolism

Mice

Folic Acid - genetics

Interleukin-18 - metabolism

Details

Title: Subtitle: Francisella tularensis live vaccine strain folate metabolism and pseudouridine synthase gene mutants modulate macrophage caspase-1 activation
Creators: Tyler K Ulland - Inflammation Program, University of Iowa, Iowa City, Iowa, USA
Ann M Janowski
Blake W Buchan
Matthew Faron
Suzanne L Cassel
Bradley D Jones
Fayyaz S Sutterwala
Resource Type: Journal article
Publication Details: Infection and immunity, Vol.81(1), pp.201-208
DOI: 10.1128/IAI.00991-12
PMID: 23115038
PMCID: PMC3536133
ISSN: 0019-9567
eISSN: 1098-5522
Grant note: P30 ES005605 / NIEHS NIH HHS P01 AI44642 / NIAID NIH HHS I01 BX000513 / BLRD VA I01 BX000167 / BLRD VA U54 AI057160 / NIAID NIH HHS P01 AI044642 / NIAID NIH HHS
Language: English
Date published: 01/2013
Academic Unit: Microbiology and Immunology
Record Identifier: 9984083887602771

Metrics

22 Record Views

13 Times Cited - Web of Science