Involvement of TLR2 in Recognition of Acute Gammaherpesvirus-68 Infection

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.

Abortively Infected Astrocytes Appear To Represent the Main Source of Interferon Beta in the Virus-Infected Brain

“…In particular, TLR3-mediated recognition was observed in the case of the neurovirulent TMEV strains DA and BeNa (32,33). Further, TLR2 and TLR4 may get activated after infection with some viruses, including VSV (34)(35)(36). Viral PAMPs triggering these latter pathways are most likely not nucleic acids but rather viral proteins, such as the VSV glycoprotein (36).…”

MyD88-Dependent Immunity to a Natural Model of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2

“…For the dsDNA herpesviruses HSV-1, MCMV, and murid herpesvirus 68 (MHV-68), more than one TLR contributes to control of the infection (10,50,71). For example, during i.p.…”

Herpesviral infection and Toll-like receptor 2

“…This strategy may be beneficial to the virus in order to induce upregulation of viral entry receptors but may also serve the host in favoring a rapid respond to viral invaders (Bieback et al, 2002;Zhu et al, 2007). Thus far, a large body of works demonstrate that TLR2 has been implicated in the recognition of structural components of several viruses (Bieback et al, 2002;Duesberg et al, 2002;Dolganiuc et al, 2004;Cooper et al, 2005), as well as members of the herpesvirus family, including HSV, VZV, murine gammaherpesvirus-68 (MHV-68), CMV, and EBV (Compton et al, 2003;Kurt-Jones et al, 2004;Wang et al, 2005a;Boehme et al, 2006;Sato et al, 2006;Szomolanyi-Tsuda et al, 2006;Gaudreault et al, 2007;Ariza et al, 2009;Michaud et al, 2010).…”

“…Taken together, these results suggest that TLR2 contributes to the production of inflammatory cytokines and IFN I as well as to the control of viral burden during infection with MHV-68. Thus, the TLR2 pathway has a relevant role in the recognition of this virus and in the subsequent activation of the innate immune response (Michaud et al, 2010).…”