Virus infection of human cells induces rapid and dynamic gene expression that leads to the activation of downstream effector pathways that control virus replication, regulate cell death, and activate and educate subsequent innate and adaptive immune responses. Analysis of master antiviral transcription regulators IRF3 and NF?B, RNA Pol II, and Pol II-associated co-regulators before and after virus infection has revealed new features of the antiviral transcriptional response, leading to an overarching hypothesis that newly recognized virus-induced RNA products and auxiliary transcription regulators represent new aspects of antiviral immunity that have the potential to produce novel classes of antiviral therapies and diagnostic tools. These new transcription pathways will be examined in molecular detail to reveal their extent of inducibility by biomedically significant representative RNA and DNA viruses, specifically Sendai virus, influenza A virus, and herpes simplex virus. In addition their inducibility by innate antiviral signaling pathways and their potential functions in antiviral immunity will be determined.
Three specific aims will use molecular and biochemical experiments to complement virological approaches and RNA-sequencing analysis to investigate the expression patterns of novel virus-induced RNAs, to determine their structures, functions, and contributions to antiviral immunity. In addition, auxiliary transcription factors in the E-Box, ETS, and CREB families that were recognized as having a role in assisting antiviral master regulators will be analyzed to determine their contributions toward driving virus-induced transcription and antiviral responses. Together these studies will provide both a broad-based and focused analysis of a newly recognized but large pool of antiviral responders that has been previously overlooked, and will identify new functional and regulatory pathways for immune control of virus infections.
Viral diseases are a major biomedical concern worldwide, with broad implications in human health and welfare. The impact of viruses on human health is underscored by recent outbreaks of Ebola virus, MERS/SARS, and enterovirus, and is well known to those who suffer from recurrent herpesvirus infections, or become infected with seasonal or pandemic influenza viruses that these illnesses not only create discomfort and loss of life, but also exact a significant economic toll by generating work absences, increasing healthcare costs, and requiring the rapid activation of medical responses. This proposal is designed to investigate the function of newly identified antiviral gene regulatory pathways that, as a newly recognized branch of the immune response, has the potential to produce new antiviral therapies and diagnostic tools for emerging and established viral diseases.
