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The AIM2 inflammasome is critical for innate immunity to Francisella tularensis.

Fernandes-Alnemri T, Yu JW, Juliana C, Solorzano L, Kang S, Wu J, Datta P, McCormick M, Huang L, McDermott E, Eisenlohr L, Landel CP, Alnemri ES - Nat. Immunol. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

ABSTRACT
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.

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The AIM2 inflammasome is critical for innate immunity against Francisella infection. (a), Survival of Aim2+/+ and Aim2−/− mice injected subcutaneously with F. novicida (1.5 × 105 CFU) (Aim2+/+ n = 9, Aim2−/− n=9), and monitored over a period of 3 weeks. 66% of Aim2+/+ survived beyond 3 weeks post-infection. (b), Livers and spleens were harvested 48 h post-infection of mice subcutaneously with F. novicida (1.0 × 105 CFU) homogenized, and dilutions plated on Cystine Heart Agar plates for enumeration of CFU. Bacterial counts from the livers and spleens of the Aim2−/− were significantly higher compared with Aim2+/+ mice (P 0.0054, and 0.0011, respectively). (c) Enzyme-linked immunosorbent assay of IL-18 in serum from Aim2+/+ mice (n = 3) and Aim2−/− mice (n = 3) at 1 d after subcutaneous infection with F. novicida. In b,c, each symbol represents an individual mouse; small horizontal lines indicate the mean. P values, Kaplan-Meier log-rank test (a) or Student’s t-test (b,c). Data are representative of two experiments.
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Figure 6: The AIM2 inflammasome is critical for innate immunity against Francisella infection. (a), Survival of Aim2+/+ and Aim2−/− mice injected subcutaneously with F. novicida (1.5 × 105 CFU) (Aim2+/+ n = 9, Aim2−/− n=9), and monitored over a period of 3 weeks. 66% of Aim2+/+ survived beyond 3 weeks post-infection. (b), Livers and spleens were harvested 48 h post-infection of mice subcutaneously with F. novicida (1.0 × 105 CFU) homogenized, and dilutions plated on Cystine Heart Agar plates for enumeration of CFU. Bacterial counts from the livers and spleens of the Aim2−/− were significantly higher compared with Aim2+/+ mice (P 0.0054, and 0.0011, respectively). (c) Enzyme-linked immunosorbent assay of IL-18 in serum from Aim2+/+ mice (n = 3) and Aim2−/− mice (n = 3) at 1 d after subcutaneous infection with F. novicida. In b,c, each symbol represents an individual mouse; small horizontal lines indicate the mean. P values, Kaplan-Meier log-rank test (a) or Student’s t-test (b,c). Data are representative of two experiments.

Mentions: The above results indicate that AIM2 is important for the pro-inflammatory and cell death responses to Francisella-infection in vitro, through a mechanism that involves the recognition of cytoplasmic DNA produced by this intracellular pathogen. To assess the precise role of AIM2 in the host innate immune defense against Francisella-infection, wild-type and Aim2−/− mice were challenged subcutaneously with live F. novicida. Compared to wild-type mice, the subcutaneous infection of Aim2−/− mice with F. novicida resulted in dramatically higher rate of mortality (Fig. 6a). The mortality rate of Aim2−/− mice on day 5 was 100% compared with just 33% in wild-type mice. The remaining wild-type mice survived beyond 20 days post infection. Consistent with these results, the bacterial burdens in tissues of Aim2−/− mice were markedly higher than those in wild-type mice 48 h post infection (Fig. 6b). These results indicate that the AIM2 inflammasome plays a crucial role in the host defense against Francisella-infection likely by decreasing bacterial burden in tissues, thereby preventing systemic infection. Consistent with the critical role of AIM2 in the production of caspase-1-generated cytokines, the serum concentration of IL-18 was much higher in wild-type mice compared to Aim2−/− mice, 24 h post-infection (Fig. 6b) Taken together, these results indicate that the lack of AIM2 inflammasome activity increases the virulence of Francisella in mice due to defective caspase-1 activation, which is critical for the production of the caspase-1-generated cytokines such as IL-1β and IL-18, and induction of pyroptotic cell death of the infected macrophages.


The AIM2 inflammasome is critical for innate immunity to Francisella tularensis.

Fernandes-Alnemri T, Yu JW, Juliana C, Solorzano L, Kang S, Wu J, Datta P, McCormick M, Huang L, McDermott E, Eisenlohr L, Landel CP, Alnemri ES - Nat. Immunol. (2010)

The AIM2 inflammasome is critical for innate immunity against Francisella infection. (a), Survival of Aim2+/+ and Aim2−/− mice injected subcutaneously with F. novicida (1.5 × 105 CFU) (Aim2+/+ n = 9, Aim2−/− n=9), and monitored over a period of 3 weeks. 66% of Aim2+/+ survived beyond 3 weeks post-infection. (b), Livers and spleens were harvested 48 h post-infection of mice subcutaneously with F. novicida (1.0 × 105 CFU) homogenized, and dilutions plated on Cystine Heart Agar plates for enumeration of CFU. Bacterial counts from the livers and spleens of the Aim2−/− were significantly higher compared with Aim2+/+ mice (P 0.0054, and 0.0011, respectively). (c) Enzyme-linked immunosorbent assay of IL-18 in serum from Aim2+/+ mice (n = 3) and Aim2−/− mice (n = 3) at 1 d after subcutaneous infection with F. novicida. In b,c, each symbol represents an individual mouse; small horizontal lines indicate the mean. P values, Kaplan-Meier log-rank test (a) or Student’s t-test (b,c). Data are representative of two experiments.
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Related In: Results  -  Collection

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Figure 6: The AIM2 inflammasome is critical for innate immunity against Francisella infection. (a), Survival of Aim2+/+ and Aim2−/− mice injected subcutaneously with F. novicida (1.5 × 105 CFU) (Aim2+/+ n = 9, Aim2−/− n=9), and monitored over a period of 3 weeks. 66% of Aim2+/+ survived beyond 3 weeks post-infection. (b), Livers and spleens were harvested 48 h post-infection of mice subcutaneously with F. novicida (1.0 × 105 CFU) homogenized, and dilutions plated on Cystine Heart Agar plates for enumeration of CFU. Bacterial counts from the livers and spleens of the Aim2−/− were significantly higher compared with Aim2+/+ mice (P 0.0054, and 0.0011, respectively). (c) Enzyme-linked immunosorbent assay of IL-18 in serum from Aim2+/+ mice (n = 3) and Aim2−/− mice (n = 3) at 1 d after subcutaneous infection with F. novicida. In b,c, each symbol represents an individual mouse; small horizontal lines indicate the mean. P values, Kaplan-Meier log-rank test (a) or Student’s t-test (b,c). Data are representative of two experiments.
Mentions: The above results indicate that AIM2 is important for the pro-inflammatory and cell death responses to Francisella-infection in vitro, through a mechanism that involves the recognition of cytoplasmic DNA produced by this intracellular pathogen. To assess the precise role of AIM2 in the host innate immune defense against Francisella-infection, wild-type and Aim2−/− mice were challenged subcutaneously with live F. novicida. Compared to wild-type mice, the subcutaneous infection of Aim2−/− mice with F. novicida resulted in dramatically higher rate of mortality (Fig. 6a). The mortality rate of Aim2−/− mice on day 5 was 100% compared with just 33% in wild-type mice. The remaining wild-type mice survived beyond 20 days post infection. Consistent with these results, the bacterial burdens in tissues of Aim2−/− mice were markedly higher than those in wild-type mice 48 h post infection (Fig. 6b). These results indicate that the AIM2 inflammasome plays a crucial role in the host defense against Francisella-infection likely by decreasing bacterial burden in tissues, thereby preventing systemic infection. Consistent with the critical role of AIM2 in the production of caspase-1-generated cytokines, the serum concentration of IL-18 was much higher in wild-type mice compared to Aim2−/− mice, 24 h post-infection (Fig. 6b) Taken together, these results indicate that the lack of AIM2 inflammasome activity increases the virulence of Francisella in mice due to defective caspase-1 activation, which is critical for the production of the caspase-1-generated cytokines such as IL-1β and IL-18, and induction of pyroptotic cell death of the infected macrophages.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus