Division of Virology, Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
J Virol. 2020 Jul 1;94(14). doi: 10.1128/JVI.00542-20.
Virus entry into host cells is a complex process that is largely regulated by access to specific cellular receptors. Human adenoviruses (HAdVs) and many other viruses use cell adhesion molecules such as the coxsackievirus and adenovirus receptor (CAR) for attachment to and entry into target cells. These molecules are rarely expressed on the apical side of polarized epithelial cells, which raises the question of how adenoviruses-and other viruses that engage cell adhesion molecules-enter polarized cells from the apical side to initiate infection. We have previously shown that species C HAdVs utilize lactoferrin-a common innate immune component secreted to respiratory mucosa-for infection via unknown mechanisms. Using a series of biochemical, cellular, and molecular biology approaches, we mapped this effect to the proteolytically cleavable, positively charged, N-terminal 49 residues of human lactoferrin (hLF) known as human lactoferricin (hLfcin). Lactoferricin (Lfcin) binds to the hexon protein on the viral capsid and anchors the virus to an unknown receptor structure of target cells, resulting in infection. These findings suggest that HAdVs use distinct cell entry mechanisms at different stages of infection. To initiate infection, entry is likely to occur at the apical side of polarized epithelial cells, largely by means of hLF and hLfcin bridging HAdV capsids via hexons to as-yet-unknown receptors; when infection is established, progeny virions released from the basolateral side enter neighboring cells by means of hLF/hLfcin and CAR in parallel. Many viruses enter target cells using cell adhesion molecules as receptors. Paradoxically, these molecules are abundant on the lateral and basolateral side of intact, polarized, epithelial target cells, but absent on the apical side that must be penetrated by incoming viruses to initiate infection. Our study provides a model whereby viruses use different mechanisms to infect polarized epithelial cells depending on which side of the cell-apical or lateral/basolateral-is attacked. This study may also be useful to understand the biology of other viruses that use cell adhesion molecules as receptors.
病毒进入宿主细胞是一个复杂的过程，在很大程度上受到特定细胞受体的限制。人类腺病毒（HAdV）和许多其他病毒使用细胞黏附分子，如柯萨奇病毒和腺病毒受体（CAR），来附着和进入靶细胞。这些分子在极化上皮细胞的顶端侧很少表达，这就提出了一个问题，即腺病毒和其他使用细胞黏附分子的病毒如何从顶端侧进入极化细胞，从而启动感染。我们之前已经表明，C 型 HAdV 通过未知机制利用乳铁蛋白（一种分泌到呼吸道黏膜的常见先天免疫成分）进行感染。使用一系列生化、细胞和分子生物学方法，我们将这种效应映射到乳铁蛋白的可蛋白水解的、带正电荷的、N 端 49 个残基上，称为人乳铁蛋白肽（hLfcin）。乳铁蛋白肽（Lfcin）与病毒衣壳上的六邻体蛋白结合，并将病毒锚定到靶细胞的未知受体结构上，从而导致感染。这些发现表明，HAdV 在感染的不同阶段使用不同的细胞进入机制。为了启动感染，进入很可能发生在极化上皮细胞的顶端侧，主要是通过 hLF 和 hLfcin 通过六邻体将 HAdV 衣壳桥接到未知的受体结构上，从而导致感染；当感染建立后，从基底外侧释放的子代病毒通过 hLF/hLfcin 和 CAR 平行进入相邻细胞。许多病毒使用细胞黏附分子作为受体进入靶细胞。矛盾的是，这些分子在上皮靶细胞完整的、极化的侧部和基底外侧部丰富，但在必须被进入的病毒穿透的顶端侧部缺失，以启动感染。我们的研究提供了一个模型，即根据攻击细胞的哪一侧（顶端或侧部/基底外侧部），病毒使用不同的机制感染极化上皮细胞。这项研究对于理解其他使用细胞黏附分子作为受体的病毒的生物学特性也可能有用。
