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@ARTICLE{Angelova:275656,
      author       = {A. L. Angelova$^*$ and K. Pierrard$^*$ and C. N. Detje and
                      E. Santiago and A. Grewenig$^*$ and J. Nüesch$^*$ and U.
                      Kalinke and G. Ungerechts$^*$ and J. Rommelaere$^*$ and L.
                      Daeffler},
      title        = {{O}ncolytic {R}odent {P}rotoparvoviruses {E}vade a {TLR}-
                      and {RLR}-{I}ndependent {A}ntiviral {R}esponse in
                      {T}ransformed {C}ells.},
      journal      = {Pathogens},
      volume       = {12},
      number       = {4},
      issn         = {2076-0817},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2023-00844},
      pages        = {607},
      year         = {2023},
      note         = {#EA:F230#},
      abstract     = {The oncolytic rodent protoparvoviruses (PVs) minute virus
                      of mice (MVMp) and H-1 parvovirus (H-1PV) are promising
                      cancer viro-immunotherapy candidates capable of both
                      exhibiting direct oncolytic activities and inducing
                      anticancer immune responses (AIRs). Type-I interferon (IFN)
                      production is instrumental for the activation of an
                      efficient AIR. The present study aims at characterizing the
                      molecular mechanisms underlying PV modulation of IFN
                      induction in host cells. MVMp and H-1PV triggered IFN
                      production in semi-permissive normal mouse embryonic
                      fibroblasts (MEFs) and human peripheral blood mononuclear
                      cells (PBMCs), but not in permissive transformed/tumor
                      cells. IFN production triggered by MVMp in primary MEFs
                      required PV replication and was independent of the pattern
                      recognition receptors (PRRs) Toll-like (TLR) and RIG-like
                      (RLR) receptors. PV infection of (semi-)permissive cells,
                      whether transformed or not, led to nuclear translocation of
                      the transcription factors NFĸB and IRF3, hallmarks of PRR
                      signaling activation. Further evidence showed that PV
                      replication in (semi-)permissive cells resulted in nuclear
                      accumulation of dsRNAs capable of activating mitochondrial
                      antiviral signaling (MAVS)-dependent cytosolic RLR signaling
                      upon transfection into naïve cells. This PRR signaling was
                      aborted in PV-infected neoplastic cells, in which no IFN
                      production was detected. Furthermore, MEF immortalization
                      was sufficient to strongly reduce PV-induced IFN production.
                      Pre-infection of transformed/tumor but not of normal cells
                      with MVMp or H-1PV prevented IFN production by classical RLR
                      ligands. Altogether, our data indicate that natural rodent
                      PVs regulate the antiviral innate immune machinery in
                      infected host cells through a complex mechanism. In
                      particular, while rodent PV replication in (semi-)permissive
                      cells engages a TLR-/RLR-independent PRR pathway, in
                      transformed/tumor cells this process is arrested prior to
                      IFN production. This virus-triggered evasion mechanism
                      involves a viral factor(s), which exert(s) an inhibitory
                      action on IFN production, particularly in transformed/tumor
                      cells. These findings pave the way for the development of
                      second-generation PVs that are defective in this evasion
                      mechanism and therefore endowed with increased
                      immunostimulatory potential through their ability to induce
                      IFN production in infected tumor cells.},
      keywords     = {cancer cells (Other) / innate immune response (Other) /
                      innate immune response evasion mechanism (Other) / oncolytic
                      (Other) / parvovirus (Other) / type-I interferons (Other)},
      cin          = {F230 / F030 / F160 / F170},
      ddc          = {610},
      cid          = {I:(DE-He78)F230-20160331 / I:(DE-He78)F030-20160331 /
                      I:(DE-He78)F160-20160331 / I:(DE-He78)F170-20160331},
      pnm          = {316 - Infektionen, Entzündung und Krebs (POF4-316)},
      pid          = {G:(DE-HGF)POF4-316},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37111493},
      doi          = {10.3390/pathogens12040607},
      url          = {https://inrepo02.dkfz.de/record/275656},
}