Measles virus (MV) infection causes 900,000 deaths per year due to the induction of severe immune suppression which is characterized by high susceptibility towards secondary (often bacterial) infections. Our long term goal is to elucidate the regulatory mechanisms controlling induction of immune suppression by measles virus as a necessary requisite to devise protocols for therapeutic intervention. In humans, 2 different receptor molecules are used by vaccine and wildtype virus. Vaccine virus can use both human CD46 and CD 150, infect lymphoid and fibroblast cell lines and is restricted in its in vivo replication. Wildtype virus uses human CD 150, only, replicates in lymphoid cell lines and is widely disseminated in patients. It is thought that the difference in receptor usage accounts for the difference in dissemination and immune suppression between vaccine and wildtype virus. We use the cotton rat model to study measles virus pathogenesis. In cotton rats, the dual receptor usage seen on human cells is reflected in infection of cotton rat cell lines. Vaccine virus can infect both fibroblast and lymphoid cell lines; wildtype virus infects lymphoid cell lines, only. After intranasal infection with wildtype virus widespread dissemination and immune suppression is seen. In contrast, vaccine virus infection is restricted to lung tissue. Based on this data, we hypothesize that in cotton rats analogs to human CD 150 and human CD46 function as measles virus receptors. We propose to characterize these receptor molecules by using techniques which have successfully been employed in the cloning and sequencing of the human receptor molecules. We will make use of a newly generated cDNA library and rely on our experience in using retroviral vectors and the production of monoclonal antibodies. With cloned receptor molecules and antibodies specific for them we will be able to analyze how the MV receptor distribution in vivo determines dissemination of virus, define the role of the MV hemagglutinin (the receptor-binding protein) as a virulence factor and address the role of MV receptors in immune suppression. ? ? ?
| Carsillo, Thomas; Huey, Devra; Levinsky, Amy et al. (2014) Cotton rat (Sigmodon hispidus) signaling lymphocyte activation molecule (CD150) is an entry receptor for measles virus. PLoS One 9:e110120 |
