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Journal of virology2020; 94(8); e01676-19; doi: 10.1128/JVI.01676-19

An Alphaherpesvirus Exploits Antimicrobial β-Defensins To Initiate Respiratory Tract Infection.

Abstract: β-Defensins protect the respiratory tract against the myriad of microbial pathogens entering the airways with each breath. However, this potentially hostile environment is known to serve as a portal of entry for herpesviruses. The lack of suitable respiratory model systems has precluded understanding of how herpesvirus virions overcome the abundant mucosal β-defensins during host invasion. We demonstrate how a central alphaherpesvirus, equine herpesvirus type 1 (EHV1), actually exploits β-defensins to invade its host and initiate viral spread. The equine β-defensins (eBDs) eBD1, -2, and -3 were produced and secreted along the upper respiratory tract. Despite the marked antimicrobial action of eBD2 and -3 against many bacterial and viral pathogens, EHV1 virions were resistant to eBDs through the action of the viral glycoprotein M envelope protein. Pretreatment of EHV1 virions with eBD2 and -3 increased the subsequent infection of rabbit kidney (RK13) cells, which was dependent on viral N-linked glycans. eBD2 and -3 also caused the aggregation of EHV1 virions on the cell surface of RK13 cells. Pretreatment of primary equine respiratory epithelial cells (EREC) with eBD1, -2, and -3 resulted in increased EHV1 virion binding to and infection of these cells. EHV1-infected EREC, in turn, showed an increased production of eBD2 and -3 compared to that seen in mock- and influenza virus-infected EREC. In addition, these eBDs attracted leukocytes, which are essential for EHV1 dissemination and which serve as latent infection reservoirs. These novel mechanisms provide new insights into herpesvirus respiratory tract infection and pathogenesis. How herpesviruses circumvent mucosal defenses to promote infection of new hosts through the respiratory tract remains unknown due to a lack of host-specific model systems. We used the alphaherpesvirus equine herpesvirus type 1 (EHV1) and equine respiratory tissues to decipher this key event in general alphaherpesvirus pathogenesis. In contrast to several respiratory viruses and bacteria, EHV1 resisted potent antimicrobial equine β-defensins (eBDs) eBD2 and eBD3 by the action of glycoprotein M. Instead, eBD2 and -3 facilitated EHV1 particle aggregation and infection of rabbit kidney (RK13) cells. In addition, virion binding to and subsequent infection of respiratory epithelial cells were increased upon preincubation of these cells with eBD1, -2, and -3. Infected cells synthesized eBD2 and -3, promoting further host cell invasion by EHV1. Finally, eBD1, -2, and -3 recruited leukocytes, which are well-known EHV1 dissemination and latency vessels. The exploitation of host innate defenses by herpesviruses during the early phase of host colonization indicates that highly specialized strategies have developed during host-pathogen coevolution.
Copyright © 2020 Van Cleemput et al.
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Publication Date: 2020-03-31 PubMed ID: 31996426PubMed Central: PMC7108845DOI: 10.1128/JVI.01676-19Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research article explores how the equine herpesvirus type 1 (EHV1) utilizes β-defensins, compounds that ordinarily protect the respiratory tract against microbial pathogens, to initiate the infection in hosts. Rather than being hindered by these antimicrobial substances, EHV1 uses them to promote the binding of virus particles to host cells.

Research Methodology and Findings

  • Scientists carried out this study by observing the behavior of EHV1 in the presence of equine β-defensins (eBDs) eBD1, -2, and -3. Under normal circumstances, these proteins perform antimicrobial actions, warding off many bacterial and viral pathogens.
  • Unexpectedly, though, EHV1 virions were found to be resistant to eBDs, courtesy of the action of a specific viral protein, the glycoprotein M envelope protein.
  • After pre-treating EHV1 virions with eBD2 and -3, an increased infection rate was observed in rabbit kidney (RK13) cells. This observation suggested that the presence of the equine β-defensins somehow promoted the virus’s ability to infect host cells.
  • Through further observation, eBD2 and -3 were seen to lead to the aggregation of EHV1 virions on the surface of RK13 cells. Similarly, pre-treating primary equine respiratory epithelial cells (EREC) with eBD1, -2, and -3 also resulted in an increase in EHV1 virion binding and subsequent infection.
  • ERECs infected by EHV1 then showed an increased production of eBD2 and -3, suggesting a self-propagating cycle where the virus induces production of the very substances that help its propagation.
  • Finally, these equine β-defensins also attracted leukocytes, white blood cells essential for EHV1 dissemination and hiding places for latent infections. This event presents another means through which the virus is able to spread through its host.

Significance of the Findings

  • The discoveries made in this study provide vital insights into how herpesviruses may be capable of bypassing the body’s natural defenses to infect new hosts through the respiratory tract.
  • Understanding that the EHV1 virus is not only resistant to equine β-defensins eBD2 and eBD3, but can actually utilize these compounds to promote infection, opens up new fronts for the development of antiviral therapies.
  • The study also highlights the intricate strategies developed by pathogens during their coevolution with hosts, pointing to a need for further research to fully comprehend these mechanisms and utilize them in combating various herpesvirus infections.

Cite This Article

APA
Van Cleemput J, Poelaert KCK, Laval K, Vanderheijden N, Dhaenens M, Daled S, Boyen F, Pasmans F, Nauwynck HJ. (2020). An Alphaherpesvirus Exploits Antimicrobial β-Defensins To Initiate Respiratory Tract Infection. J Virol, 94(8), e01676-19. https://doi.org/10.1128/JVI.01676-19

Publication

Journal of virology
ISSN: 1098-5514
NlmUniqueID: 0113724
Country: United States
Language: English
Volume: 94
Issue: 8
PII: e01676-19

Researcher Affiliations

Van Cleemput, Jolien
  • Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
  • Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
Poelaert, Katrien C K
  • Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
  • Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Laval, Kathlyn
  • Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
Vanderheijden, Nathalie
  • Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Dhaenens, Maarten
  • Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Daled, Simon
  • Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Boyen, Filip
  • Department of Pathology, Bacteriology and Poultry Diseases, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Pasmans, Frank
  • Department of Pathology, Bacteriology and Poultry Diseases, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Nauwynck, Hans J
  • Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium hans.nauwynck@ugent.be.

MeSH Terms

  • Alphaherpesvirinae / physiology
  • Animals
  • Anti-Infective Agents / adverse effects
  • Anti-Infective Agents / pharmacology
  • Cell Line
  • Epithelial Cells / virology
  • Herpesviridae Infections / virology
  • Herpesvirus 1, Equid
  • Horse Diseases / virology
  • Horses
  • Host-Pathogen Interactions / physiology
  • Immune Evasion
  • Rabbits
  • Respiratory Tract Infections / drug therapy
  • Respiratory Tract Infections / immunology
  • Respiratory Tract Infections / virology
  • Viral Envelope Proteins
  • beta-Defensins / adverse effects
  • beta-Defensins / pharmacology

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