Redundant and Synergistic Mechanisms Control the Sequestration of Blood-born Adenovirus in the Liver
Redundant and Synergistic Mechanisms Control the Sequestration of Blood-born Adenovirus in the Liver
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DOI：
10.1038/mt.2008.307
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发表时间：
2009-04-01
影响因子：
12.4
通讯作者：
Shayakhmetov, Dmitry M.
中科院分区：
文献类型：
--
作者：
Di Paolo, Nelson C.;van Rooijen, Nico;Shayakhmetov, Dmitry M.
人腺病毒（humanadenovirus，Ad）是一种广泛存在的病原体，可引起多种疾病。虽然人Ad血清型5（Ad 5）与体外易感细胞的相互作用是非常详细的，但控制体内Ad 5感染的组织特异性的宿主因素仍然知之甚少。在这里，我们分析了由肝脏隔离血液出生的人类广告和Ad 5为基础的载体的机制。我们的数据表明，几个已知的机制，导致Ad 5隔离的肝脏成为从事冗余，顺序和协同的方式，以确保快速清除循环病毒颗粒从血液中。这些机制包括（i）通过肝驻留巨噬细胞、枯否细胞捕获病毒;（ii）通过血液因子-六邻体相互作用感染Ad 5肝细胞;和（iii）Ad 5五邻体RGD基序介导的与肝内皮细胞和肝细胞的相互作用，介导病毒保留在Disse间隙中。更重要的是，我们表明，当所有这些机制同时通过突变的Ad 5衣壳蛋白和药理学干预失活时，肝脏的病毒隔离显着减少。因此，我们的研究是第一次证明的主要可能性消融隔离的血液出生的广告在肝脏中通过特定的一套机制，控制这个过程的失活。
Human adenovirus (Ad) is a ubiquitous pathogen causing a wide range of diseases. Although the interactions of human Ad serotype 5 (Ad5) with susceptible cells in vitro are known in great detail, host factors controlling the tissue specificity of Ad5 infection in vivo remain poorly understood. Here, we analyzed the mechanisms of sequestration by the liver for blood-born human Ads and Ad5-based vectors. Our data suggest that several known mechanisms that lead to Ad5 sequestration by the liver become engaged in a redundant, sequential, and synergistic manner to ensure the rapid clearance of circulating virus particles from the blood. These mechanisms include (i) trapping of the virus by liver residential macrophages, Kupffer cells; (ii) Ad5 hepatocyte infection via blood factor-hexon interactions; and (iii) Ad5 penton RGD motif-mediated interactions with liver endothelial cells and hepatocytes, mediating virus retention in the space of Disse. More important, we show that when all of these mechanisms are simultaneously inactivated via mutations of Ad5 capsid proteins and pharmacological interventions, virus sequestration by the liver is markedly reduced. Therefore, our study is the first demonstration of the principal possibility of ablating the sequestration of blood-born Ad in the liver via specific inactivation of a defined set of mechanisms that control this process.