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Differential Initiation of Innate Immune Responses Induced by Human Cytomegalovirus Entry into Fibroblast Cells¹

Laura K. Juckem^*, Karl W. Boehme^*, Adam L. Feire^*, and Teresa Compton^2,*

^* McArdle Laboratory for Cancer Research, University of Wisconsin-Madison Medical School, Madison, WI 53706; and Novartis Institute for Biomedical Research, Cambridge, MA 02139

Infection of permissive fibroblasts with human CMV (HCMV, AD169) is accompanied by a robust activation of innate immune defense. In this study, we show that inflammatory cytokine (IC) secretion and activation of the type I IFN pathway (β IFN) are initiated through distinct mechanisms. HCMV is recognized by TLR2 leading to the NF-B activation and IC secretion. However, the IFN response to HCMV is not a TLR2-dependent process, as a dominant negative TLR2 does not affect the antiviral response to infection. Additionally, bafilomycin, an endosomal acidification inhibitor, has no effect on HCMV-induced IFN responses suggesting that IFN signaling is independent of endosomal resident TLRs. By contrast, disruption of lipid rafts by depletion of cellular cholesterol inhibits both HCMV entry as well as IFN responses. Cholesterol depletion had no effect on the induction of ICs by HCMV, illustrating a biological distinction at the cellular level with the initiation of innate immune pathways. Furthermore, HCMV entry inhibitors block IFN responses but not IC signaling. In particular, blocking the interaction of HCMV with β₁ integrin diminished IFN signaling, suggesting that this virus-cell interaction or subsequent downstream steps in the entry pathway are critical for downstream signal transduction events. These data show that HCMV entry and IFN signaling are coordinated processes that require cholesterol-rich microdomains, whereas IC signaling is activated through outright sensing via TLR2. These findings further highlight the complexity and sophistication of innate immune responses at the earliest points in HCMV infection.

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 Grant R01 AI054915 (to T.C.) from the National Institutes of Health and National Institutes of Health Training Grant T32GM07215 (to K.W.B.).

² Address correspondence and reprint requests to Dr. Teresa Compton, Novartis Institute for Biomedical Research, 500 Technology Square, Cambridge, MA 02139. E-mail address: teresa.compton{at}novartis.com

³ Abbreviations used in this paper: HCMV, human CMV; IC, inflammatory cytokine; ISG, IFN-stimulated gene; IRF, IFN regulatory factor; NHDF, normal human dermal fibroblast; VSV, vesicular stomatitis virus; MβCD, methyl-β-cyclodextrin; MOI, multiplicity of infection; gB, glycoprotein B; gH, glycoprotein H; PAMP, pathogen-associated molecular pattern.