As a pediatrician with a background in cell biology and infectious diseases, my interest in the host-pathogen interaction has been longstanding. The development of new therapeutic modalities that will ultimately lead to improvements in healthcare is dependent on the continued investment in well-designed biomedical research. Tissue-specific expression of viral receptor molecules is an important determinant of viral tropism. Group B coxsackieviruses and many adenoviruses initiate infection by binding to the coxsackievirus and adenovirus receptor (CAR). We believe that detailed understanding of virus entry and its relation to virus tropism will require us to understand the biology of viral receptors- including their subcellular localization, their intracellular trafficking, and their interactions with other proteins that may function in virus entry, or restrict receptor accessibility to virus. This belief is grounded in the recent unexpected observation that, despite CAR expression on respiratory epithelial cells, intact respiratory epithelium is impervious to adenovirus entry. Our collaborators and we have found that in well-differentiated epithelium, signals within the CAR cytoplasmic domain target receptor expression to the basolateral cell surface, where it is inaccessible to virus. CAR's primary biologic function remains uncertain, and its cell biology remains poorly understood. We have found that CAR localizes to intercellular contacts where it may be involved in adhesion, intercellular recognition, or contact-dependent signaling. In polarized epithelium, CAR is expressed at the tight junction--a specific epithelial structure regulating paracellular transport of molecules and inflammatory cells--in association with the protein ZO-l. The recently identified reovirus receptor is also a tight junction component, raising questions about why three unrelated virus groups, all of which traverse epithelial surfaces in the course of infection, have evolved to interact with molecules that may be sequestered in intercellular contacts. The experiments outlined below will define CAR's function in virus infection of epithelial cells, and its contribution to the formation and structure of the epithelial tight junction.