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I am perpetually intrigued by the interactions between pathogens and their hosts and I am particularly interested in understanding how cells are equipped to counteract viral infection. Broadly, my current research is focused on identifying and characterizing novel regulators of the intracellular antiviral response.
The vertebrate innate immune response is based on 1) the detection of molecular signatures associated with pathogens; 2) cytokine-based signaling to activate defense systems; and 3) initiation and regulation of these antimicrobial defenses. (See Figure 1)
My graduate research is specifically focused on identifying and characterizing novel regulatory controls over the cellular response to type I interferons, which are cytokines that activate a potent antiviral response program. I have identified novel transcriptional and post-transcriptional regulators of this response and am working to characterize the molecular mechanisms underlying their functions.
1) The RNA modification N6-methyladenosine promotes antiviral gene expression. RNA modifications include a number of chemical moieties that can be added to RNA, generally as transcription occurs. N6-methyladenosine (m6A) has recently emerged as an important regulator of RNA functions and has been shown to regulate cellular stress responses. To better understand the role of m6A at the virus-host interface, I explored its role in regulation of the response to type I interferons, which induce the transcription of interferon stimulated genes (ISGs). By mapping m6A in the interferon-induced transcriptome, I have discovered that m6A is present on the mRNAs of nearly 85% of ISGs. Additionally, I found that m6A promotes the translation of a subset of these ISGs, many of which encode antiviral effector proteins. Importantly, my research shows that m6A is required for the full potency of the antiviral effects of the type I interferon response, likely through its promotion of the production of antiviral effector proteins. Thus, m6A is an important contributor to the establishment of an antiviral cellular state in response to type I interferons.
2) The fat mass and obesity-associated protein FTO is a novel transcriptional suppressor of a subset of interferon-stimulated genes. The FTO gene is crucial for human health and certain mutations in this gene are associated with fat mass, obesity, and type II diabetes. Loss of function mutations cause severe impairments in development of the central nervous system and cardiac system, and are lethal. However, the molecular functions of FTO are not well understood, and the cellular processes that FTO exerts control over have not been completely characterized. Therefore, we do not yet understand how mutations in FTO lead to deleterious phenotypes. I have found that FTO suppresses the transcription of a subset of interferon-stimulated genes. In addition to their roles in antimicrobial responses, many of these genes also regulate inflammation, and I found that FTO suppresses the transcription of many proinflammatory genes. Future work will characterize the mechanisms by which FTO governs this subset of interferon-stimulated genes. This will contribute to our understanding of the molecular functions of FTO and how defects in the gene lead to disease phenotypes.
Figure 1: Intracellular Response to Viral Pathogens.
Cells are equipped with proteins called Pattern Recognition Receptors (PRRs) to detect molecular components of invading viruses. This initiates signaling cascades that activate Transcription Factors (TF) to activate the production of cytokines, like interferons (IFN), which are secreted and serve as signals to activate antiviral responses. Type I IFNs are detected and elicit potent antiviral responses and inflammatory responses. Type I IFNs activate the JAK-STAT signaling pathway and result in the production of interferon-stimulated genes (ISGs), many of which encode antiviral effector proteins that restrict viral processes.
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