Abstract
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.
Highlights
Rodent parvoviruses MVMp and H-1PV are small, non-enveloped, single-stranded DNA viruses that replicate during the S-phase of the cell cycle within the host nucleus [1]
We show that upon rodent parvovirus infection, human peripheral blood mononuclear cells produce and release both IFN-a and -b molecules and show hallmarks of activation of an antiviral response whereas human transformed/tumor cells, being or not of immune origin, never showed such effects upon MVMp- or H1PV infection
peripheral blood mononuclear cells (PBMCs) were used here as normal cellular model since this cell mixture is composed among others of plasmacytoid dendritic cells known to represent the almost unique cell type in humans able to produce a large amount of type-I IFNs upon its infection [56,57,58] and because the whole repertoire of so far known pattern recognition receptor (PRR) is expressed in a functional state in this mixed cell population
Summary
Rodent parvoviruses MVMp (mouse) and H-1PV (rat) are small, non-enveloped, single-stranded (ss) DNA viruses that replicate during the S-phase of the cell cycle within the host nucleus [1]. Both viruses share around 86% DNA sequence homology. The viral genome contains two overlapping openreading frames encoding nonstructural regulatory polypeptides (NS1 and NS2) and capsid proteins (VP1 and VP2). Expression of the former polypeptides is regulated by the early P4 promoter whereas the VP expression is controlled by the NS1-inducible P38 promoter [2]. MVMp and H-1PV are, in contrast to AAVs, endowed with oncotropic and oncolytic properties making them attractive for the development of alternative anticancer therapies [5,6], while AAVs are classically used as vectors for gene therapy purposes [7]
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