Cell type-specific MxA-mediated inhibition of measles virus transcription in human brain cells

Abstract

Measles virus (MV)-specific transcription in human brain cells is characterized by particularly low abundances of the distal mRNAs encoding the MV envelope proteins. Similar transcriptional restrictions of the closely related vesicular stomatitis virus have been observed in mouse fibroblasts constitutively expressing the interferon-inducible MxA protein (P. Staeheli and J. Pavlovic, J. Virol. 65:4498-4501, 1991). We found that MV infection of human brain cells is accompanied by rapid induction and high-level expression of endogenous MxA proteins. After stable transfection of MxA, human glioblastoma cells (U-87-MxA) released 50- to 100-fold less infectious virus and expression of viral proteins was highly restricted. The overall MV-specific transcription levels were reduced by up to 90%, accompanied by low relative frequencies of the distal MV-specific mRNAs. These restrictions were linked to an inhibition of viral RNA synthesis and not to a decreased stability of the viral RNAs. Our results indicate that expression of MxA is associated with transcriptional attenuation of MV in brain cells, thus probably contributing to the establishment of persistent MV central nervous system infections. In addition, the mechanism of MxA-dependent resistance against MV infection, in contrast to that of vesicular stomatitis virus, is cell type specific, because an inhibition of MV glycoprotein synthesis independent of transcriptional alterations was observed in MxA-transfected human monocytes (J. J. Schnorr, S. Schneider-Schaulies, A. Simon-Jödicke, J. Pavlovic, M. A. Horisberger, and V. ter Meulen, J. Virol. 67: 4760-4768, 1993).

Measles virus-induced promotion of dendritic cell maturation by soluble mediators does not overcome the immunosuppressive activity of viral glycoproteins on the cell surface

“…This could imply that insufficient amounts of IFN are produced to induce an anti-viral state in DC or, alternatively, that MV replication in DC is not as sensitive to IFN-mediated inhibition as compared to other cell types. As suggested by previous studies, the interference of at least MxA protein with MV replication is dependent on the host cell [28]. Type I IFN is known to contribute to differentiation of Mo-DC by enhancing the up-regulation of MHC class II, CD86 and CD80 molecules when added at the initiation of the culture [29][30][31].…”

Virus Demyelination

“…Inhibition of translation of virus transcripts in some cell types has also been described (Schneider-Schaulies et al, 1989, Ogura et al, 1987Miller and Carrigan, 1982;Yoshikawa and Yamanouchi, 1984). Interferon responses may be important and Mx protein is expressed in areas of infection in SSPE brains (Schneider-Schaulies et al, 1994.…”

Paramyxovirus Accessory Proteins as Interferon Antagonists

“…Activation of PKR and 2 '-5'OAS by dsRNA results in inhibition of translation of mRNA and extensive cleavage of single stranded RNA, respectively. Mx proteins interfere with growth of some viruses such as influenza virus (32,33,93,94), vesicular stomatitis virus (VSV) (94) and paramyxoviruses (103,130), by mechanisms which are not well understood. IFNs further augment cell-mediated immune response (7).…”