Human cytomegalovirus paralyzes macrophage motility through down-regulation of chemokine receptors, reorganization of the cytoskeleton, and release of macrophage migration inhibitory factor.
Macrophages contribute to host defense and to the maintenance of immune homeostasis. Conversely, they are important targets of human cytomegalovirus (HCMV), a herpesvirus that has evolved many strategies to modulate the host immune response. Because an efficient macrophage trafficking is required for triggering an adequate immune response, we investigated the effects exerted by HCMV infection on macrophage migratory properties. By using endotheliotropic strains of HCMV, we obtained high rates of productively infected human monocyte-derived macrophages (MDM). Twenty-four hours after infection, MDM showed reduced polar morphology and became unable to migrate in response to inflammatory and lymphoid chemokines, bacterial products and growth factors, despite being viable and metabolically active. Although chemotactic receptors were only partially affected, HCMV induced a dramatic reorganization of the cytoskeleton characterized by rupture of the microtubular network, stiffness of the actin fibers, and collapse of the podosomes. Furthermore, supernatants harvested from infected MDM contained high amounts of macrophage migration inhibitory factor (MIF) and were capable to block the migration of neighboring uninfected MDM. Because immunodepletion of MIF from the conditioned medium completely restored MDM chemotaxis, we could show for the first time a functional role of MIF as an inhibitor of macrophage migration in the context of HCMV infection. Our findings reveal that HCMV uses different mechanisms to interfere with movement and positioning of macrophages, possibly leading to an impairment of antiviral responses and to an enhancement of the local inflammation.
Frascaroli
Giada
G
Institute for Virology, University of Ulm, Ulm, Germany.
Varani
Stefania
S
Blankenhorn
Nina
N
Pretsch
Robert
R
Bacher
Michael
M
Leng
Lin
L
Bucala
Richard
R
Landini
Maria Paola
MP
Mertens
Thomas
T
D002464:Cell Migration Inhibition / Q000276:immunology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000378:metabolism* / Q000821:virology; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000502:physiology; D014779:Virus Replication / Q000276:immunology
D008263:Macrophage Migration-Inhibitory Factors; D019707:Receptors, Chemokine; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human