Measles virus replication in lymphatic cells and organs of CD150 (SLAM) transgenic mice

doi:10.1073/pnas.0505945102

Measles virus replication in lymphatic cells and organs of CD150 (SLAM) transgenic mice

^*Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, ON, Canada M5C 2C8; ^†Ontario Cancer Institute, 620 University Avenue, Suite 706, Toronto, ON, Canada M5G 2C1; and ^‡Molecular Medicine Program, Mayo Clinic, and Virology and Gene Therapy, Mayo Clinic College of Medicine, Rochester, MN 55905

Edited by Bernard Moss, National Institutes of Health, Bethesda, MD (received for review July 15, 2005)

Abstract

A transgenic mouse containing the complete human SLAM (hSLAM/CD150) gene, including its endogenous promoter for transcription, was generated by using human genomic DNA cloned into a bacterial artificial chromosome. hSLAM, the primary receptor for measles viruses (MV), was expressed on activated B, T, and dendritic cells with an expression profile equivalent to that of humans. We demonstrated that hSLAM⁺ cells obtained from the transgenic mouse, including activated B, T, and dendritic cells, were susceptible to MV infection in a receptor-dependent manner. Evidence was provided for transient infection in the nasal lymph nodes of hSLAM⁺ mice after intranasal inoculation. Virus was rapidly cleared without signs of secondary replication. To improve the efficiency of MV production, the hSLAM⁺ mice were bred with mice having a Stat1-deficient background. These mice were more susceptible to MV infection and produced more virus particles. After intranasal and intraperitoneal inoculation of these mice with MV, infections of the thymus, spleen, nasal, mesenteric, and leg lymph nodes were detected. Upon necropsy, enlarged lymph nodes and spleen were apparent. Flow cytometric analysis showed that abnormally large numbers of mature neutrophils and natural killer cells caused the splenomegaly. The hSLAM transgenic mouse constitutes an improved rodent model for studying the interaction of MV with immune cells that more accurately reflects the infection pattern found in humans.

Footnotes

↵ § To whom correspondence should be sent at the † address. E-mail: chrisr{at}uhnres.utoronto.ca.
Author contributions: C.D.R. designed research; G.G.W., C.I., R.D., and J.B. performed research; J.B., J.S., S.V., and R.C. contributed new reagents/analytic tools; G.G.W., C.I., R.C., and C.D.R. analyzed data; and G.G.W. and C.D.R. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: BAC, bacterial artificial chromosome; DC, dendritic cells; i.n., intranasal(ly); MV, measles viruses; NK, natural killer; p.i., postinfection.