Research

In the Stetson Lab, we study innate immune detection of nucleic acids. All living organisms employ sophisticated antiviral defense systems that use sensors of foreign nucleic acids. We study these sensors, how they are activated, how they are regulated, how they organize protective immunity to virus infection, how we can trigger them with better immunotherapies for cancer and vaccines, and how we can treat human diseases caused by inappropriate activation of these pathways.

Current research projects in the lab include:

A STING-independent DNA sensing pathway in humans

We have discovered that humans – but not laboratory mice – have a second, potent, STING-independent DNA sensing pathway (SIDSP). We identified the DNA damage response kinase DNA-PK as the sensor of the SIDSP, and we showed that human DNA-PK has two modalities of activation: one triggered by DNA damage and one triggered by foreign DNA. Ongoing work on the SIDSP includes the characterization of the two modalities of DNA-PK, exploring its role in antiviral responses and human autoimmune diseases, and developing new ways to specifically trigger it in tumors for therapeutic benefit.

Regulation and function of nuclear cGAS

We have found that cGAS, long thought to be exclusively a cytosolic protein, is in fact predominantly a nuclear protein that is tightly tethered to chromatin (BioRxiv 486118). We are studying how nuclear tethering prevents activation of cGAS by self-DNA, what is holding cGAS in place, and how cGAS is remodeled upon activation by foreign DNA.

The relationship between ADAR1 RNA editing and MDA5-dependent antiviral responses

ADAR1 is an RNA editing enzyme that converts adenosines to inosines in RNA. Loss of function mutations in the human gene that encodes ADAR1 cause a number of severe inflammatory diseases that are driven by inappropriate activation of MDA5. We are exploring the nature of the RNA ligands of MDA5 that are edited by ADAR1, and we are developing new mouse models of ADAR1 mutation that more closely resemble the human diseases.

Regulation of cGAMP metabolism and transport

We are studying how the cyclic GMP-AMP (cGAMP) product of cGAS is regulated through enzymatic degradation, and how cGAMP moves from cell to cell.

New mechanisms of interferon regulation

Inappropriate production of type I interferons (IFNs) is associated with numerous rare and common human autoimmune diseases, including Aicardi-Goutieres Syndrome, Lupus, Sjogrens Syndrome, and Systemic Sclerosis. Although several key regulators of the IFN response have been identified, we propose that the landscape of IFN regulation is far from complete. We have developed new mouse models and tools to enable the identification of novel regulators of the IFN response.

Merging innate immunity and protein engineering to develop new therapies

In an exciting collaboration with the labs of Neil King and David Baker at the UW Institute for Protein design, we are using protein engineering to manipulate innate immune pathways to make better vaccines and create new treatments for cancer.