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* Institute for Virology, University of Ulm, Ulm, Germany;
Department of Hematology and Oncology "L. and A. Seragnoli", University of Bologna, Bologna, Italy;
Department of Neurology, Philipps-University of Marburg, Marburg, Germany; and
Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by Project SFB 451-A2 from the Deutsche Forschungsgemeinschaft (to T.M.), by AIDS Project from the Ministry of Public Health, by Basic Target Research, ex Fundus 60% from the University of Bologna (to M.P.L. and S.V.), and by the National Institutes of Health (to R.B. and L.L.).
2 Address correspondence and reprint requests to Dr. Thomas Mertens, Institute for Virology, University of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany. E-mail address: thomas.mertens{at}uniklinik-ulm.de
3 Abbreviations used in this paper: HCMV, human cytomegalovirus; MDM, monocyte-derived macrophage; MOI, multiplicity of infection; p.i., postinfection; MIF, macrophage migration inhibitory factor; hrMIF, human recombinant MIF; MFI, mean fluorescence intensity; PI, propidium iodide; VEGF, vascular endothelial growth factor.
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