Institute for Virology, University of Veterinary Medicine Hannover, Hannover, Germany.
Department of Virology, National Veterinary Research Institute, Puławy, Poland.
J Virol. 2021 Apr 12;95(9). doi: 10.1128/JVI.02186-20.
Pestiviruses such as bovine viral diarrhea virus (BVDV) and classical swine fever virus (CSFV) belong to the family and represent pathogens of outstanding veterinary relevance. Pestiviruses enter cells via receptor-mediated endocytosis. For entry in bovine cells, complement regulatory protein CD46 serves as a cellular receptor for BVDV. In this study, the role of porcine CD46 in cellular entry was investigated for the recently discovered atypical porcine pestivirus (APPV), CSFV, and Bungowannah virus (BuPV) in order to elucidate the observed differences in host cell tropism. A cell culture-adapted APPV variant, which shows enhanced viral replication , was generated and demonstrated a strict tropism of APPV for porcine cells. One of the porcine cell lines displayed areas of CD46-expressing cells and areas of nonexpressing cells, and one single cell line revealed not to express any CD46 The CD46-deficient porcine lymphoma cell line, known to facilitate CSFV replication, was the only porcine cell line nonpermissive to APPV, indicating a significant difference in the entry mechanism of APPV and CSFV. Infection experiments with a set of genetically engineered CD46 knockout cells confirmed that CD46 is a major receptor of APPV as CD46 is for BVDV. In contrast, it is apparently not an essential determinant in host cell entry of other porcine pestiviruses such as CSFV and BuPV. Existence of a CD46-independent entry mechanism illustrates that the pestiviral entry process is more diverse than previously recognized. Pestiviruses comprise animal pathogens such as classical swine fever virus (CSFV) and bovine viral diarrhea virus (BVDV) that cause notifiable diseases with great economic impact. Several additional pestivirus species affecting animal health were recently identified, including atypical porcine pestivirus (APPV). APPV is associated with health problems in piglets and is highly abundant in pig populations worldwide. Complement control protein CD46 serves as a receptor for diverse bacterial and viral pathogens, including particular adenoviruses, herpesviruses, measles virus (MeV), and BVDV. Porcine CD46 (CD46) was suggested to be a major receptor for CSFV. Here, we identified remarkable differences in relevance of CD46 during entry of porcine pestiviruses. Resembling BVDV, efficient APPV infection in cell culture depends on CD46, while other porcine pestiviruses can efficiently enter and infect cells in the absence of CD46 Thus, the study provides insights into the entry process of these pathogens and may help to understand differences in their biology.
瘟病毒科如牛病毒性腹泻病毒（BVDV）和古典猪瘟病毒（CSFV）属于该科，是具有重要兽医意义的病原体。瘟病毒通过受体介导的内吞作用进入细胞。牛细胞中的 BVDV 利用补体调节蛋白 CD46 作为细胞受体。在这项研究中，为了阐明观察到的宿主细胞嗜性差异，研究了最近发现的非典型猪瘟病毒（APPV）、CSFV 和本戈瓦那病毒（BuPV）在猪细胞中进入的过程中猪 CD46 的作用。生成了一种细胞培养适应的 APPV 变体，该变体显示出增强的病毒复制，表明 APPV 对猪细胞具有严格的嗜性。其中一个猪细胞系显示出表达 CD46 的细胞区域和不表达细胞的区域，并且一个单一的细胞系显示不出表达任何 CD46。已知促进 CSFV 复制的猪淋巴瘤细胞系是唯一不允许 APPV 进入的猪细胞系，表明 APPV 和 CSFV 的进入机制存在显著差异。一组基因工程 CD46 敲除细胞的感染实验证实，CD46 是 APPV 的主要受体，就像 CD46 是 BVDV 的主要受体一样。相比之下，在 CSFV 和 BuPV 等其他猪瘟病毒的宿主细胞进入中，它显然不是必需的决定因素。存在 CD46 非依赖性进入机制表明，瘟病毒的进入过程比以前认识的更为多样化。瘟病毒包括引起具有重大经济影响的法定疾病的动物病原体，如古典猪瘟病毒（CSFV）和牛病毒性腹泻病毒（BVDV）。最近还发现了几种影响动物健康的其他瘟病毒物种，包括非典型猪瘟病毒（APPV）。APPV 与仔猪的健康问题有关，并且在全球猪群中高度丰富。补体控制蛋白 CD46 是多种细菌和病毒病原体的受体，包括特定的腺病毒、疱疹病毒、麻疹病毒（MeV）和 BVDV。猪 CD46（CD46）被认为是 CSFV 的主要受体。在这里，我们在猪瘟病毒进入过程中发现了 CD46 相关性的显著差异。与 BVDV 相似，APPV 在细胞培养中的有效感染依赖于 CD46，而其他猪瘟病毒可以在没有 CD46 的情况下有效进入和感染细胞。因此，该研究提供了对这些病原体进入过程的深入了解，并有助于理解它们在生物学上的差异。
