Syndecan-1 and syndecan-2 play key roles in herpes simplex virus type-1 infection

Abstract

Herpes simplex virus type 1 (HSV-1) is an important human pathogen and a leading cause of infectious blindness in the developed world. HSV-1 exploits heparan sulfate proteoglycans (HSPG) for attachment to cells. While the significance of heparan sulphate (HS) moieties in HSV-1 infection is well established, the role of specific proteoglycan core proteins in the infection process remains poorly understood. The objective of this study was to assess the roles of syndecan-1 and syndecan-2 core proteins in HSV-1 infection, both of which are expressed by many HSV-1 target cell types. Our results demonstrate that syndecan-1 and syndecan-2 gene silencing by RNA interference reduces HSV-1 entry, plaque formation and facilitates cell survival. Furthermore, HSV-1 infection increases syndecan-1 and syndecan-2 protein synthesis and a resultant increase in cell surface expression of HS. Our observations suggest that changes in syndecan-1 and syndecan-2 expression levels may be related to active viral infection. Taken together, our findings provide new insights into HSPG functions during HSV-1 entry and spread. INTRODUCTIONHerpes simplex virus type 1 (HSV-1) is a clinically important pathogen and a leading cause of infectious blindness in the developed world. HSV-1 productively infects epithelial cells and establishes latent infection in sensory ganglia for the life of the host (Kumaraguru & Rouse, 2002;Terasaka et al., 2010). Currently, no cure exists against HSV-1, which can be transmitted via asymptomatic shedding by latently infected individuals (Hill & Clement, 2009). Prevention of virus transmission to uninfected people is a real challenge compounded by our limited understanding of HSV-1-host cell interactions including virus entry, which is the first essential step for the establishment of an acute and/or latent infection.Enveloped viruses including HSV-1 penetrate host cells by inducing fusion between the virus envelope and the host cell membrane. HSV-1 entry is a stepwise process, which starts when HSV-1 envelope glycoproteins gB and gC attach to cell surface heparan sulfate proteoglycans (HSPGs) (Herold et al., 1991;Nicola et al., 2003;Trybala et al., 2000). This initial interaction enables HSV-1 glycoprotein D (gD) to bind to one of the known gD entry co-receptors. There are three classes of gD co-receptors that have been characterized: nectin-1 (HveC) and nectin-2 (HveB), which are both members of the immunoglobulin superfamily (Geraghty et al., 1998), herpesvirus entry mediator (HVEM) that belongs to the tumour necrosis factor receptor family (Montgomery et al., 1996), and 3-O-sulfated heparan sulfate (3-OS HS) which is a specifically modified form of heparan sulfate (HS) (Shukla et al., 1999b; O'Donnell et al., 2010). The binding of gD to one of its receptors leads to conformational changes in gD that allows it to activate a multiglycoprotein complex involving gB, gD, gH and gL that triggers the viral fusion with the host cell membrane (Atanasiu et al., 2007;Spear et al., 2000). This fusion mechanism is utilized...

Analysis on the expression and function of syndecan in the Pacific white shrimp Litopenaeus vannamei

“…This was very similar to previous reports in human hepatocytes that interference of the syndecan gene by specific siRNAs could block hepatitis C virus (HCV) attachment and resulted in reduction of HCV infection (Shi et al, 2013). Down-regulation of syndecan in Hela cell could also reduce Herpes simplex virus type 1 entry and facilitate cell survival (Bacsa et al, 2011). Depletion of syndecan in HaCaT cell lines could also reduce the human papillomavirus (HPV) infections (Surviladze et al, 2012).…”

Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release

“…HS is a glycosaminoglycan (GAG) that is present in almost all mammalian tissues on cell surfaces and in the extracellular matrix (17,26,27). It plays a key role in ECM integrity, barrier function, and cell-ECM interactions and is used by many viruses for initial attachment to target cells.…”

Herpes simplex virus downregulation of secretory leukocyte protease inhibitor enhances human papillomavirus type 16 infection

“…Given that we examined one specific mechanism that could enhance HPV16 infectious uptake, our data warrant a further investigation into the other cellular changes induced by HSV infection that may lead to an environment that promotes HPV infection. For example, significant increases in the levels of syndecan-1 and syndecan-2 produced by HSV-1-infected HeLa cells have been reported (Bacsa et al, 2011). As syndecan-1 is the most abundant HSPG expressed on the surface of keratinocytes, it is logical to hypothesize that epithelium infected by HSV has localized increases in the levels of syndecan-1 and syndecan-2, potentially resulting in faster HSPG-mediated binding and subsequent conformational changes of the HPV16 capsid that expose the N terminus of L2 allowing for furin cleavage (Alexopoulou et al, 2007;Raff et al, 2013;Shafti-Keramat et al, 2003).…”