Despite significant progress over 40 years, the pathogenesis of IgA nephropathy (IgAN) remains unknown. A majority (~60%) of patients with IgAN experience disease exacerbations associated with acute respiratory or gastrointestinal illness that appears to represent viral infection. The renal disease itself is considered to be a form of immune complex glomerulo- nephritis, but the identity of the antigen remains a source of controversy, and the mechanism(s) whereby the IgA-rich immune complexes deposit in the glomeruli and lead to glomerular dysfunction is/are unknown. Particularly, the specific receptor(s) responsible for IgA binding and the pathways that transduce such binding to cellular responses are poorly characterized. In experimental systems, challenge of immune mice with infectious virus, but not with non- infectious virus or viral products, leads to altered glomerular function. We hypothesize that innate immune responses to replication of viruses modulate, directly or indirectly, the capacity of glomeruli and mesangial cells to respond to binding of IgA immune complexes. This proposal focuses on glomerular responses to double-stranded (ds) RNA, an intermediate unique to viral infection that is distinct from other stimuli that are shared by noninfectious virus or viral products. Our Specific Objectives are to: 1. identify the key intracellular pathway whereby viral infection exacerbates or intensifies glomerular disease in vivo; 2. evaluate the contribution of the known sensor(s) of dsRNA to increase the key mesangial and podocyte responses to a defined load of IgA immune complexes in vitro; 3. elucidate the principal signal transduction pathway that mediates intensified cellular responses to IgA immune complexes after exposure to dsRNA and 4. determine whether dsRNA or viral infection promotes binding of IgA immune complexes via increased synthesis of IgA receptors. Overall, we will compare and contrast responses to IgA immune complexes between wild type mice or cells to those in mice or cells bearing targeted genetic deletions of selected transcriptional factors or receptors. This work will offer mechanistic insights to the genesis of IgAN, and perhaps to other virally-associated glomerulo- nephritis (e.g. that associated with hepatitis C infection). This work has a potential impact on Veterans' health care, because such mechanistic insights might guide development of novel therapeutic strategies for IgAN. IgAN is a common but currently poorly treatable chronic kidney disease that affects Veterans, especially males in their second and third decades of life. New therapies to treat IgAN can reduce morbidity, mortality and costs of treatment of this common cause of dialysis or renal transplantation in Veterans and non-Veterans alike. PUBLIC HEALTH RELEVANCE: Relevance to Veterans' Health This work will provide insight to the mechanisms of pathogenesis and progression of IgA nephropathy, a common form of glomerulonephritis that affects Veterans and leads (in ~30% of patients) to end stage renal disease. The disease is especially prevalent in males in the second and third decades of life, a population that is enriched among those returning from active military deployment. The chronic nature and progressive potential of a disease that initiates in young Veterans makes this topic highly relevant to the VA. Development of novel therapeutic strategies to treat IgA nephropathy, a disease for which no specific or established effective therapy now exists, can reduce morbidity, mortality and costs of treatment in Veterans and non-Veterans alike. For example, depending on the outcome of the experiments proposed herein, off label uses of recombinant interferon or IFNAR antagonists, both now used clinically for other conditions, might ultimately prove salutary for treatment of IgAN. Furthermore, given an increased prevalence of both hepatitis C and human immunodeficiency virus infections in our patient population, this work may be of even wider value to our Veterans.