Enhancement of Chemokine Function as an Immunomodulatory Strategy Employed by Human Herpesviruses

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Abel Viejo-Borbolla¹, Nadia Martinez-Martín¹, Hendrik J. Nel², Patricia Rueda³^,⁴, Rocío Martín¹, Soledad Blanco¹, Fernando Arenzana-Seisdedos³^,⁴, Marcus Thelen⁵, Padraic G. Fallon², Antonio Alcamí¹^,⁶^*

1 Department of Virology and Microbiology, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas – Universidad Autónoma de Madrid, Madrid, Spain, 2 School of Medicine, St James's Hospital, Trinity College Dublin, Dublin, Ireland, 3 Viral Pathogenesis Laboratory, Institute Pasteur, Paris, France, 4 INSERM U819, Paris, France, 5 Institute for Research in Biomedicine, Bellinzona, Switzerland, 6 Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom

Abstract Top

Herpes simplex virus (HSV) types 1 and 2 are highly prevalent human neurotropic pathogens that cause a variety of diseases, including lethal encephalitis. The relationship between HSV and the host immune system is one of the main determinants of the infection outcome. Chemokines play relevant roles in antiviral response and immunopathology, but the modulation of chemokine function by HSV is not well understood. We have addressed the modulation of chemokine function mediated by HSV. By using surface plasmon resonance and crosslinking assays we show that secreted glycoprotein G (SgG) from both HSV-1 and HSV-2 binds chemokines with high affinity. Chemokine binding activity was also observed in the supernatant of HSV-2 infected cells and in the plasma membrane of cells infected with HSV-1 wild type but not with a gG deficient HSV-1 mutant. Cell-binding and competition experiments indicate that the interaction takes place through the glycosaminoglycan-binding domain of the chemokine. The functional relevance of the interaction was determined both in vitro, by performing transwell assays, time-lapse microscopy, and signal transduction experiments; and in vivo, using the air pouch model of inflammation. Interestingly, and in contrast to what has been observed for previously described viral chemokine binding proteins, HSV SgGs do not inhibit chemokine function. On the contrary, HSV SgGs enhance chemotaxis both in vitro and in vivo through increasing directionality, potency and receptor signaling. This is the first report, to our knowledge, of a viral chemokine binding protein from a human pathogen that increases chemokine function and points towards a previously undescribed strategy of immune modulation mediated by viruses.

Author Summary Top

Chemokines are chemotactic cytokines that direct the flux of leukocytes to the site of injury and infection, playing a relevant role in the antiviral response. An uncontrolled, unorganized chemokine response is beneath the onset and maintenance of several immunopathologies. During millions of years of evolution, viruses have developed strategies to modulate the host immune system. One of such strategies consists on the secretion of viral proteins that bind to and inhibit the function of chemokines. However, the modulation of the chemokine network mediated by the highly prevalent human pathogen herpes simplex virus (HSV) is unknown. We have addressed this issue and show that HSV-1, causing cold sores and encephalitis and HSV-2, causing urogenital tract infections, interact with chemokines. We determined that the viral protein responsible for such activity is glycoprotein G (gG). gG binds chemokines with high affinity and, in contrast to all viral chemokine binding proteins described to date that inhibit chemokine function, we found that HSV gG potentiates chemokine function in vitro and in vivo. The implications of such potentiation in HSV viral cycle, pathogenesis and chemokine function are discussed.

Citation: Viejo-Borbolla A, Martinez-Martín N, Nel HJ, Rueda P, Martín R, et al. (2012) Enhancement of Chemokine Function as an Immunomodulatory Strategy Employed by Human Herpesviruses. PLoS Pathog 8(2): e1002497. doi:10.1371/journal.ppat.1002497
Editor: Laurent Coscoy, University of California-Berkeley, United States of America
Received: June 14, 2011; Accepted: December 6, 2011; Published: February 2, 2012
Copyright: © 2012 Viejo-Borbolla et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was funded by grants from the Spanish Ministry of Science and Innovation (SAF2009-07857), Wellcome Trust (051087/Z/97/Z) and Red Española de Esclerosis Múltiple (Instituto de Salud Carlos III, RD07/0060/0014). A.V.-B. has been supported by postdoctoral fellowships from the Instituto de Salud Carlos III and Consejo Superior de Investigaciones Científicas (Spanish Ministry of Science and Innovation). N.M.-M. is funded by a graduate fellowship from the Consejo Superior de Investigaciones Científicas (Spanish Ministry of Science and Innovation). PGF is supported by Science Foundation Ireland (07/IN.1/B902). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: aalcami@cbm.uam.es