Measles remains one of the most important causes of child morbidity and mortality worldwide with the greatest burden in the youngest children. Most measles deaths are due to secondary infections that result from a poorly understood measles-induced suppression of immune responses to other pathogens. Although infectious virus can no longer be recovered after the rash fades, measles virus (MV) RNA can be detected in respiratory secretions, urine and blood for several months and this persistence may be causally related to measles-induced immunosuppression. In addition to the risks of acute infection, children under the age of 2 yrs and immune-compromised (e.g. HIV-infected) children and adults are vulnerable to development of fatal progressive neurologic disease due to failure to clear virus and infection of the nervous system. Although gains have been made in measles control by implementing mass vaccination campaigns, these campaigns have been difficult to sustain. As a result, measles has again become widespread and deaths are predicted to continue to increase, rather than decrease, in the future. The only available "treatment" for measles is vitamin A. Vitamin A given during the acute phase of disease decreases mortality, but the mechanism for this protective effect is not known and many children do not receive this supplementation. An understanding of how vitamin A improves recovery from measles could result in more widespread use of this simple inexpensive intervention, more effective prevention of the severe complications of MV infection and perhaps identification of related treatments for measles or other childhood infections with high mortality in developing countries. There are no satisfactory small animal models for measles, but rhesus macaques are susceptible to wild type MV infection and develop a rash disease that faithfully mimics measles in humans, including prolonged suppression of lymphocyte proliferation. As in humans, MV RNA can be detected for several months after infection. Antibody and T cell responses appear during the rash. An understanding of the effect of vitamin A supplementation on measles will only come from studies of macaques because controlled studies in humans are not possible due to ethical considerations. We hypothesize that vitamin A improves the immune-mediated clearance of MV and shortens the period of immune suppression. Because the experimental effects of all trans-retinoic acid are to boost Th2, Treg and CD8+ T cell responses and to suppress Th1 and Th17 responses, we predict that vitamin A-supplemented monkeys will have improved antibody, CD8+ T cell and CD4+ Th2 responses to measles that will correlate with improved virus clearance and reduced immune suppression. We plan the following specific aims: (1) Determine the effect of supplemental vitamin A on clearance of infectious virus and viral RNA;(2) Identify the effect of supplemental vitamin A on MV-specific antibody and T cell responses after infection;(3) Determine whether supplemental vitamin A decreases the magnitude or duration of MV-induced suppression of lymphocyte proliferation.
Measles is one of the 10 most important causes of death due to infectious disease with the highest burden in the youngest children. This project will define how supplementation with vitamin A at the time of the measles rash provides protection from the complications of measles and decreases measles-associated mortality.