The AIM2 inflammasome is critical for innate immunity to Francisella tularensis.
Francisella tularensis, the causative agent of tularemia, infects host macrophages, which triggers production of the proinflammatory cytokines interleukin 1beta (IL-1beta) and IL-18. We elucidate here how host macrophages recognize F. tularensis and elicit this proinflammatory response. Using mice deficient in the DNA-sensing inflammasome component AIM2, we demonstrate here that AIM2 is required for sensing F. tularensis. AIM2-deficient mice were extremely susceptible to F. tularensis infection, with greater mortality and bacterial burden than that of wild-type mice. Caspase-1 activation, IL-1beta secretion and cell death were absent in Aim2(-/-) macrophages in response to F. tularensis infection or the presence of cytoplasmic DNA. Our study identifies AIM2 as a crucial sensor of F. tularensis infection and provides genetic proof of its critical role in host innate immunity to intracellular pathogens.
Fernandes-Alnemri
Teresa
T
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Yu
Je-Wook
JW
Juliana
Christine
C
Solorzano
Leobaldo
L
Kang
Seokwon
S
Wu
Jianghong
J
Datta
Pinaki
P
McCormick
Margaret
M
Huang
Lan
L
McDermott
Erin
E
Eisenlohr
Laurence
L
Landel
Carlisle P
CP
Alnemri
Emad S
ES
D000818:Animals; D020013:Calcium Signaling / Q000276:immunology; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005604:Francisella tularensis / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D055503:Protein Multimerization; D014406:Tularemia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
C540422:Aim2 protein, mouse; D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D053583:Interleukin-1beta; C494233:Irf3 protein, mouse; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D007770:L-Lactate Dehydrogenase; D020170:Caspase 1