The aim of this project is to define the molecular mechanisms by which blood leukocytes migrate to specific tissue sites that are inflamed or infected. We have focused on chemoattractant proteins that mediate this process and have identified members of a large family of chemoattractant receptors that are deployed on the leukocyte cell surface. We have also identified members of a diverse group of chemoattractant and chemoattractant receptor mimics made by viruses, including herpesviruses, poxviruses and HIV. We use genomics, molecular biology, cell biology and epidemiology, and collaborations with virologists, as the principle methods for analyzing these molecules. A major question addressed in previous years and continued in FY2004 is to identify specific disease associations of individual chemoattractant and chemoattractant receptors, in order to identify potential new therapeutic targets. In this regard, we have studied a mouse model of SARS-CoV virus pulmonary infection in which the virus localizes to some bonchi and bronchioles, but not alveoli, and replicates transiently to high titers. Viral replication induces intense but transient production of a subset of inflammatory chemokines in the lung, without much leukocyte accumulation. The virus spreads beyond the respiratory tract to multiple other organs, particularly the brain, but again in these organs there is little inflammation, and no obvious clinical disease save a subtle relative failure to thrive. The significance of this work is that it provides a mouse model of subclinical SARS-CoV infection, identifies a role for other factors in potentiating the leukocyte migration activity of chemokines in vivo, and suggests a potential role for specific inflammatory chemokines in SARS-CoV clearance in this model. In an unrelated published finding coming from this project, we have reported that simian cytomegalovirus has five ORFs that encode distinct chemokine receptor homologues. This represents an astounding 3% of the genome of this virus that is devoted to these types of molecules and suggests an important role for molecular piracy/mimicry in its life cycle. To date we have defined the evolutionary history of these ORFs and have been able to express them as proteins on the surface of mammalian cells, but we have not yet defined putative ligands and functions.
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