The interaction between measles virus and its receptor, SLAM

At the outset of this thesis, our lab and two others reported that human SLAM (hSLAM) is a receptor for all strains of measles virus (MV) [78, 79, 81]. Since hSLAM is expressed on activated lymphocytes, macrophages and dendritic cells, and it seems to determine Th2 cytokine profiles in T cells, it was hypothesized that hSLAM is involved in the immunopathogenesis of MV infection. The focus of this thesis, therefore, was the interaction between MV and hSLAM and the role that this relationship has in MV infection and pathogenesis. Two separate approaches were undertaken in order to accomplish this goal. The first used biochemical techniques to analyze the interaction between the hemagglutinin protein of MV (MVH) and its binding partner, hSLAM. In Chapter 2, the method by which MV down regulates hSLAM was elucidated. It was determined that MVH inhibits hSLAM expression through two independent mechanisms and that both contribute to the complete removal of hSLAM from the surface of infected cells. In order to study the relevance of this type of interaction and others in vivo, we successfully generated a novel transgenic mouse model (Chapter 3). These mice expressed hSLAM in a human-like manner and lacked STAT1, a key transducer of interferon responses. In this mouse model, MV entry and replication was observed, which led to the enlargement of the lymph nodes and spleen of infected mice. Analysis of the cellular populations in the spleen revealed that infiltration by NK cells and mature neutrophils were the primary contributors to the increase in the size of the spleen. This observation has raised the possibility that these cell types play a critical role in MV clearance, a novel observation in the study of MV. Most importantly, this model will be useful for the study of fundamental immune responses and MV pathology.