TLR-9 contributes to the antiviral innate immune sensing of rodent parvoviruses MVMp and H-1PV by normal human immune cells

• Published in: PloS one Vol. 8; no. 1; p. e55086
• Main Authors: Raykov, Zahari, Grekova, Svitlana P, Hörlein, Rita, Leuchs, Barbara, Giese, Thomas, Giese, Nathalia A, Rommelaere, Jean, Zawatzky, Rainer, Daeffler, Laurent
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.01.2013; Public Library of Science (PLoS)
• Subjects: Analysis; Animal models; Animals; Biology; Cancer; Cell culture; Cell cycle; Cell Line, Tumor; Cell proliferation; Cell Transformation, Viral - immunology; Cells (Biology); Cytokines; Defects; Dendritic cells; Deoxyribonucleic acid; Diabetes; DNA; Gene expression; Gene therapy; Genome, Viral - genetics; Genomes; Genomics; Health aspects; HEK293 Cells; Herpes viruses; Homology; Humans; Immune system; Immunity, Innate; Infections; Interferon; Interferon Type I - metabolism; Leukocytes (mononuclear); Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - virology; Medical research; Mice; Minute Virus of Mice - genetics; Minute Virus of Mice - physiology; Multiplication; Neutralization; Parvoviruses; Pattern recognition; Pattern recognition receptors; Peripheral blood mononuclear cells; Polypeptides; Rats; Rodents; Signal Transduction - immunology; TLR9 protein; Toll-Like Receptor 9 - metabolism; Toll-like receptors; Transcription factors; Transformed cells; Tumor cells; Viral infections; Viruses; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0055086

The oncotropism of Minute Virus of Mice (MVMp) is partially related to the stimulation of an antiviral response mediated by type-I interferons (IFNs) in normal but not in transformed mouse cells. The present work was undertaken to assess whether the oncotropism displayed against human cells by MVMp and its rat homolog H-1PV also depends on antiviral mechanisms and to identify the pattern recognition receptor (PRR) involved. Despite their low proliferation rate which represents a drawback for parvovirus multiplication, we used human peripheral blood mononuclear cells (hPBMCs) as normal model specifically because all known PRRs are functional in this mixed cell population and moreover because some of its subsets are among the main IFN producers upon infections in mammals. Human transformed models consisted in lines and tumor cells more or less permissive to both parvoviruses. Our results show that irrespective of their permissiveness, transformed cells do not produce IFNs nor develop an antiviral response upon parvovirus infection. However, MVMp- or H-1PV-infected hPBMCs trigger such defense mechanisms despite an absence of parvovirus replication and protein expression, pointing to the viral genome as the activating element. Substantial reduction of an inhibitory oligodeoxynucleotide (iODN) of the latter IFN production identified TLR-9 as a potential PRR for parvoviruses in hPBMCs. However, neither the iODN treatment nor an antibody-induced neutralization of the IFN-triggered effects restored parvovirus multiplication in these cells as expected by their weak proliferation in culture. Finally, given that a TLR-9 activation could also not be observed in parvovirus-infected human lines reported to be endowed with a functional TLR-9 pathway (Namalwa, Raji, and HEK293-TLR9(+/+)), our data suggest that transformed human cells do not sense MVMp or H-1PV either because of an absence of PRR expression or an intrinsic, or virus-driven defect in the endosomal sensing of the parvovirus genomes by TLR-9.