Lehmann Michael H, Kastenmuller Wolfgang, Kandemir Judith D, Brandt Florian, Suezer Yasemin, Sutter Gerd
Division of Virology, Paul-Ehrlich-Institut, D-63255 Langen, Germany.
J Virol. 2009 Mar;83(6):2540-52. doi: 10.1128/JVI.01884-08. Epub 2009 Jan 7.
Orthopoxviruses commonly enter into humans and animals via the respiratory tract. Herein, we show that immigration of leukocytes into the lung is triggered via intranasal infection of mice with modified vaccinia virus Ankara (MVA) and not with the vaccinia virus (VACV) Elstree, Wyeth, or Western Reserve (WR) strain. Immigrating cells were identified as monocytes, neutrophils, and CD4(+) lymphocytes by flow cytometry and could be detected 24 h and 48 h postinfection. Using an in vitro chemotaxis assay, we confirmed that infection with MVA induces the expression of a soluble chemotactic factor for monocytes, identified as CCL2 (monocyte chemotactic protein-1 [MCP-1]). In contrast to infection with several other VACV strains, MVA induced the expression of CCL2, CCL3, CCL4, and CXCL10 in the human monocytic cell line THP-1 as well as in primary human monocytes. Thus, MVA, and not the VACV Elstree, Wyeth, or WR strain, consistently triggered the expression of a panel of chemokines, including CCL2, in the murine lung, correlating considerably with the immigration of leukocytes. Using CCL2-deficient mice, we demonstrate that CCL2 plays a key role in MVA-triggered respiratory immigration of leukocytes. Moreover, UV irradiation of MVA prevented CCL2 expression in vitro and in vivo as well as respiratory immigration of leukocytes, demonstrating the requirement for an activated molecular viral life cycle. We propose that MVA-triggered chemokine expression causes early immigration of leukocytes to the site of infection, a feature that is important for rapid immunization and its safety and efficiency as a viral vector.
正痘病毒通常通过呼吸道进入人和动物体内。在此，我们发现，用安卡拉痘苗病毒（MVA）而非痘苗病毒（VACV）的伊斯特里、惠氏或西储（WR）株经鼻感染小鼠会引发白细胞向肺部的迁移。通过流式细胞术鉴定出迁移的细胞为单核细胞、中性粒细胞和CD4(+)淋巴细胞，且在感染后24小时和48小时均可检测到。使用体外趋化试验，我们证实感染MVA会诱导一种可溶性单核细胞趋化因子的表达，该因子被鉴定为CCL2（单核细胞趋化蛋白-1 [MCP-1]）。与感染其他几种VACV株不同，MVA在人单核细胞系THP-1以及原代人单核细胞中诱导CCL2、CCL3、CCL4和CXCL10的表达。因此，MVA而非VACV的伊斯特里、惠氏或WR株持续触发包括CCL2在内的一组趋化因子在小鼠肺部的表达，这与白细胞的迁移密切相关。使用CCL2缺陷小鼠，我们证明CCL2在MVA触发的白细胞呼吸道迁移中起关键作用。此外，MVA的紫外线照射可防止其在体外和体内诱导CCL2表达以及白细胞的呼吸道迁移，这表明需要一个激活的分子病毒生命周期。我们提出，MVA触发的趋化因子表达导致白细胞早期迁移至感染部位，这一特征对于快速免疫及其作为病毒载体的安全性和有效性至关重要。
