Legionnaires' disease is a highly fatal pneumonia that occurs worldwide in both epidemic and endemic form. An estimated 100,000 cases occur annually in the United States. The causative bacterial agent, Legionella pneumophila, is an intracellular pathogen, and thus belongs to a group of human pathogens that are extremely important causes of morbidity and mortality worldwide. Previous studies from this laboratory have extensively explored the interaction of L. pneumophila with human mononuclear phagocytes and defined immune responses to this pathogen. These studies have indicated that cell-mediated immunity plays a dominant role in host defense against this organism. These studies have also advanced a novel hypothesis for a mechanism by which activated human monocytes inhibit the intracellular multiplication of L. pneumophila, i.e. by limiting the availability of intracellular iron. These studies have also demonstrated that activated monocytes down-regulate transferrin receptors. These studies have laid the foundation for further studies aimed at enhancing our understanding of the role of iron in L. pneumophila intracellular biology and in monocyte activation against this intracellular pathogen. Such studies should enhance our understanding of L. pneumophila-mononuclear phagocyte interaction and may ultimately provide new strategies for prevention and treatment of Legionnaires' disease and hopefully other diseases caused by intracellular pathogens.
Specific aims are to: A. Determine if iron-saturated transferrin enters the L. pneumophila phagosome in activated and nonactivated monocytes. B. Determine if apotransferrin enters the L.pneumophila phagosome. C. Determine the pathway that iron takes through the infected monocyte and the influence of activation on this pathway. D. Determine the levels of free iron and ferritin in activated and nonactivated monocytes. E. Determine if lactoferrin reverses the capacity of activated monocytes to inhibit L.pneumophila multiplication. F. Determine if a transferrin-independent iron delivery system can neutralize the capacity of activated monocytes to inhibit L.pneumophila multiplication. G. Determine if limiting iron availability in vivo protects the host against L.pneumophila infection.
