Pilot Award Recipient: David Leitenberg, MD, PhD

Infection with Toxoplasma gondii can cause significant morbidity and mortality in patients with HIV/AIDS-associated immunosuppression. As factors that regulate immune cell function are becoming increasingly well defined, there is considerable potential for the development of novel approaches to augment immune system function in immunodeficient HIV patients. Attractive targets for these therapeutic approaches are molecules that regulate immune cell receptors that detect signals from the environment and translate that information into patterns of gene transcription that regulate the development of both beneficial and harmful immune and inflammatory responses. The CD45 protein tyrosine phosphatase is the predominant transmembrane tyrosine phosphatase in all leukocytes and plays a critical role in both positively and negatively regulating many of these signaling events mediated by immune cell receptors. Over the last 15 years, my laboratory has largely focused on the role and regulation of CD45 in the regulation of antigen receptor signaling in T lymphocytes. Using biochemical, genetic and cell biology-based approaches we have helped to define the role of CD45 in regulating specific aspects of T lymphocyte activation and development and identified important factors that regulate CD45 activity. In order to develop new research areas relevant to HIV/AIDs, we are beginning to evaluate the role of CD45 in chronic infectious disease settings, and have recently developed a collaboration with Dr. Imtiaz Khan in the Department of Microbiology, Immunology and Tropical Medicine at the George Washington University, who is an internationally recognized expert on the host-immune response to Toxoplasma gondii infection. The main goal of this project is to develop preliminary data that characterize the changes in immune responses during the acute and chronic phases of the immune response to Toxoplasma in mice that express decreased levels of CD45. Then, using adoptive transfer approaches, we will determine how changes in CD45 activity affect specific aspects of innate and adaptive immune cell function, and identify the critical factors affected by CD45 that promote disease protection from Toxoplasma.