Interactions between herpes simplex virus and cell-surface glycosaminoglycans: the role of viral protein-glycosylation and cellular GAGs in modulating virus binding and diffusion.
Our lab is interested in how virus attachment, detachment, and diffusion is modulated at the cell surface to ensure efficient virus entry and infection. Specifically, we have long focused on glycosaminoglycan(GAG)-binding viruses. These viruses take advantage of linear sulfated polysaccharides found at the cell surface, such as heparan and chondroitin sulfate, to initiate the infection process (Figure A). In this context, herpes simplex virus has been our model virus of choice.
Our research efforts focus on dissecting HSV-GAG interactions systematically from both virus and cell sides. From the virus’s side, we explore the role of mucin-like domains (MLD) [1], highly glycosylated domains present on f viral glycoproteins. From the cell’s side, we investigate the influence of the biochemical profile of the GAGs (i.e., their degree of sulfation, GAG type, etc.).
Our initial work was extensively based on biophysical approaches relying on cell-surface mimics (Figure B) to study virus attachment, detachment, and diffusion on GAGs using both TIRF microscopy [2-5] and AFM-based force spectroscopy [3]. We have shown that MLDs play a key role in facilitating the detachment of HSV-1 and HSV-2 from the cell surface, while also facilitating GAG-recognition. We speculate that the MLDs mode of action is based on a delicate balance between: specific recognition of the GAG-binding domain, electrostatic repulsion between negatively charged MLD and GAGs, and steric hinderances; which together regulate the number of bonds involved in the multivalent virus-GAG interaction[5]. The MLD may also act by hiding other viral glycoproteins, thereby preventing their premature engagement during initial virus recruitment at the cell surface. In our work, we have shown that HSV has the ability of diffusing on GAG molecules, presumably through a hopping behavior associated with binding and unbinding of individual ligand-receptor interactions, mediating the multivalent virus-GAG interaction (Figure C). This diffusion behavior appears to be dependent on the nature of the GAGs on the cell surface. All observations obtained using a minimal molecular model of the glycocalyx (Figure B) have been further confirmed on the cellular level in single particle tracking experiments with live cell microscopy [6]. Their biological relevance is further supported by virus binding and infection experiments in cells of relevance.
Many GAG-binding viruses carry mucin-like domains on their glycoproteins. It will therefore be exciting to see if the molecular mechanisms proposed in the context of our HSV work can be applied across viral species.
Our work on HSV has been supported for many years by valuable and exciting collaborations with Tomas Bergström and Sigvard Olofsson at Gothenburg University. It has received funding by the Swedish Research council, the Area of Advance Material Sciences (Chalmers University of Technology), and the Wenner-Gren Foundations.
Key References
1. Structure and role of O-linked glycans in viral envelope proteins
S. Olofsson, M. Bally, E. Trybala, T. Bergström
Annurev Virology, 2023, 10, 283-304.
2. Mucin-like region of herpes simplex virus type 1 attachment protein gC modulates the virus-glycosaminoglycan interaction
N. Altgärde, C. Eriksson, N. Peerboom, T. Phan-Xuan, S. Moeller, M. Schnabelrauch, S. Svedhem, E. Trybala, T. Bergström, M. Bally.
Journal of Biological Chemistry, 2015, 290, 35, 21473-21485.
3. Binding kinetics and lateral mobility of herpes simplex virus type 1 on end-grafted sulfated glycosaminoglycans
N. Peerboom, S. Block, N. Altgärde, O. Wahlsten, S. Möller, M. Schnabelrauch, T. Bergström and M. Bally
Biophysical Journal 113, 2017, 1223–1234.
4. Regulatory Mechanisms of the Mucin-Like Region on Herpes Simplex Virus during Cellular Attachment
M. Delguste, N. Peerboom, G. LeBrun, E. Trybala, S. Olofsson, T. Bergström, D. Alsteens, M. Bally
ACS Chem Biol. 2019, 14(3):534-542.
5. Herpes Simplex Virus Type 2 Mucin-Like Glycoprotein mgG Promotes Virus Release from the Surface of Infected Cells
E. Trybala, N. Peerboom, B. Adamiak, M. Krzyzowska, J.Å. Liljeqvist, M. Bally and T. Bergström
Viruses, 2021, 13(5), 887
6. Cellular Chondroitin Sulfate and the Mucin-like Domain of Viral Glycoprotein C Promote Diffusion of Herpes Simplex Virus 1 While Heparan Sulfate Restricts Mobility
Y. Abidine, L. Liu, O. Wallén, E. Trybala, S. Olofsson, T. Bergström and M. Bally
Viruses, 2022, 14, 8, 1836