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Journal of Virology, March 2009, p. 2540-2552, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.01884-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Modified Vaccinia Virus Ankara Triggers Chemotaxis of Monocytes and Early Respiratory Immigration of Leukocytes by Induction of CCL2 Expression{triangledown}

Michael H. Lehmann,1,2* Wolfgang Kastenmuller,2,{dagger} Judith D. Kandemir,2,3 Florian Brandt,2,{ddagger} Yasemin Suezer,1 and Gerd Sutter1

Division of Virology, Paul-Ehrlich-Institut, D-63255 Langen, Germany,1 Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, D-81675 Munich, Germany,2 Institute for Clinical Chemistry, Hannover Medical School, D-30625 Hannover, Germany3

Received 8 September 2008/ Accepted 24 December 2008

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.

* Corresponding author. Mailing address: Paul-Ehrlich-Institut, Division of Virology, Paul-Ehrlich-Str. 51-59, 6322 5 Langen, Germany. Phone: 49-6103-77-5405. Fax: 49-3212-5047880. E-mail: Orlataler{at}web.de

{triangledown} Published ahead of print on 7 January 2009.

{dagger} Present address: Lymphocyte Biology Section, NIAID, NIH, Bethesda, MD 20892-1892.

{ddagger} Present address: Department of Molecular Structural Biology, Max-Planck-Institute of Biochemistry, D-82152 Martinsried, Germany.

Journal of Virology, March 2009, p. 2540-2552, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.01884-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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