The AIM2 inflammasome is critical for innate immunity to Francisella tularensis

Abstract

Summary Francisella tularensis, the causative agent of tularemia, infects host macrophages, which triggers production of the proinflammatory cytokines interleukin 1 β (IL-1 β) and IL-18. We elucidate here how host macrophages recognize Francisella and elicit this pro-inflammatory response. Using mice deficient in the DNA-sensing inflammasome component AIM2, we demonstrate here that AIM2 is required for sensing Francisella. AIM2-deficient mice were extremely susceptible to Francisella infection with higher mortality and bacterial burden compared to wild-type mice. Caspase-1, activation, IL-1β secretion and cell death were absent in Aim2−/− macrophages in response to Francisella infection or presence of cytoplasmic DNA. This study identifies AIM2 as a crucial sensor of F. tularensis infection, and provides genetic proof for its critical role in the host innate immunity to intracellular pathogens.

Pyroptotic Neuronal Cell Death Mediated by the AIM2 Inflammasome

“…This response, along with our finding that anti-AIM2 pulled down caspase-1 cleavage products in unstimulated neurons, is consistent with previous reports in macrophages, in which AIM2 inflammasome proteins are preassembled and 5 mg poly(dA:dT) stimulation for three hours induces caspase-1 processing. 29 There was a less robust response at 20 mg/mL, the highest concentration tested. As with any innate immune response, the host is tasked with eradication of the offending agent while minimizing inflammation and tissue damage.…”

Gut–Liver Axis: Role of Inflammasomes

“…66 Likewise, AIM2 deficient mice infected with F. tularensis novicida have high bacterial loads, low levels of serum IL-18 and lower survival than do wild type mice. 65 Mice deficient in ASC or caspase-1 show similar phenotype as described for the AIM2 deficient mice. This evidence suggests that AIM2, ASC and caspase-1 function in a single signaling pathway that helps in detecting infection with Francisella, vaccinia virus or mCMV and provokes protective host responses.…”

“…65,66 In vivo studies have highlighted low levels of serum IL-18 and less secretion of interferon-g (IFN-g) by splenic NK cells in AIM2 deficient mice infected with mCMV. 66 Likewise, AIM2 deficient mice infected with F. tularensis novicida have high bacterial loads, low levels of serum IL-18 and lower survival than do wild type mice.…”

“…Deficiency of AIM2 has been found to increase the interferon response to dsDNA transfection or Francisella infection but elicits a normal response in the case of mCMV infection. 65,66 A recent study by Liu and group 68 established that the production of IL-1b and IL-18 in NLRP3 and NLRC4 inflammasomes plays a critical role in host defense against enteric infection caused by C. rodentium. An enteric bacterial pathogen in the intestinal tract of the mouse, C. rodentium triggers inflammatory responses similar to those seen in humans infected with enteropathogenic and enterohemorrhagic E. coli.…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Interestingly, induction of IFN-b during F. tularensis infection is dependent on access of the bacterium to the cytoplasm (102). This cytokine induction appears to be IRF3 dependent but TLR independent (102,103). Although the PRR responsible for type I IFN induction during F. tularensis infection remains to be identified, IFN-b expression is greatly reduced in STING-deficient cells (104), suggesting a possible involvement of DNA-sensing receptors, such as cGAS and IFI16, in the process (105).…”