Access to a main alphaherpesvirus receptor, located basolaterally in the respiratory epithelium, is masked by intercellular junctions.
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The respiratory epithelium of humans and animals is frequently exposed to alphaherpesviruses, originating from either external exposure or reactivation from latency. To date, the polarity of alphaherpesvirus infection in the respiratory epithelium and the role of respiratory epithelial integrity herein has not been studied. Equine herpesvirus type 1 (EHV1), a well-known member of the alphaherpesvirus family, was used to infect equine respiratory mucosal explants and primary equine respiratory epithelial cells (EREC), grown at the air-liquid interface. EHV1 binding to and infection of mucosal explants was greatly enhanced upon destruction of the respiratory epithelium integrity with EGTA or N-acetylcysteine. EHV1 preferentially bound to and entered EREC at basolateral cell surfaces. Restriction of infection via apical inoculation was overcome by disruption of intercellular junctions. Finally, basolateral but not apical EHV1 infection of EREC was dependent on cellular N-linked glycans. Overall, our findings demonstrate that integrity of the respiratory epithelium is crucial in the host's innate defence against primary alphaherpesvirus infections. In addition, by targeting a basolaterally located receptor in the respiratory epithelium, alphaherpesviruses have generated a strategy to efficiently escape from host defence mechanisms during reactivation from latency.
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Disruption of respiratory epithelial intercellular junctions by EGTA or N-acetylcysteine significantly increases EHV-1 plaques, plaque latitude and infectious virus titer in equine mucosal explants compared to untreated explants.
“The number of EHV-1 plaques, the plaque latitude and infectious virus titer were significantly increased in explants pretreated with EGTA or NAC compared to untreated ones (Van Cleemput et al., 2017).”
From The Pathogenesis and Immune Evasive Mechanisms of Equine Herpesvirus Type 1 (2021) · cites this paper as Van Cleemput et al., 2017
The Results section (‘Intercellular junctions protect respiratory mucosal explants from EHV1 infection’; page unavailable) reports more plaques, wider plaques, and higher infectious-virus titers after EGTA or NAC pretreatment than after control treatment. It explicitly reports significant plaque-count increases in nasal explants and significant plaque-latitude increases for the 97P70 strain, but does not establish that every stated increase in plaque latitude and titer was significant. The claim overstates the statistical significance across all three outcomes. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAfter primary replication in the horse respiratory epithelium, EHV-1 enters nerve endings of the peripheral nervous system, including those from trigeminal ganglia, sympathetic and parasympathetic neurons that innervate the epithelium.
“After primary replication in the horse respiratory epithelium, EHV-1 enters nerve endings of the PNS, including those coming from the trigeminal ganglia (TG), sympathetic and parasympathetic neurons that innervate the epithelium (Figure 1.1e; Van Cleemput et al., 2017).”
From The Pathogenesis and Immune Evasive Mechanisms of Equine Herpesvirus Type 1 (2021) · cites this paper as Van Cleemput et al., 2017
The Introduction says that viral DNA has been found in trigeminal ganglia, suggesting neuronal latency. The Discussion hypothesizes that primary respiratory replication can infect neurons, but neither passage establishes entry through nerve endings or identifies sympathetic and parasympathetic neurons as routes of infection. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDisruption of intercellular junctions results in enhanced EHV-1 binding to explant basolateral surfaces.
“Interestingly, the authors demonstrated that disruption of ICJ results in enhanced EHV-1 binding to explant basolateral surfaces.”
From The Pathogenesis and Immune Evasive Mechanisms of Equine Herpesvirus Type 1 (2021) · cites this paper as Van Cleemput et al., 2017
The presence of an EHV-1 receptor located at the basolateral side of the respiratory epithelium is a key advantage for the virus to efficiently bind and infect epithelial cells upon reactivation.
“The presence of an EHV-1 receptor located at the basolateral side of the respiratory epithelium is a key advantage for the virus to efficiently bind and infect epithelial cells upon reactivation (Van Cleemput et al., 2017).”
From The Pathogenesis and Immune Evasive Mechanisms of Equine Herpesvirus Type 1 (2021) · cites this paper as Van Cleemput et al., 2017
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The Pathogenesis and Immune Evasive Mechanisms of Equine Herpesvirus Type 1
Laval, K., Poelaert, K. C. K., Van Cleemput, J., Zhao, J., Vandekerckhove, A. P., Gryspeerdt, A. C., Garré, B., van der Meulen, K., Baghi, H. B., Dubale, H. N., et al. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.662686 · Cited by 54 · see citing works
“The presence of an EHV1 receptor located at the basolateral side of the respiratory epithelium is a key advantage for the virus to efficiently bind and infect epithelial cells upon reactivation (Van Cleemput et al., 2017).”
BackgroundInfluentialPollens destroy respiratory epithelial cell anchors and drive alphaherpesvirus infection
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An alphaherpesvirus exploits antimicrobial β-Defensins to initiate respiratory tract infection.
Van Cleemput, J., Poelaert, K. C. K., Laval, K., Vanderheijden, N., Dhaenens, M., Daled, S., Boyen, F., Pasmans, F., & Nauwynck, H. J. (2020) · Journal of Virology · doi:10.1128/jvi.01676-19 · Cited by 13 · see citing works
Oh, D., Han, S., Tignon, M., Balmelle, N., Cay, A. B., Griffioen, F., Droesbeke, B., & Nauwynck, H. (2023) · Veterinary Research · doi:10.1186/s13567-023-01249-8 · Cited by 12 · see citing works
Cleemput, J. V., Poelaert, K. C., Laval, K., den Broeck, W. V., & Nauwynck, H. (2019) · Veterinary Microbiology · doi:10.1016/j.vetmic.2019.05.009 · Cited by 13 · see citing works
Poelaert, K. C. K., Cleemput, J. V., Laval, K., Xie, J., Favoreel, H. W., & Nauwynck, H. (2019) · Journal of General Virology · doi:10.1099/jgv.0.001317 · Cited by 10 · see citing works
Characterization of feline herpesvirus-1 deletion mutants in tissue explant cultures
Lee, Y., Maes, R. K., Kiupel, M., Nauwynck, H., & Hussey, G. S. (2020) · Virus Research · doi:10.1016/j.virusres.2020.197981 · Cited by 9 · see citing works
EHV-1 Pathogenesis: Current in vitro Models and Future Perspectives
Kamel, M. S., Pavulraj, S., Osterrieder, N., & Azab, W. (2019) · Frontiers in Veterinary Science · doi:10.3389/fvets.2019.00251 · Cited by 9 · see citing works
Portaels, J., Crombrugge, E. V., Broeck, W. V. D., Lagrou, K., Laval, K., & Nauwynck, H. (2024) · Viruses · doi:10.3390/v16081208 · Cited by 7 · see citing works
Zarski, L. M., VAALA, W. E., Barnett, D. C., Bain, F. T., & Hussey, G. S. (2021) · Frontiers in Veterinary Science · doi:10.3389/fvets.2021.674850 · Cited by 7 · see citing works
Crombrugge, E. V., Vanbeylen, E., Cleemput, J. V., Broeck, W. V. D., Laval, K., & Nauwynck, H. (2022) · Viruses · doi:10.3390/v14010149 · Cited by 7 · see citing works
Zhang, D., Lin, L., Yang, J., Lv, Q., Wang, M., Hua, L., Zhang, K., Chen, H., Wu, B., & Peng, Z. (2024) · mSphere · doi:10.1128/msphere.00297-24 · Cited by 7 · see citing works
Gammaherpesvirus BoHV-4 infects bovine respiratory epithelial cells mainly at the basolateral side
Yang, B., Xie, J., Cleemput, J. V., Wei, R., Opsomer, G., & Nauwynck, H. (2019) · Veterinary Research · doi:10.1186/s13567-019-0629-z · Cited by 7 · see citing works
Crombrugge, E. V., Ren, X., Glorieux, S., Žarak, I., Broeck, W. V. D., Bachert, C., Zhang, N., Zele, T. V., Kim, D., Smith, G. A., et al. (2024) · mBio · doi:10.1128/mbio.01873-24 · Cited by 6 · see citing works
Kydd, J. H., Hannant, D., Robinson, R. S., Bryant, N. A., & Osterrieder, N. (2019) · Vaccine · doi:10.1016/j.vaccine.2019.09.106 · Cited by 6 · see citing works
Weldearegay, Y. B., Brogaard, L., Rautenschlein, S., Meens, J., Valentin‐Weigand, P., & Schaaf, D. (2025) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2025.1565513 · Cited by 5 · see citing works
Mohamed, E., Žarak, I., Vereecke, N., Theuns, S., Laval, K., & Nauwynck, H. (2025) · Veterinary Research · doi:10.1186/s13567-024-01434-3 · Cited by 4 · see citing works
Stasi, D., Wagner, B., Barnum, S. M., & Pusterla, N. (2023) · Journal of Equine Veterinary Science · doi:10.1016/j.jevs.2023.104992 · Cited by 3 · see citing works
Mohamed, E., Cleemput, J. V., Şahin, B., Broeck, W. V. D., Boyen, F., & Nauwynck, H. (2025) · Viruses · doi:10.3390/v17070980 · Cited by 1 · see citing works
Proteomic analysis of the secretome of equine herpesvirus-1 infected rabbit kidney cells
Rożek, W., Kwaśnik, M., Malinowska, A., Stasiak, K., Larska, M., & Rola, J. (2021) · Research in Veterinary Science · doi:10.1016/j.rvsc.2021.08.014 · Cited by 1 · see citing works
Equine Herpes Virus-1. A clinician’s perspective.
Tyrnenopoulou, P., & Diakakis, N. E. (2023) · Journal of the Hellenic Veterinary Medical Society · doi:10.12681/jhvms.29907 · Cited by 1 · see citing works
Oh, D., Han, S., Tignon, M., Balmelle, N., Cay, A. B., Griffioen, F., Droesbeke, B., & Nauwynck, H. J. (2024) · Figshare · doi:10.6084/m9.figshare.26654707
Oh, D., Han, S., Tignon, M., Balmelle, N., Cay, A. B., Griffioen, F., Droesbeke, B., & Nauwynck, H. J. (2024) · Figshare · doi:10.6084/m9.figshare.26654716
Oh, D., Han, S., Tignon, M., Balmelle, N., Cay, A. B., Griffioen, F., Droesbeke, B., & Nauwynck, H. J. (2024) · Figshare · doi:10.6084/m9.figshare.24844728
Oh, D., Han, S., Tignon, M., Balmelle, N., Cay, A. B., Griffioen, F., Droesbeke, B., & Nauwynck, H. J. (2023) · Figshare · doi:10.6084/m9.figshare.24844631
Oh, D., Han, S., Tignon, M., Balmelle, N., Cay, A. B., Griffioen, F., Droesbeke, B., & Nauwynck, H. J. (2024) · Figshare · doi:10.6084/m9.figshare.26654713
Aslam, A., Saleem, W., Žarak, I., Cleemput, J. V., & Nauwynck, H. (2026) · Veterinary Research · doi:10.1186/s13567-026-01767-1
- Authors
- Van Cleemput, J., Poelaert, K. C. K., Laval, K., Maes, R., Hussey, G. S., Van den Broeck, W., & Nauwynck, H. J.
- Affiliations
- Ghent University (BE)
- Princeton University (US)
- Michigan State University (US)
- Corresponding author
- Nauwynck, Hans J.
- Venue
- Scientific Reports
- Published
- 2017-11-30
- Volume
- 7
- Issue
- 1
- Pages
- 16656-16656
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5709510
- OpenAlex
- W2770240216
- Cited by
- 34
- References
- 77
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 8 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 8 · 2018: 1
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion, other-oa)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- Funders
- Fonds Wetenschappelijk Onderzoek (11Y5415N)
- Vlaamse regering
- Topics
- Health Sciences › Medicine › Epidemiology › Herpesvirus Infections and Treatments
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Keywords
- alphaherpesvirus, equine herpesvirus 1, respiratory epithelium, intercellular junctions, epithelial barrier integrity, viral entry, N-glycans, air-liquid interface, viral reactivation
- MeSH terms
- Animals, Herpesvirus 1, Equid, Herpesviridae Infections, Horse Diseases, Horses, Intercellular Junctions, Polysaccharides, Receptors, Virus, Virus Replication, Alphaherpesvirinae, Viral Load, Respiratory Mucosa
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