Adenovirus-directed ocular innate immunity:: The role of conjunctival defensin-like chemokines (IP-10, I-TAC) and phagocytic human defensin-α
Adenovirus-directed ocular innate immunity:: The role of conjunctival defensin-like chemokines (IP-10, I-TAC) and phagocytic human defensin-α
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DOI：
10.1167/iovs.05-0438
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发表时间：
2005-10-01
影响因子：
4.4
通讯作者：
Gordon, YJ
中科院分区：
文献类型：
--
作者：
Harvey, SAK;Romanowski, EG;Gordon, YJ
目的。腺病毒 (Ad) 是全世界病毒性结膜炎的主要原因，最初由眼表面的先天免疫反应控制。在本研究中，使用培养的人结膜上皮细胞来鉴定对临床分离的Ad5感染有反应的宿主基因，并研究了其一些肽产物的抗病毒活性。方法。用 Ad5 以高 (1.0)、低 (0.1) 或零 (0.0) 感染复数 (MOI) 感染培养物中的原代人结膜上皮细胞，并在感染后的不同时间（1.5、6 和 16 小时）收获。使用寡核苷酸微阵列（GeneChips；Affymetrix，Santa Clara，CA）分析宿主基因表达。在针对呼吸道血清型（Ad3、Ad5）、眼部血清型（Ad8、Ad19）和 HSV-1 的直接抑制测定中，测试了感兴趣的肽产品的抗病毒活性。结果。在高 MOI 下，病毒感染抑制了在低 MOI 下观察到的干扰素 (IFN) 介导的宿主抗病毒反应。感染后 16 小时，鉴定出 63 个具有独特特征的转录本，这些转录本被高 MOI 强有力且显着地抑制（即 MOI [0.1]/MOI [0.1] >= 2，P < 0.006）。其中，29 个（46%）转录物参与 IFN 信号传导或由 IFN 或病毒诱导。该子集包括 CXCL10 和 CXCL11，分别编码 IP-10 和 I-TAC。这些防御素样趋化因子和人 α-防御素-1 直接抑制 Ad3 和 Ad5，但不抑制 Ad8 或 Ad19。 结论。为了应对低水平的 Ad5 感染，结膜上皮细胞表现出 IFN 相关基因的上调。其中两种的肽产物IP-10和I-TAC直接具有抗Ad3活性，IP-10具有抗Ad5活性。 Ad8 和 Ad19 的眼向性可能部分归因于它们对这些防御素样趋化因子的抵抗。
PURPOSE. Adenovirus (Ad), a major cause of viral conjunctivitis worldwide, is controlled initially by the innate immune response on the ocular surface. In the present study, cultured human conjunctival epithelial cells were used to identify host genes responsive to infection by a clinical isolate of Ad5, and the antiviral activity of some of their peptide products was investigated.METHODS. Primary human conjunctival epithelial cells in culture were infected with Ad5 at high (1.0), low (0.1), or zero (0.0) multiplicities of infection (MOI) and harvested at different times after infection (1.5, 6, and 16 hours). Host gene expression was profiled with oligonucleotide microarrays (GeneChips; Affymetrix, Santa Clara, CA). Peptide products of interest were tested for antiviral activity in direct inhibition assays against respiratory serotypes (Ad3, Ad5), ocular serotypes (Ad8, Ad19), and HSV-1.RESULTS. At high MOI, viral infection suppressed the interferon (IFN)-mediated host antiviral response seen at low MOI. At 16 hours after infection, 63 unique characterized transcripts were identified that were robustly and significantly suppressed by high MOI, (i.e., MOI [0.1]/MOI [0.1] >= 2, P < 0.006). Of these, 29 ( 46%) transcripts are involved in IFN signaling or are IFN or virus induced. This subset included CXCL10 and CXCL11, encoding IP-10 and I-TAC, respectively. These defensin-like chemokines and human alpha-defensin-1 directly inhibited Ad3 and Ad5 but not Ad8 or Ad19.CONCLUSIONS. In response to low-level Ad5 infection, conjunctival epithelial cells showed upregulation of IFN-associated genes. The peptide products of two of these, IP-10 and I-TAC, are directly active against Ad3, and IP-10 is active against Ad5. The ocular tropism of Ad8 and Ad19 may be due in part to their resistance to these defensin-like chemokines.