Self vs non-Self Recognition and Nucleic Acid Sensing
The RIG-I-like receptors (RLRs) are double-stranded RNA binding proteins that play a role in initiating and modulating cell intrinsic immunity through the recognition of RNA features typically absent from the host transcriptome. The RLRs are best characterized as an innate restriction mechanism of RNA virus infection. Interestingly, however, we and others have described the RLRs as prominent restriction factors for DNA virus infection. Moreover, recently my laboratory has discovered an intricate relationship between defective noncoding RNA processing and RLR activation. Our studies have resulted in a paradigm shift whereby it is now appreciated that an antiviral innate immune response can be elicited by the sensing of misprocessed cellular RNAs. Our current studies are defining novel mechanisms and pathways regulating RLR activation. These findings have important implications for intrinsic immune responses to pathogens as well as provide insight into how the RLRs can be leveraged to enhance antitumor responses.
RNA Modifications
To date, there are over a 170 known RNA modifications. The biological function of RNA modifications can be best stated as an optimization of RNA structure and function. We are are interested in the functional significance of RNA modifications in viral lifecycles as well as in cancer progression. Ongoing studies in the lab have comprehensively categorized and mapped locations for several modifications in the genomes of both DNA and RNA viruses. Moreover, studies have identified modifications that are important for viral gene expression, pathogenesis, and immune activation and evasion.
Function of Viral Noncoding RNAs
It has become increasingly apparent that viruses, much like the cells they infect, utilize noncoding RNAs in their gene regulatory systems. In fact, many of the species of noncoding RNA that are encoded in the human genome can also be found in viruses, including transfer RNAs (tRNA), small nucleolar RNAs (snoRNAs), microRNAs (miRNAs), and long noncoding RNAs (lncRNAs); γHVs produce all of these, and in many cases their functional relevance to pathogenesis is unknown. We are employing novel biochemical purification and sequencing strategies aimed at characterizing γHV noncoding RNAs and their role in pathogenesis. These studies are revealing unanticipated roles for viral-derived noncoding RNAs in the regulation of gene expression.
Viral Co-Option of Mobile Genetic Elements
Approximately 50% of the human genome is comprised of repetitive elements. By far, the largest fraction of repetitive DNA is contributed by transposons (45% of the genome). While in healthy somatic cells transposon expression is typically silenced, under conditions of stress, such as viral infection, transposon expression is robustly induced. We previously demonstrated that Short Interspersed Nuclear Elements (SINEs), a family of transposons that occupy ~10 of the mammalian genome, our robustly induced during gammaherpesviral infection and stimulate the activation of the cell-intrinsic innate immune system. We are continuing this work by addressing the role of other transposon families in gammaherpesviral pathogenesis.