Specialized functions of endogenous retroviruses in innate immune cells

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The overarching goal of my research program is to understand how the persistent interaction between viruses or viral elements and components of the immune system shapes basic immune functions. My main focus is on viral sequences called endogenous retroviruses (ERVs), which have largely been ignored as "junk DNA." In 2001, the first human genome sequence was released, and it revealed that 8% of the human genome is made up of ERVs. Yet how ERVs impact our biology and our immune system remains largely unknown. My research program seeks to discover fundamental functions of ERVs in immunity, and the outcomes of our research could greatly impact our understanding of the immune system. ERVs originated from integration of exogenous retrovirus genomes into the host genome that became fixed in the germ line. ERV sequences vastly outnumber coding genes across eukaryotes. In humans, most of these were stably inherited through millions of years of evolution in the primate lineage, and ERV sequences constitute 8% of the genome versus 2% of the genome that is protein-coding. The major function of ERVs is gene regulation through their long terminal repeat (LTR) promoter sequences. However, the physiological functions of the ERVs that have retained a proviral sequence consisting of protein-coding potential are largely unknown and understudied. Moreover, there is a fundamental gap in our understanding of the basic functions of ERVs and their protein products in immunity. We propose to identify cellular interacting partners of ERV proteins in immune cells to inform us of their functionality. Neutrophils are the most abundant innate immune cell subset in the blood and are the first responders to tissue damage, viruses, bacteria, and toxins. The effector functions of neutrophils are highly conserved in vertebrates and invertebrates. Neutrophils are wired to interact with and respond to viruses including retroviruses, and a number of cellular proteins may interact with proteins derived from ERVs. We will use neutrophils as a focal point to uncover novel interactions between ERVs and components of the immune system to determine their functions. My lab will test the hypothesis that ERV proteins regulate basic innate immune functions through conserved interactions with cellular proteins. To test this, we will apply cutting-edge technologies towards three objectives (Objs.): Obj. 1: Use ribosome sequencing to comprehensively identify ERV-encoded proteins in neutrophils. Obj. 2: Map the ERV interactome between ERV proteins and cellular proteins in neutrophils. Obj. 3: Determine the role of ERVs in neutrophil function in vivo. Our work will yield novel insights into the physiological roles of viral sequences that have been largely ignored and expand our knowledge of the immune system, and in parallel, broadly impact many fields including virology, evolutionary biology, and genomics.