To defend against infection, our innate immune system needs to “sense” the invading pathogen, sound the alarm signals, and then engage a protective response to fight the threat. My lab studies innate immunity at these three levels: 1) at the level of detection, to understand how viruses such as HIV-1 are sensed by pattern recognition receptors, 2) at the level of signaling, to understand the transcriptional controls that underpin our defense systems, and 3) at the level of the response, to determine how host factors block infection. We are “question-driven” more so than “technique-driven,” and try to tackle important questions in virology, immunology, and gene delivery using a combination of classic and creative experimental approaches. Our lab has expertise in molecular virology, biochemistry, cell biology, imaging, gene editing, and systems biology tools (to harness -omics data). We strive to answer questions such as:

How is HIV-1 detected?

Innate immune responses during acute HIV‑1 infection are protective and exert strong selective pressure on the virus. However, dysregulated innate responses can exacerbate non-specific inflammation, increase target cell susceptibility, and contribute to HIV pathogenesis. Since we don’t fully understand how the innate immune response can shift from being protective to pathogenic over the course of infection, it’s critical that we gain a mechanistic understanding of how HIV‑1 is sensed by the innate immune system and how downstream responses are regulated. My lab uses forward genetic screens to identify cellular factors that are important for steps in the virus life cycle, innate immune sensing, signal transduction, and virus restriction. We also study the collateral damage that accompanies virus infection and its impact on innate immunity. Our goal is to gain mechanistic insight into how cellular components “sense” infection of HIV‑1 and other viruses.

How do cells “tune” innate immune responses?

Transcriptional regulation of innate immunity requires tight control. The system must maintain a sensitive response to infectious threats while avoiding unwanted inflammation and autoimmunity. When control is lost, errors in innate immunity can lead to many disorders including cancer, neurodegeneration, diabetes, autoimmune disease, and chronic virus infections. However, the mechanisms that “tune” innate immune signaling remain poorly understood (i.e. those that increase or decrease responses, or control expression of gene subsets). My lab studies how innate immune responses are regulated in several model systems, including primary human myeloid cells. We make genetic modifications of monocytes, dendritic cells, and macrophages using CRISPR and lentivirus technologies and then test how these modifications impact transcriptional control of antiviral signaling (such as type I interferon circuitry). We hope that our studies will illuminate new strategies to treat inflammatory disorders and combat infectious disease.