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* McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, WI 53706; and
Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53706
Human CMV (HCMV) is a ubiquitous member of the Herpesviridae family and an opportunistic pathogen that poses significant health risks for immunocompromised patients. HCMV pathogenesis is intimately tied to the immune status of the host, thus characterization of the innate immune response to HCMV infection is critical for understanding disease progression. Previously, we identified TLR2 as a host factor that detects and initiates inflammatory cytokine secretion in response to HCMV independent of viral replication. In this study, we show that two entry-mediating envelope gp, gp B (gB) and gp H (gH), display determinants recognized by TLR2. Neutralizing Abs against TLR2, gB and gH inhibit inflammatory cytokine responses to HCMV infection, suggesting that inflammatory cytokine stimulation by HCMV is mediated by interactions between these envelope gp and TLR2. Furthermore, both gB and gH coimmunoprecipitate with TLR2 and TLR1, indicating that these envelope gp directly interact with TLR2 and that a TLR2/TLR1 heterodimer is a functional sensor for HCMV. Because our previous studies were conducted in model cell lines, we also show that TLR2 is expressed by HCMV permissive human fibroblast cell strains, and that TLR2 is a functional sensor in these cells. This study further elucidates the importance and potency of envelope gp as a class of molecules displaying pathogen-associated molecular patterns that are recognized with immediate kinetics by TLRs in permissive cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants RO1AI34998 and R21A154915 (to T.C.) and National Institutes of Health Training Grant T32GM07215 (to K.W.B. and M.G.).
2 Address correspondence and reprint requests to Dr. Teresa Compton, 100 Technology Square, Novartis Institute for Biomedical Research, Cambridge, MA 02139. E-mail address: teresa.compton{at}novartis.com
3 Abbreviations used in this paper: HCMV, human CMV; PAMP, pathogen-associated molecular pattern; gB, gp B; gH, gp H; gL, gp L; gO, gp O; NHDF, normal human dermal fibroblast; HEK, human embryonic kidney; MOI, multiplicity of infection; eGFP, enhanced GFP; VSV-G, vesicular stomatitis virus G; HSV-1, herpes simplex virus type 1; CHO, Chinese hamster ovary.
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