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Price, P.J.* ; Luckow, B.* ; Torres-Domínguez, L.E.* ; Brandmüller, C.* ; Zorn, J. ; Kirschning, C.J.* ; Sutter, G.* ; Lehmann, M.H.*

Chemokine (C-C motif) receptor 1 (CCR1) is required for efficient recruitment of neutrophils during respiratory infection with Modified Vaccinia virus Ankara.

J. Virol. 88, 10840-10850 (2014)

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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. IMPORTANCE: 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, that 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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Sequential Release; Viral-infections; Binding-protein; T1/35kda Family; Host-defense; Bone-marrow; Tnf-alpha; In-vitro; Expression; Ccr1

ISSN (print) / ISBN 0022-538X

e-ISSN 1098-5514

Journal Journal of Virology

Quellenangaben Volume: 88, Issue: 18, Pages: 10840-10850

Publisher American Society for Microbiology (ASM)

Publishing Place Washington

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) CF Comparative Medicine (AVM)