Teresa Fernandes-Alnemri, PhD

The research in my lab focuses on the signaling pathways involved in caspase-1 activation and pro-inflammatory cytokine production by members of the NLR family including NLRP1, NLRP3, NLRC4, NOD1 & NOD2, and the interferon-induced protein AIM2 (absent in melanoma 2).

We are interested in how NLR proteins and other cytosolic danger sensors such as AIM2 can recognize microbial pathogen- and tissue damage-derived molecular danger signals, and assemble inflammasome complexes. These complexes serve as molecular platforms to recruit and activate procaspase-1 to produce the active caspase-1, which processes pro-IL-1² and pro-IL-18 into their corresponding mature pro-inflammatory cytokines, IL-1² and IL-18.

Although pro-inflammatory cytokine production is an innate immune response important for protection against infections with different pathogens, abnormal or chronic activation of the pro-inflammatory innate immune system could lead to a wide variety of digestive diseases such as Crohns disease and autoimmune disorders afflicting the kidney, like systemic lupus erythematosus. Chronic inflammatory responses have also been implicated in anemia of inflammation and chronic disease (AI/ACD). Some of the diseases that could lead to AI/ACD include rheumatoid arthritis, lupus, diabetes, heart failure, degenerative joint disease, kidney diseases, cancer and inflammatory bowel disease (IBD) including Crohn's disease.

We also recently demonstrated that the interferon-inducible AIM2 protein functions in cytosolic surveillance of cytoplasmic dsDNA, which is produced as a consequence of infection with viral and bacterial pathogens. Activation of the AIM2 inflammasome by binding to cytosolic dsDNA results in proinflammatory cytokine production. We have generated AIM2 knock out mice, and successfully used our model system to demonstrate that AIM2 is the innate sensor of pathological DNA complexes formed when cells are infected with dangerous pathogens like the 'rabbit fever' bacteria Francisella, and viruses such as the poxvirus Vaccinia.

Because activation of AIM2 by DNA triggers a strong inflammatory response, we are actively investigating whether the antibody-DNA complexes found in systemic lupus erythematosus (SLE) are in fact recognized by AIM2. Lupus nephritis, is an inflammatory renal disease that often results in kidney failure in SLE patients. Understanding the molecular pathways that modulate these inflammatory responses in lupus patients would be paramount to designing effective therapeutics.

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