Differential initiation of innate immune responses induced by human cytomegalovirus entry into fibroblast cells

被引:75
作者
Juckem, Laura K.
Boehme, Karl W.
Feire, Adam L.
Compton, Teresa
机构
[1] Novartis Inst Biomed Res, Cambridge, MA 02139 USA
[2] Univ Wisconsin, Sch Med, McArdle Lab Canc Res, Madison, WI 53706 USA
关键词
D O I
10.4049/jimmunol.180.7.4965
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 (alpha beta IFN) are initiated through distinct mechanisms. HCMV is recognized by TLR2 leading to the NF-kappa 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 13, 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.
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页码:4965 / 4977
页数:13
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