: Despite treatment programs, schistosomiasis remains a major public health problem on several continents (1). Experimental work using the mouse as a model for the definitive human host has revealed that disease severity is modulated by the nature of the immune response that develops during infection. Immunoepidemiological studies in areas endemic for schistosomiasis support this view. Typically, mice and humans respond to infection with a strong Th2 response that appears to be crucial for allowing the host to survive while infected. This proposal has two major goals. The first, addressed in Aims 1 and 2, is to begin to understand the underlying pathophysiology of infection. The second, targeted by aim 3, is to advance the understanding of Th2 response development through the study of a mouse strain (the CD 154-I- mouse) that has been found to be incapable of making a Th2 response during infection. The areas chosen for study reflect findings in the previous funding period and incorporate relevant and exciting new developments in the field.
The specific aims of the proposal are: 1) To assess the relative roles of NO and superoxide in disease development during infection, and to establish the immunological requirements for the production of these reactive species; 2) To establish the source and function of NO in vascular regulation during infection; 3) To investigate the role of CD 154 during infection.
These aims will be addressed using a variety of immunological, biochemical and molecular biological techniques, and will take full advantage of available gene knockout mice for the definitive assessment of the role of p47-phox (of the NADPH oxidase) and endothelial and inducible nitric oxide synthases during infection. Additionally, the development by cross-breeding of new mutant mouse strains carrying disruptions in IL-4IeNOS, IL-4/iNOS, and IL-4/p47-phox is proposed in order to establish the roles of NO and superoxide in the severe disease that develops in IL-4 deficient, Th2-response defective mice. In addition the contribution of parasite derived NO to the regulation of host responses will be addressed through the cloning and expression of the putative parasite NOS, the identification of an inhibitor capable of inhibiting this NOS, and the treatment of infected eNOS or iNOS or eNOS/iNOS knockout mice with the inhibitor. The development of the Th2 response, which is postulated to be crucial for the regulation of the production of NO and 0 during infection, will be examined from the novel approach of investigating the role of CD 154, the ligand for CD4O. The latter studies are expected to shed light on the precise role of B cells during infection, an important question that is unresolved at this time. The examination of these issues in detail should increase the understanding of: 1) the innate physiological response of the host to parasitism by schistosomes; 2) how the adaptive immune response integrates with and regulates the innate response; 3) how the immune response regulates itself, and 4) how the parasite intervenes to influence these processes.
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