Measles virus (MV) is an important pathogen that remains a worldwide health problem both in developing countries as well as in the United States and Europe. MV causes approximately 1.5 to 2 million deaths per year, primarily in children under 5 years of age. One of the characteristics of measles virus infections is prolonged abnormalities of cell-mediated immunity (CMI) which results in immunosuppression and is thought to contribute to the increased susceptibility to secondary infections which is primarily responsible for most of the morbidity and mortality of the disease. The underlying mechanism(s) responsible for this immunosuppression is not known. Interleukin 12 (IL-12) is an important regulator of the cell-mediated response which is produced primarily by monocytes/macrophages. It has been shown that in vitro infection of monocytes with MV specifically downregulates production of IL-12. Similar effects on IL-12 production are seen when CD46, a complement regulatory protein and the cellular receptor for MV, is crosslinked either by antibody, polymerized C3b (an endogenous complement ligand for CD46), or with transiently expressed MV hemagglutinin. These finding provide a plausible mechanism for the MV-induced suppression of CMI. This proposal will test the hypothesis that the utilization of CD46 by MV results in suppression of CMI through the inhibition of IL-12 production. The goals are to define the mechanism(s) of CD46-mediated suppression of IL-12 production, and to characterize IL-12 responses in perpherial blood mononuclear cells from patients with measles.
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