BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 249, 432–437 (1998) ARTICLE NO. RC989173 Expression of Human Complement Regulatory Protein CD46 Restricts Measles Virus Replication in Mouse Macrophages Jennifer Korte-Sarfaty, Vinh Dang Pham, Stephen Yant, Akiko Hirano, and Timothy C. Wong 1 Department of Microbiology, University of Washington School of Medicine, Seattle, Washington 98195 Received July 11, 1998 pression of production of interleukein-12 (IL-12), a mo- Measles virus (MV) can infect mouse macrophages to nokine essential for activating T helper 1 and natural cause a prolonged non-cytopathic infection that pro- killer cells (8, 18). Ligation of macrophage receptors duces low levels of infectious virus for days. We have including the receptor for MV reproduces the suppres- generated RAW264.7 mouse macrophages expressing hu- sion on IL-12 production (18, 33). These observations man CD46, a cell surface complement regulatory protein suggest that interactions between MV and cellular re- that serves as a receptor for laboratory-adapted strains ceptors play a role in MV-induced immunosuppression. of MV. Laboratory-adapted MV strains efficiently enter The human cell receptor for laboratory-adapted the CD46-positive mouse macrophages to cause a cyto- strains of MV is membrane cofactor protein (CD46), a pathic infection with extensive multinucleated cells and transmembrane complement regulatory protein widely pseudopodia-like extensions. However, MV infection of expressed on nucleated human cells (5, 25). CD46 nor- mouse macrophages through CD46 is self-limiting. Both mally protects autologous cells from complement lysis viral protein synthesis and infectious virus production by binding and promoting degradation of C3b and C4b are abruptly terminated after the second day of infec- in the complement activation cascades (21, 32). The tion. This novel virus–cell interaction is seen only in extracellular portion of CD46 contains binding sites mouse macrophages but not in mouse or hamster fibro- blasts expressing human CD46. The possible role of CD46 for C3b, C4b as well as MV (17, 22). The intracellular in macrophage antiviral response restricting MV repli- portion of CD46 consists of a common juxtamembrane cation is discussed.  1998 Academic Press region followed by alternative distal cytoplasmic se- quences called Cyt1 and Cyt2 that are generated by differential mRNA splicing (26, 27). We have pre- viously shown that the CD46 cytoplasmic domains can Monocytes and macrophages are major targets for the interact with cellular kinases in mouse macrophage measles virus (MV) in measles patients (6). These cells lysates (37). Tyrosine-containing sequences in these cy- serve important roles in innate immune responses. Along toplasmic domains apparently influence surface ex- with dendritic cells, macrophages also process antigens pression of CD46 as well as interaction with macro- and instruct lymphocytes to mount adaptive immune re- phage kinases in vitro (37, 39). We have generated sponses (7, 23). Recent evidence indicates that MV inter- mouse macrophages (RAW264.7) expressing human feres with the communication of macrophages and den- CD46 with a Cyt1 or Cyt2 cytoplasmic domain. Here, dritic cells with lymphocytes, thus disrupting a critical we demonstrate that MV can infect mouse macro- cross talk between the innate and adaptive arms of the phages through CD46-independent or CD46-dependent immune system (8, 11, 18, 31). Immune suppression lead- pathways with different outcomes. MV infection of ing to secondary infections is believed to be a major cause mouse macrophages without CD46 causes a prolonged of death in measles patients (3, 10, 24). non-cytopathic infection. By contrast, MV infection of MV-infected cells can suppress proliferation of unin- mouse macrophages through CD46 leads to a cyto- fected peripheral blood mononuclear cells (PBMC) pathic but self-limiting infection, due to drastic sup- through cell contact (28, 29). MV infection of mono- pression of viral protein synthesis and infectious virus cytes, macrophages, and dendritic cells leads to sup- production after the second day of infection. MATERIALS AND METHODS Cells and viruses. Mouse macrophages expressing human CD46 1 To whom correspondence should be addressed. Fax: (206)543- 8297. E-mail: timwong@u.washington.edu. were generated by electroporation of RAW264.7 cells with pME18S- 0006-291X/98 $25.00 Copyright  1998 by Academic Press All rights of reproduction in any form reserved. 432