Porphyromonas gingivalis selectively up-regulates the HIV-1 coreceptor CCR5 in oral Keratinocytes
Porphyromonas gingivalis selectively up-regulates the HIV-1 coreceptor CCR5 in oral Keratinocytes
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DOI：
10.4049/jimmunol.179.4.2542
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Herzberg, Mark C.
中科院分区：
文献类型：
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作者：
Giacaman, Rodrigo A.;Nobbs, Angela H.;Herzberg, Mark C.
如果发生HIV-1对口腔上皮细胞的原发性感染，可能会促进全身感染。大多数原发性系统性感染与R5型HIV-1相关，靶向R5特异性辅助受体CCR 5，其通常不表达于口腔角质形成细胞。由于与其他微生物的共感染已被认为是调节细胞感染的HIV-1，我们假设，口腔角质形成细胞可能上调CCR 5响应口腔内源性病原体牙龈卟啉单胞菌通过半胱氨酸蛋白酶（gingipains）激活的蛋白酶激活受体（PAR）或LPS信号通过TLR。OKF 6/TERT 2永生化的正常人口腔角质形成细胞系表达CXCR 4，而未检测到CCR 5。当暴露于牙龈卟啉单胞菌ATCC 33277时，TERT-2细胞诱导的CCR 5特异性mRNA和表面辅助受体的时间依赖性表达高于CXCR 4。通过比较arg-（Rgp）和lys-gingipain（Kgp）突变体（一种同时缺乏这两种蛋白酶的突变体）和胰蛋白酶的作用，牙龈卟啉单胞菌Rgp是。强烈提示切割PAR-1和PAR-2以上调CCR 5。CCR 5也略有上调的同基因gingipain缺陷突变体，这表明存在的非gingipain介导的机制。纯化的牙龈卟啉单胞菌LPS也上调CCR 5。用Ab阻断TLR 2和TLR 4受体减弱了CCR 5的诱导，表明LPS通过TLR信号传导。因此，牙龈卟啉单胞菌通过两个独立的信号通路选择性上调CCR 5，Rgp作用于PAR-1和PAR-2，LPS作用于TLR 2和TLR 4。牙龈卟啉单胞菌联合感染可通过诱导CCR 5的表达促进R5型HIV-1选择性感染口腔角质形成细胞。
Primary infection of oral epithelial cells by HIV-1, if it occurs, could promote systemic infection. Most primary systemic infections are associated with R5-type HIV-1 targeting the R5-specific coreceptor CCR5, which is not usually expressed on oral keratinocytes. Because coinfection with other microbes has been suggested to modulate cellular infection by HIV-1, we hypothesized that oral keratinocytes may up-regulate CCR5 in response to the oral endogenous pathogen Porphyromonas gingivalis by cysteineprotease (gingipains) activation of the protease-activated receptors (PARs) or LPS signaling through the TLRs. The OKF6/TERT2-immortalized normal human oral keratinocyte line expressed CXCR4, whereas CCR5 was not detectable. When exposed to P. gingivalis ATCC 33277, TERT-2 cells induced greater time-dependent expression of CCR5-specific mRNA and surface coreceptors than CXCR4. By comparing arg- (Rgp) and lys-gingipain (Kgp) mutants, a mutant deficient in both proteases, and the action of trypsin, P. gingivalis Rgp was. strongly suggested to cleave PAR-1 and PAR-2 to up-regulate CCR5. CCR5 was also slightly up-regulated by an isogenic gingipain-deficient mutant, suggesting the presence of a nongingipain-mediated mechanism. Purified P. gingivalis LPS also up-regulated CCR5. Blocking TLR2 and TLR4 receptors with Abs attenuated induction of CCR5, suggesting LPS signaling through TLRs. P. gingivalis, therefore, selectively up-regulated CCR5 by two independent signaling pathways, Rgp acting on PAR-1 and PAR-2, and LPS on TLR2 and TLR4. By inducing CCR5 expression, P. gingivalis coinfection could promote selective R5-type HIV-1 infection of oral keratinocytes.