Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells.
A crucial event for the induction of an anti-viral immune response is the coordinated, phenotype-dependent migration of dendritic cells (DC) to sites of infection and secondary lymphoid organs. Here we show that the vaccinia virus (VV) strains Western Reserve (WR) and modified virus Ankara (MVA) inhibit directional migration of mature DC toward the lymphoid chemokines CCL19 and CXCL12 without affecting surface expression of the respective chemokine receptors or impairing undirected cellular locomotion. Instead, infection with VV results in a deficiency of extracellular signal-regulated kinase-1 and a disturbance of intracellular calcium mobilization, indicating a viral interference with signaling events downstream of the surface chemokine receptors. In immature DC, apart from inhibiting chemokine-induced migration of infected DC, infection with both VV strains increases expression of the inflammatory chemokine receptors CCR1 and CXCR1 on non-infected bystander DC, which depends on the activity of IFN-alpha. Although functional, these chemokine receptors are resistant to lipopolysaccharide-induced down-regulation. In addition, VV-infected and non-infected bystander DC fail to up-regulate the lymphoid chemokine receptor CCR7 upon activation, together pointing to a disability to undergo the chemokine receptor switch. This study shows that VV targets directional migration of professional antigen-presenting cells at multiple functional levels, revealing a potent viral strategy of immune escape.
Humrich
Jens Y
JY
University Hospital of Erlangen-Nuremberg, Department of Dermatology, Erlangen, Germany. humrich@drfz.de
Thumann
Peter
P
Greiner
Sebastian
S
Humrich
Jan H
JH
Averbeck
Marco
M
Schwank
Christiane
C
Kämpgen
Eckhart
E
Schuler
Gerold
G
Jenne
Lars
L
D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000502:physiology*; D014616:Vaccinia virus / Q000276:immunology*
D019707:Receptors, Chemokine