Abstract
The molecular mechanism of herpes simplex virus (HSV) entry and the associated inflammatory response in the nervous system remain poorly understood. Using mouse-derived ex vivo dorsal root ganglia (DRG) explant model and single cell neurons (SCNs), in this study, we provided a visual evidence for the expression of heparan sulfate (HS) and 3-O-sulfated heparan sulfate (3-OS HS) followed by their interactions with HSV-1 glycoprotein B (gB) and glycoprotein D (gD) during cell entry. Upon heparanase treatment of DRG-derived SCN, a significant inhibition of HSV-1 entry was observed suggesting the involvement of HS role during viral entry. Finally, a cytokine array profile generated during HSV-1 infection in DRG explant indicated an enhanced expression of chemokines (LIX, TIMP-2, and M-CSF)—known regulators of HS. Taken together, these results highlight the significance of HS during HSV-1 entry in DRG explant. Further investigation is needed to understand which isoforms of 3-O-sulfotransferase (3-OST)-generated HS contributed during HSV-1 infection and associated cell damage.
Highlights
The hallmark of herpes simplex virus type 1 (HSV-1) infection is to establish life-long latency in the sensory ganglia mainly in the dorsal root ganglia (DRG) of the host following an initial infection in epithelial cells (Roizman and Whitley 2013; Fraser and Valyi-Nagy 1993; Wilson and Mohr 2012)
We developed mouse-derived DRG explants and single cell neurons (SCNs) models to investigate early stages of HSV-1 infectivity
We first demonstrated that diverse chains of heparan sulfate (HS) (HS and 3-O-sulfated heparan sulfate (3-OS HS)) are present on the surface of DRGs and SCNs as evident from the results of the immunofluorescence experiments (Figs. 2 and 3)
Summary
The hallmark of herpes simplex virus type 1 (HSV-1) infection is to establish life-long latency in the sensory ganglia mainly in the dorsal root ganglia (DRG) of the host following an initial infection in epithelial cells (Roizman and Whitley 2013; Fraser and Valyi-Nagy 1993; Wilson and Mohr 2012). The process of HSV-1 entry initiates with the specific interaction between viral envelope glycoproteins and host cell surface receptors (Antoine et al 2013; Spear 2004; Hadigal and Shukla 2013; Connolly et al 2011). The HSV glycoproteins B and C (gB and gC, respectively) mediate their initial attachment to host cell surface heparan sulfate proteoglycans (HSPG) (Shukla and Spear 2001; Tiwari et al 2015; WuDunn and Spear 1989; Herold et al 1991; Shieh et al 1992). The initial binding step of the virus to HSPG results in a conformational change that brings major viral glycoprotein D (gD) binding domain to interact with any given host cell receptors (nectin, HVEM, and 3-O-sulfated heparan sulfate; 3-OS HS). The later process involves three additional HSV glycoproteins, gB, gH, and gL, and possibly an additional gH co-receptor, which trigger the fusion of the viral envelope with the
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