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

PLoS Pathogens

Nadia Martinez-Martín¹  Abel Viejo-Borbolla¹  Fernando Arenzana-Seisdedos¹  Soledad Blanco¹  Rocío Martín²  Padraic G. Fallon²  Antonio Alcamí³  Hendrik J. Nel⁴  Marcus Thelen⁵  Patricia Rueda⁵ 

[1] Department of Virology and Microbiology, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas – Universidad Autónoma de Madrid, Madrid, Spain;INSERM U819, Paris, France;Institute for Research in Biomedicine, Bellinzona, Switzerland;School of Medicine, St James's Hospital, Trinity College Dublin, Dublin, Ireland;Viral Pathogenesis Laboratory, Institute Pasteur, Paris, France

关键词: Chemokines;    Chemotaxis;    Cell migration;    Monocytes;    Cell binding;    Herpes simplex virus;    White blood cells;    Pathogenesis;   

DOI  :  10.1371/journal.ppat.1002497

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY