Abstract
BackgroundToll-like receptors (TLRs) play a crucial role in the activation of innate immunity in response to many viruses. We previously reported the implication of TLR2 in the recognition of Epstein-Barr virus (EBV) by human monocytes. Because murine gammaherpesvirus-68 (MHV-68) is a useful model to study human gammaherpesvirus pathogenesis in vivo, we evaluated the importance of mouse TLR2 in the recognition of MHV-68.Methodology/Principal FindingsIn studies using transfected HEK293 cells, MHV-68 lead to the activation of NF-κB reporter through TLR2. In addition, production of interleukin-6 (IL-6) and interferon-α (IFN-α) upon MHV-68 stimulation was reduced in murine embryonic fibroblasts (MEFs) derived from TLR2−/− and MyD88−/− mice as compared to their wild type (WT) counterpart. In transgenic mice expressing a luciferase reporter gene under the control of the mTLR2 promoter, MHV-68 challenge activated TLR2 transcription. Increased expression levels of TLR2 on blood granulocytes (CD115−Gr1+) and inflammatory monocytes (CD115+Gr1+), which mobilized to the lungs upon infection with MHV-68, was also confirmed by flow cytometry. Finally, TLR2 or MyD88 deficiency was associated with decreased IL-6 and type 1 IFN production as well as increased viral burden during short-term challenges with MHV-68.Conclusions/SignificanceTLR2 contributes to the production of inflammatory cytokines and type 1 IFN as well as to the control of viral burden during infection with MHV-68. Taken together, our results suggest that the TLR2 pathway has a relevant role in the recognition of this virus and in the subsequent activation of the innate immune response.
Highlights
murine gammaherpesvirus-68 (MHV-68) is a virus naturally present in rodent populations [1]
In order to investigate whether MHV-68 could be recognized by TLR2, HEK293 cells were transiently cotransfected with a control vector or with a murine TLR2 expression plasmid along with a NF-kB luciferase reporter plasmid
We demonstrate that secretion of the proinflammatory cytokine IL-6 and of type 1 IFN induced by MHV-68 significantly relies on TLR2- and MyD88-dependent signaling
Summary
MHV-68 is a virus naturally present in rodent populations [1]. It is genetically and biologically related to the two major human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) [2]. Several reports have highlighted the crucial role of the TLR system in host defense against microbial agents In this regard, many members of the herpesvirus family have already been shown to activate TLRs. For example, different cell populations infected by herpes simplex virus 1 or 2 (HSV-1 and HSV-2) were found to secrete robust levels of type 1 IFN, IL-6 and tumor necrosis factor-a (TNF-a) through the activation of TLR2 and TLR9 [8,9,10]. The increase of lytic and latent viral loads observed in spleen, but not in lungs of TLR92/2 mice as compared to control groups suggest that TLR9 is important in organ-specific immunity against MHV-68 during both lytic and latent infection [14]. Because murine gammaherpesvirus-68 (MHV-68) is a useful model to study human gammaherpesvirus pathogenesis in vivo, we evaluated the importance of mouse TLR2 in the recognition of MHV-68
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