Increased natural killer cell cytotoxicity and NKp30 expression protects against hepatitis C virus infection in high-risk individuals and inhibits replication in vitro.
Increased natural killer cell cytotoxicity and NKp30 expression protects against hepatitis C virus infection in high-risk individuals and inhibits replication in vitro.
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DOI：
10.1002/hep.23896
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发表时间：
2010-11
期刊：
影响因子：
13.5
通讯作者：
Rosen, Hugo R.
中科院分区：
文献类型：
--
作者：
Golden-Mason, Lucy;Cox, Andrea L.;Randall, Jessica A.;Cheng, Linling;Rosen, Hugo R.
CD56pos NK/NT细胞是重要的先天效应细胞，提供了抵抗病毒感染的第一道防线。增强NK活性已被证明可以预防HIV-1感染。然而，这些先天效应物在预防或发展HCV感染中所起的作用尚不清楚。我们对11名静脉注射吸毒者（IDUs）的CD56pos群体进行了特征分析，这些吸毒者尽管反复暴露于HCV，但仍未感染。将暴露的未感染（EU）个体的NK谱与从随后感染（EI）的14名注射吸毒者和未暴露的正常对照（NC, n=8）收集的感染前样本（中位在HCV血清转化前90天）进行比较。CD56pos群体的流式细胞分析表明，与随后感染的受试者相比，EUs具有更高比例的CD56low成熟NK细胞（p=0.0011）。从EUs中分离的nk珠状蛋白（纯度为>90%）对nk敏感细胞系K562具有显著更高的IL-2诱导的细胞溶解活性，效应靶比为10:1 （p<0.0001）。NKp30是一种参与NK活化的天然细胞毒性受体，相对于感染的受试者，在EUs中NK/NT细胞上的含量最高。使用JFH-1感染系统，我们证明nkp30高细胞在没有外源刺激的情况下显著减少肝细胞的感染。我们证明，EUs中的CD56pos群体富含IL-2诱导的细胞溶解活性增强的效应NKs和更高水平的NCR NKp30激活受体。此外，NKp30high NK细胞比NKp30low/neg NK细胞更有效地预防Huh 7.5细胞的感染。这些数据首次支持了NK细胞在感染早期参与体内抗HCV防御的假设，为HCV获得提供先天保护。
CD56pos NK/NT cells are important innate effectors providing the first line of defense against viral infection. Enhanced NK activity has been shown to protect from HIV-1 infection. However, the role played by these innate effectors in protection against or development of HCV infection is unknown. We characterized CD56pos populations in 11 intravenous drug users (IDUs) who remained uninfected despite being repeatedly exposed to HCV. NK profiles in exposed uninfected (EU) individuals were compared to pre-infection samples (median 90 days prior to HCV seroconversion) collected from 14 IDUs who subsequently became infected (EI) and unexposed normal control subjects (NC, n=8). Flow cytometric analysis of CD56pos populations demonstrated that EUs had a higher proportion of CD56low mature (p=0.0011) NK cells compared to subjects who subsequently became infected. Bead-isolated NKs (>90% purity) from EUs had significantly higher IL-2 induced cytolytic activity against the NK-sensitive cell line K562 at an effector to target ratio of 10:1 (p<0.0001). NKp30, a natural cytotoxicity receptor involved in NK activation, is highest on NK/NT cells in EUs relative to infected subjects. Using the JFH-1 infection system we demonstrate that NKp30high cells in the absence of exogenous stimulation significantly reduce infection of hepatocytes. We demonstrate that CD56pos populations in EUs are enriched for effector NKs displaying enhanced IL-2 induced cytolytic activity and higher levels of NCR NKp30 activating receptor. In addition NKp30high NK cells are more effective in preventing infection of Huh 7.5 cells than their NKp30low/neg counterparts. For the first time, these data support the hypothesis that NK cells contribute to anti-HCV defense in vivo in the earliest stages of infection, providing innate protection from HCV acquisition.
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影响因子：
15.3
作者：
Crotta, Stefania;Stilla, Annalisa;Wack, Andreas;D'Andrea, Annalisa;Nuti, Sandra;D'Oro, Ugo;Mosca, Marta;Filliponi, Franco;Brunetto, R Maurizia;Bonino, Ferruccio;Abrignani, Sergio;Valiante, Nicholas M
通讯作者：
Valiante, Nicholas M
影响因子：
25.7
作者：
Deignan, T;Curry, MP;O'Farrelly, C
通讯作者：
O'Farrelly, C
影响因子：
5.4
作者：
Fogli, M;Costa, P;De Maria, A
通讯作者：
De Maria, A
影响因子：
6.4
作者：
Chisholm, Susan E.;Howard, Keith;Reyburn, Hugh T.
通讯作者：
Reyburn, Hugh T.
影响因子：
11.8
作者：
Cox, AL;Netski, DM;Thomas, DL
通讯作者：
Thomas, DL