Price Philip J R, Luckow Bruno, Torres-Domínguez Lino E, Brandmüller Christine, Zorn Julia, Kirschning Carsten J, Sutter Gerd, Lehmann Michael H
Institute for Infectious Diseases and Zoonoses, Ludwig-Maximilians-Universität München, Munich, Germany German Centre for Infection Research (DZIF), Munich, Germany.
Klinikum der Universität München, Medizinische Klinik and Poliklinik IV, Arbeitsgruppe Klinische Biochemie, Munich, Germany.
J Virol. 2014 Sep;88(18):10840-50. doi: 10.1128/JVI.01524-14. Epub 2014 Jul 9.
Modified vaccinia virus Ankara (MVA) serves as a versatile platform in vaccine development. This highly attenuated orthopoxvirus, which cannot replicate in mammalian cells, triggers strong innate immune responses, including cell migration. Previously, we have shown that induction of chemokine (C-C motif) ligand 2 (CCL2) by MVA is necessary for the recruitment of monocytes and T cells, but not neutrophils, to the lung. Here, we identified neutrophil-attracting chemokines produced by MVA-infected primary murine lung fibroblasts and murine bone marrow-derived macrophages. We demonstrate that MVA, but not vaccinia virus (VACV) strain WR, induces chemokine expression, which is independent of Toll-like receptor 2 (TLR2) signaling. Additionally, we show that both chemokine (C-C motif) receptor 1 (CCR1) and chemokine (C-X-C motif) receptor 2 (CXCR2) are involved in MVA-induced neutrophil chemotaxis in vitro. Finally, intranasal infection of Ccr1(-/-) mice with MVA, as well as application of the CCR1 antagonist J-113863, revealed a role for CCR1 in leukocyte recruitment, including neutrophils, into the lung.
Rapid attraction of leukocytes to the site of inoculation is unique to MVA in comparison to other VACV strains. The findings here extend current knowledge about the regulation of MVA-induced leukocyte migration, particularly regarding neutrophils, which could potentially be exploited to improve other VACV strains currently in development as oncolytic viruses and viral vectors. Additionally, the data presented here indicate that the inflammatory response may vary depending on the cell type infected by MVA, highlighting the importance of the site of vaccine application. Moreover, the rapid recruitment of neutrophils and other leukocytes can directly contribute to the induction of adaptive immune responses elicited by MVA inoculation. Thus, a better understanding of leukocyte migration upon MVA infection is particularly relevant for further development and use of MVA-based vaccines and vectors.
安卡拉痘苗病毒（MVA）是疫苗研发中的一个多功能平台。这种高度减毒的正痘病毒无法在哺乳动物细胞中复制，能引发强烈的先天免疫反应，包括细胞迁移。此前，我们已经表明，MVA诱导趋化因子（C-C基序）配体2（CCL2）对于单核细胞和T细胞而非中性粒细胞募集到肺部是必要的。在此，我们鉴定了MVA感染的原代小鼠肺成纤维细胞和小鼠骨髓来源的巨噬细胞产生的吸引中性粒细胞的趋化因子。我们证明，MVA而非痘苗病毒（VACV）WR株可诱导趋化因子表达，且该表达不依赖于Toll样受体2（TLR2）信号传导。此外，我们表明趋化因子（C-C基序）受体1（CCR1）和趋化因子（C-X-C基序）受体2（CXCR2）均参与MVA体外诱导的中性粒细胞趋化作用。最后，用MVA鼻内感染Ccr1(-/-)小鼠以及应用CCR1拮抗剂J-113863，揭示了CCR1在包括中性粒细胞在内的白细胞募集到肺部过程中的作用。
与其他VACV株相比，白细胞迅速募集到接种部位是MVA独有的特点。此处的研究结果扩展了当前关于MVA诱导白细胞迁移调控的知识，特别是关于中性粒细胞的知识，这可能有助于改进目前作为溶瘤病毒和病毒载体正在研发的其他VACV株。此外，此处呈现的数据表明炎症反应可能因MVA感染的细胞类型而异，突出了疫苗接种部位的重要性。而且，中性粒细胞和其他白细胞的快速募集可直接有助于MVA接种引发的适应性免疫反应的诱导。因此，更好地理解MVA感染后的白细胞迁移对于基于MVA的疫苗和载体的进一步开发和应用尤为重要。
