The alphaherpesvirus gE/gI glycoprotein complex and proteases jointly orchestrate invasion across the host’s upper respiratory epithelial barrier
ABSTRACT Alphaherpesviruses, including herpes simplex virus type 1 (HSV-1), pseudorabies virus (PRV), and bovine herpesvirus type 1 (BoHV-1), are significant pathogens affecting humans and animals. These viruses penetrate the upper respiratory tract mucosa, yet the mechanisms facilitating this invas...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2024-11-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01873-24 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846168730148536320 |
|---|---|
| author | E. Van Crombrugge X. Ren S. Glorieux I. Zarak W. Van den Broeck C. Bachert N. Zhang T. Van Zele D. Kim G. A. Smith K. Laval H. Nauwynck |
| author_facet | E. Van Crombrugge X. Ren S. Glorieux I. Zarak W. Van den Broeck C. Bachert N. Zhang T. Van Zele D. Kim G. A. Smith K. Laval H. Nauwynck |
| author_sort | E. Van Crombrugge |
| collection | DOAJ |
| description | ABSTRACT Alphaherpesviruses, including herpes simplex virus type 1 (HSV-1), pseudorabies virus (PRV), and bovine herpesvirus type 1 (BoHV-1), are significant pathogens affecting humans and animals. These viruses penetrate the upper respiratory tract mucosa, yet the mechanisms facilitating this invasion are not fully understood. This study investigates the role of the gE/gI glycoprotein complex and proteases in mucosal invasion by these viruses. Using species-specific respiratory mucosal explants, we observed that the removal of extracellular calcium disrupts epithelial junction integrity, enhancing viral infection across all viruses and suggesting a common mechanism of targeting a basolaterally located receptor. PRV exhibited significantly faster replication and deeper invasion compared to HSV-1 and BoHV-1. The gE glycoprotein was consistently polarized at the basement membrane across all viruses, indicating a critical role in the process of viral entry and subsequent spread through the epithelium. In this context, “infection” refers to the virus’s attachment to its cell-surface receptor, entry into the cell, and completion of the viral life cycle, culminating in the production of progeny virions. Notably, in gE/gI null mutants of PRV and HSV-1, while the infection was not abortive and the viral life cycle was completed, the infection was delayed, and the invasion into the deeper layers of the epithelium and underlying mucosa was significantly reduced. In BoHV-1 mutants, this effect was even more pronounced, with infection restricted to the apical cells, failing to progress to the basal cells. In addition, PRV and HSV-1 invasion involved serine protease activity, unlike BoHV-1, which correlates with its slower invasion pace. Notably, the protease facilitating PRV invasion was identified as a urokinase plasminogen activator (uPA), while the specific protease for HSV-1 remains unidentified. These findings highlight the critical roles of the gE/gI complex and proteases in alphaherpesvirus pathogenesis, offering potential targets for therapeutic intervention.IMPORTANCEHerpes simplex virus type 1 (HSV-1) infections are a worldwide issue. More than three billion people are infected with HSV-1 globally. Although most infections with HSV-1 occur subclinically, severe symptoms and complications are numerous and can be life-threatening. Complications include encephalitis and blindness. Recently, HSV-1 infections have been associated with the development of Alzheimer's Disease. To date, no effective vaccines against HSV-1 are on the market. Pseudorabies virus (PRV) and bovine herpesvirus type 1 (BoHV-1) are two alphaherpesviruses of major veterinary importance. Although efforts have been made to eradicate these viruses from livestock animals, clinical problems still occur, resulting in great economic losses for farmers. It is evident that new insights into the pathogenesis of alphaherpesviruses are needed, to develop effective treatments and novel preventive therapies. |
| format | Article |
| id | doaj-art-cbddc01b84c14963a3963b65f7d032f0 |
| institution | Kabale University |
| issn | 2150-7511 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-cbddc01b84c14963a3963b65f7d032f02024-11-13T14:03:28ZengAmerican Society for MicrobiologymBio2150-75112024-11-01151110.1128/mbio.01873-24The alphaherpesvirus gE/gI glycoprotein complex and proteases jointly orchestrate invasion across the host’s upper respiratory epithelial barrierE. Van Crombrugge0X. Ren1S. Glorieux2I. Zarak3W. Van den Broeck4C. Bachert5N. Zhang6T. Van Zele7D. Kim8G. A. Smith9K. Laval10H. Nauwynck11Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Laboratory of Virology, Ghent University, Merelbeke, BelgiumDepartment of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Laboratory of Virology, Ghent University, Merelbeke, BelgiumCenter for Human Body Material, Faculty of Medicine and Health Sciences, Ghent University, Ghent, BelgiumDepartment of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Laboratory of Virology, Ghent University, Merelbeke, BelgiumDepartment of Morphology, Imaging, Orthopedics, Rehabilitation and Nutrition, Faculty of Veterinary Medicine, Ghent University, Merelbeke, BelgiumDepartment of Otorhinolaryngology – Head and Neck Surgery, University Hospital of Münster, Münster, GermanyDepartment of Head and Skin, Upper Airways Research Laboratory, Faculty of Medicine and Health Sciences, Ghent University, Ghent, BelgiumDepartment of Head and Skin, Upper Airways Research Laboratory, Faculty of Medicine and Health Sciences, Ghent University, Ghent, BelgiumDepartment of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USADepartment of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USADepartment of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Laboratory of Virology, Ghent University, Merelbeke, BelgiumDepartment of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Laboratory of Virology, Ghent University, Merelbeke, BelgiumABSTRACT Alphaherpesviruses, including herpes simplex virus type 1 (HSV-1), pseudorabies virus (PRV), and bovine herpesvirus type 1 (BoHV-1), are significant pathogens affecting humans and animals. These viruses penetrate the upper respiratory tract mucosa, yet the mechanisms facilitating this invasion are not fully understood. This study investigates the role of the gE/gI glycoprotein complex and proteases in mucosal invasion by these viruses. Using species-specific respiratory mucosal explants, we observed that the removal of extracellular calcium disrupts epithelial junction integrity, enhancing viral infection across all viruses and suggesting a common mechanism of targeting a basolaterally located receptor. PRV exhibited significantly faster replication and deeper invasion compared to HSV-1 and BoHV-1. The gE glycoprotein was consistently polarized at the basement membrane across all viruses, indicating a critical role in the process of viral entry and subsequent spread through the epithelium. In this context, “infection” refers to the virus’s attachment to its cell-surface receptor, entry into the cell, and completion of the viral life cycle, culminating in the production of progeny virions. Notably, in gE/gI null mutants of PRV and HSV-1, while the infection was not abortive and the viral life cycle was completed, the infection was delayed, and the invasion into the deeper layers of the epithelium and underlying mucosa was significantly reduced. In BoHV-1 mutants, this effect was even more pronounced, with infection restricted to the apical cells, failing to progress to the basal cells. In addition, PRV and HSV-1 invasion involved serine protease activity, unlike BoHV-1, which correlates with its slower invasion pace. Notably, the protease facilitating PRV invasion was identified as a urokinase plasminogen activator (uPA), while the specific protease for HSV-1 remains unidentified. These findings highlight the critical roles of the gE/gI complex and proteases in alphaherpesvirus pathogenesis, offering potential targets for therapeutic intervention.IMPORTANCEHerpes simplex virus type 1 (HSV-1) infections are a worldwide issue. More than three billion people are infected with HSV-1 globally. Although most infections with HSV-1 occur subclinically, severe symptoms and complications are numerous and can be life-threatening. Complications include encephalitis and blindness. Recently, HSV-1 infections have been associated with the development of Alzheimer's Disease. To date, no effective vaccines against HSV-1 are on the market. Pseudorabies virus (PRV) and bovine herpesvirus type 1 (BoHV-1) are two alphaherpesviruses of major veterinary importance. Although efforts have been made to eradicate these viruses from livestock animals, clinical problems still occur, resulting in great economic losses for farmers. It is evident that new insights into the pathogenesis of alphaherpesviruses are needed, to develop effective treatments and novel preventive therapies.https://journals.asm.org/doi/10.1128/mbio.01873-24alphaherpesvirusupper respiratory tractpathogenesis, mucosa invasiongE/gI complexproteasesurokinase plasminogen activator |
| spellingShingle | E. Van Crombrugge X. Ren S. Glorieux I. Zarak W. Van den Broeck C. Bachert N. Zhang T. Van Zele D. Kim G. A. Smith K. Laval H. Nauwynck The alphaherpesvirus gE/gI glycoprotein complex and proteases jointly orchestrate invasion across the host’s upper respiratory epithelial barrier mBio alphaherpesvirus upper respiratory tract pathogenesis, mucosa invasion gE/gI complex proteases urokinase plasminogen activator |
| title | The alphaherpesvirus gE/gI glycoprotein complex and proteases jointly orchestrate invasion across the host’s upper respiratory epithelial barrier |
| title_full | The alphaherpesvirus gE/gI glycoprotein complex and proteases jointly orchestrate invasion across the host’s upper respiratory epithelial barrier |
| title_fullStr | The alphaherpesvirus gE/gI glycoprotein complex and proteases jointly orchestrate invasion across the host’s upper respiratory epithelial barrier |
| title_full_unstemmed | The alphaherpesvirus gE/gI glycoprotein complex and proteases jointly orchestrate invasion across the host’s upper respiratory epithelial barrier |
| title_short | The alphaherpesvirus gE/gI glycoprotein complex and proteases jointly orchestrate invasion across the host’s upper respiratory epithelial barrier |
| title_sort | alphaherpesvirus ge gi glycoprotein complex and proteases jointly orchestrate invasion across the host s upper respiratory epithelial barrier |
| topic | alphaherpesvirus upper respiratory tract pathogenesis, mucosa invasion gE/gI complex proteases urokinase plasminogen activator |
| url | https://journals.asm.org/doi/10.1128/mbio.01873-24 |
| work_keys_str_mv | AT evancrombrugge thealphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT xren thealphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT sglorieux thealphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT izarak thealphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT wvandenbroeck thealphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT cbachert thealphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT nzhang thealphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT tvanzele thealphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT dkim thealphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT gasmith thealphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT klaval thealphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT hnauwynck thealphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT evancrombrugge alphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT xren alphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT sglorieux alphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT izarak alphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT wvandenbroeck alphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT cbachert alphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT nzhang alphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT tvanzele alphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT dkim alphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT gasmith alphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT klaval alphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier AT hnauwynck alphaherpesvirusgegiglycoproteincomplexandproteasesjointlyorchestrateinvasionacrossthehostsupperrespiratoryepithelialbarrier |