Despite generally successful vaccination efforts, measles virus (MV) remains a leading cause of preventable illness and death, causing an estimated 30 million acute infections that result in ~150-200,000 deaths annually. The virus has a well-established propensity to invade the central nervous system (CNS) and develop an apparently noncytopathic, persistent infection within neurons, and some recent evidence suggests that persistence may occur in other organs as well. However, the factors that allow this otherwise highly cytopathic virus to persist remain unknown. MicroRNAs (miRs) are a class of ~22 nt long noncoding RNAs transcribed from the genomes of all multicellular organisms and some viruses. Specific miRs have been implicated in development, differentiation, proliferation, apoptosis, and oncogenesis, and individual miRs may regulate several hundred genes. In this proposal, the potential contribution of host-encoded miRs to the establishment and maintenance of persistent infections is explored using MV as a model system. The core hypothesis is that MV (which does not encode miRs) can nevertheless modulate the expression profile and levels of host cell- encoded miRs, thus regulating the expression of target genes with known immunomodulatory characteristics. Standard biological and bioinformatic tools will be used to determine the expression profile and levels of host- encoded miRs, and targets for candidate miRs will be identified and experimentally manipulated to identify mechanistic links between altered expression of cellular proteins and the status of the viral life cycle. Emphasis will be placed on genes within interferon signaling pathways (Aim 1), and those miRs that may directly bind to the viral genome (Aim 2). A more defined understanding of the interplay between MV and its host cell during noncytopathic infection may identify novel strategies to resolve chronic viral infections that contribute to human disease.
Despite increased attention to the potential role of chronic viral infections in human disease, little is known about the factors that favor establishment of noncytolytic infections. In this proposal, two collaborating investigators with complementary expertise will pursue preliminary efforts that found unique microRNA expression profiles associated with chronic measles virus infection in cell lines. The potential of these microRNAs to influence cellular gene expression, which in turn may foster a cellular environment conducive to viral persistence, will be explored.