Early innate recognition of herpes simplex virus in human primary macrophages is mediated via the MDA5/MAVS-dependent and MDA5/MAVS/RNA polymerase III-independent pathways

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  • Jesper Melchjorsen, Denmark
  • Johanna Rintahaka, Denmark
  • Stine Søby, Denmark
  • Kristy A Horan, Denmark
  • Alina Poltajainen, Denmark
  • Lars Østergaard
  • Søren R Paludan
  • Sampsa Matikainen, Denmark
  • The Department of Infectious Diseases
  • Department of Medical Microbiology and Immunology
  • Department of Molecular Biology
Innate recognition of viruses is mediated by pattern recognition receptors (PRRs) triggering expression of antiviral interferons (IFNs) and proinflammatory cytokines. In mice, Toll-like receptor 2 (TLR2) and TLR9 as well as intracellular nucleotide-sensing pathways have been shown to recognize herpes simplex virus (HSV). Here, we describe how human primary macrophages recognize early HSV infection via intracellular pathways. A number of inflammatory cytokines, IFNs, and IFN-stimulated genes were upregulated after HSV infection. We show that early recognition of HSV and induction of IFNs and inflammatory cytokines are independent of TLR2 and TLR9, since inhibition of TLR2 using TLR2 neutralizing antibodies did not affect virus-induced responses and the macrophages were unresponsive to TLR9 stimulation. Instead, HSV recognition involves intracellular recognition systems, since induction of tumor necrosis factor alpha (TNF-α) and IFNs was dependent on virus entry and replication. Importantly, expression of IFNs was strongly inhibited by small interfering RNA (siRNA) knockdown of MAVS, but this MAVS-dependent IFN induction occurred independently of the recently discovered polymerase III (Pol III)/RIG-I DNA sensing system. In contrast, induction of TNF-α was largely independent of MAVS, suggesting that induction of inflammatory cytokines during HSV infection proceeds via a novel pathway. Transfection with ODN2006, a broad inhibitor of intracellular nucleotide recognition, revealed that nucleotide-sensing systems are employed to induce both IFNs and TNF-α. Finally, using siRNA knockdown, we found that MDA5, but not RIG-I, was the primary mediator of HSV recognition. Thus, innate recognition of HSV by human primary macrophages occurs via two distinct intracellular nucleotide-sensing pathways responsible for induction of IFNs and inflammatory cytokine expression, respectively.
Original languageEnglish
JournalJournal of Virology
Volume84
Issue21
Pages (from-to)11350-8
Number of pages8
ISSN0022-538X
DOIs
Publication statusPublished - 2010

    Research areas

  • Adaptor Proteins, Signal Transducing, Cells, Cultured, Cytokines, DEAD-box RNA Helicases, Immunity, Innate, Interferons, Macrophages, RNA Polymerase III, Signal Transduction, Simplexvirus

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