title: Chemokine (C-C Motif) receptor 1 is required for efficient recruitment of neutrophils during respiratory infection with modified vaccinia virus Ankara.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Institute for Infectious Diseases and Zoonoses, Ludwig-Maximilians-Universität München, Munich, Germany German Centre for Infection Research (DZIF), Munich, Germany.
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Price
authors.affiliation: Klinikum der Universität München, Medizinische Klinik and Poliklinik IV, Arbeitsgruppe Klinische Biochemie, Munich, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Luckow
authors.affiliation: Institute for Infectious Diseases and Zoonoses, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Lino E
authors.initials: LE
authors.lastname: Torres-Domínguez
authors.affiliation: Institute for Infectious Diseases and Zoonoses, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Brandmüller
authors.affiliation: Helmholtz Zentrum München-German Research Center for Environmental Health, Research Unit Comparative Medicine, Neuherberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Zorn
authors.affiliation: Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirschning
authors.affiliation: Institute for Infectious Diseases and Zoonoses, Ludwig-Maximilians-Universität München, Munich, Germany German Centre for Infection Research (DZIF), Munich, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Sutter
authors.affiliation: Institute for Infectious Diseases and Zoonoses, Ludwig-Maximilians-Universität München, Munich, Germany German Centre for Infection Research (DZIF), Munich, Germany Michael.Lehmann@lmu.de.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008168:Lung / Q000276:immunology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D054389:Receptors, CCR1 / Q000235:genetics / Q000276:immunology*; D012141:Respiratory Tract Infections / Q000276:immunology* / Q000821:virology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D014615:Vaccinia; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*
chemical_list: C515301:Ccr1 protein, mouse; D054389:Receptors, CCR1; D051195:Toll-Like Receptor 2