The DNA sensor AIM2 is crucial for host defence against cytosolic pathogens and DNA viruses; it not only senses these intracellular intruders but also promotes inflammatory mechanisms as part of our innate immune system.
In a research double whammy, Nature Immunology has published two studies online—Rathinam et al. and Fernandes-Alnemri et al.—that both discuss how the AIM2 inflammasome is essential for innate immunity against cytosolic pathogens.
The body’s innate immune system is the first line of defence against invading pathogens, it acts non-specifically and immediately in response to any infection but, unlike adaptive immunity, innate immunity is not long-lasting. Inflammasomes are multiprotein complexes that activate inflammatory processes (including the inflammatory cytokines IL-1β and IL-18) and pyroptosis (a type of programmed cell death that occurs during inflammation) that helps our body resolve an infection.
Both sets of researchers took advantage of AIM2-/- knockout mice to elucidate the role of AIM2 in innate immunity to cytosolic pathogens. First off, Rathinam and colleagues generated and bred mice that were deficient in AIM2. By comparing macrophages from AIM2-/- mice to macrophages from mice that expressed AIM2 they showed that AIM2 senses dsDNA in the host cell cytosol and is essential for the activation of the inflammasome—AIM2 was important for the caspase 1-dependent maturation of inflammatory cytokines (IL-1β and IL-18) and for regulating pyroptosis. The scientists then focused their efforts on whether AIM2 was important for the inflammatory response to microbial pathogens. Loss of AIM2 led to loss of inflammasome activation; macrophages lacking AIM2 had reduced caspase-1 activation and IL-1β in response to a number of intracellular microbes including Francisella tularensis, the vaccinia virus and the mouse cytomegalovirus. Finally, they showed in vivo that AIM2 was essential for the early control of cytomegalovirus infection in mice. This AIM-2 dependent response led to the production of IL-18 and natural killer cell-dependent production of IFNγ, which successfully decreased the viral load AIM+/+ mice.
Fernandes-Alnemri and colleagues focused their research efforts on understanding the importance of AIM2 in the innate immunity to a specific pathogen—Francisella tularensis, a highly infectious bacterium that causes tularemia, a disease that is high up on the biological warfare list. Again the researchers generated and bred AIM2-/- knockout mice and found that AIM2 was important for detecting cytosolic DNA and activating caspase-1 and inflammasome production. When comparing AIM2-/- and AIM2+/+ macrophages, the investigators found that AIM2 was required for sensing F. tularensis and subsequent activation of caspase-1 and proinflammatory responses, including IL-1β production and induction of pyroptotic cell death. On a mechanistic level, they found that activation of the AIM2 inflammasome by F. tularensis required depleted intracellular postassium levels, lysosomal acidification and IRF3 signalling (an intact type I interferon response). Finally, the scientists showed that AIM2-deficient mice were overwhelmed by infection with F. tularensis; all AIM2-/- mice infected with F. tularensis were dead 5 days after they were infected with the bacteria whilst 77% of wild-type mice were still alive at this timepoint and in fact 66% of AIM2+/+ mice survived for more than 20 days after F. tularensis infection. Moreover, mice lacking AIM2 had a higher bacterial burden in both their liver and spleen, and decreased serum levels of IL-18, compared with wild-type mice.
Both Rathinam et al. and Fernandes-Alnemri et al. conclude that AIM2 has an important role in the innate immune response to intracellular pathogens, and that future research on the AIM2 inflammasome could determine whether it also has a role in nucleic-acid dependent autoinflammatory and autoimmune diseases such as systemic lupus erythematosus.
Rathinam, V., Jiang, Z., Waggoner, S., Sharma, S., Cole, L., Waggoner, L., Vanaja, S., Monks, B., Ganesan, S., Latz, E., Hornung, V., Vogel, S., Szomolanyi-Tsuda, E., & Fitzgerald, K. (2010). The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses Nature Immunology DOI: 10.1038/ni.1864
Fernandes-Alnemri, T., Yu, J., Juliana, C., Solorzano, L., Kang, S., Wu, J., Datta, P., McCormick, M., Huang, L., McDermott, E., Eisenlohr, L., Landel, C., & Alnemri, E. (2010). The AIM2 inflammasome is critical for innate immunity to Francisella tularensis Nature Immunology DOI: 10.1038/ni.1859