The Pathogenesis of Kawasaki Disease

Kawasaki Disease (KD) is an infectious disease of unknown etiology that can be difficult to diagnose and can lead to lifelong heart disease or death from coronary artery aneurysms in previously healthy children. KD is the leading cause of acquired heart disease in children in developed nations. Our recent study of arterial pathology in 41 KD patients identified three linked vasculopathic processes: 1) necrotizing arteritis, which appeared consistent with an innate immune response to a virus and was complete by week two; 2) subacute/chronic vasculitis, which was composed of lymphocytes and plasma cells, was consistent with an acquired immune response, persisted for years, and was closely associated with the third process; and 3) luminal myofibroblastic proliferation, a unique smooth muscle cell-derived myofibroblastic proliferative process that was observed in all arteries throughout the body and could lead to progressive arterial stenosis. It is likely that markers of coronary artery damage are present in acute KD sera as a result of these processes, which could serve as urgently needed biomarkers of diagnosis and/or prognosis. In this study, dysregulated mRNA and microRNA gene expression in acute KD coronary arteries will be identified and the corresponding secreted proteins and microRNAs tested as potential serum diagnostic/prognostic biomarkers (aims 1 and 2). In addition, we have identified RNA-containing intracytoplasmic inclusion bodies with closely associated virus-like particles using a synthetic antibody derived from the KD arterial IgA response. We hypothesize that KD results from a “new” persistent RNA virus with limited homology to known viruses that enters via the respiratory tract, infects and forms intracytoplasmic inclusion bodies in ciliated bronchial epithelium, enters the circulation in macrophages, and infects target tissues such as the coronary arteries. We have identified promising candidate sequences of this virus by high-throughput sequencing of multiple KD and control tissues; we will extend these sequences, determine their presence in additional KD and control patients, and test for seroconversion to encoded proteins in KD patients (aim 3). These studies are aimed at identifying candidate serum diagnostic/prognostic biomarkers and viral sequences of the putative etiologic agent. The project will increase knowledge of the molecular pathogenesis of KD vasculopathy. Discovery of the etiologic agent of KD would revolutionize the diagnosis and treatment of this potentially fatal illness of childhood, and ultimately allow for prevention.