Cutting edge: mutation of Francisella tularensis mviN leads to increased macrophage absent in melanoma 2 inflammasome activation and a loss of virulence.
The mechanisms by which the intracellular pathogen Francisella tularensis evades innate immunity are not well defined. We have identified a gene with homology to Escherichia coli mviN, a putative lipid II flippase, which F. tularensis uses to evade activation of innate immune pathways. Infection of mice with a F. tularensis mviN mutant resulted in improved survival and decreased bacterial burdens compared to infection with wild-type F. tularensis. The mviN mutant also induced increased absent in melanoma 2 inflammasome-dependent IL-1beta secretion and cytotoxicity in macrophages. The compromised in vivo virulence of the mviN mutant depended upon inflammasome activation, as caspase 1- and apoptosis-associated speck-like protein containing a caspase recruitment domain-deficient mice did not exhibit preferential survival following infection. This study demonstrates that mviN limits F. tularensis-induced absent in melanoma 2 inflammasome activation, which is critical for its virulence in vivo.
Ulland
Tyler K
TK
Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.
Buchan
Blake W
BW
Ketterer
Margaret R
MR
Fernandes-Alnemri
Teresa
T
Meyerholz
David K
DK
Apicella
Michael A
MA
Alnemri
Emad S
ES
Jones
Bradley D
BD
Nauseef
William M
WM
Sutterwala
Fayyaz S
FS
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000502:physiology; D001428:Bacterial Vaccines / Q000235:genetics / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005604:Francisella tularensis / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008545:Melanoma / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics / Q000276:immunology; D009687:Nuclear Proteins / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D014774:Virulence / Q000235:genetics / Q000276:immunology; D037521:Virulence Factors / Q000235:genetics* / Q000502:physiology
C540422:Aim2 protein, mouse; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; C553043:MviN protein, Francisella tularensis; D009687:Nuclear Proteins; D037521:Virulence Factors