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An alphaherpesvirus exploits antimicrobial beta-defensins to initiate respiratory tract infection

Jolien Van Cleemput (UGent) , Katrien Poelaert (UGent) , Kathlyn Laval (UGent) , Nathalie Vanderheijden (UGent) , Maarten Dhaenens (UGent) , Simon Daled (UGent) , Filip Boyen (UGent) , Frank Pasmans (UGent) and Hans Nauwynck (UGent)
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Abstract
beta-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 p-defensins during host invasion. We demonstrate how a central alphaherpesvirus, equine herpesvirus type 1 (EHV1), actually exploits p-defensins to invade its host and initiate viral spread. The equine beta-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. IMPORTANCE How herpesviruses circumvent mucosal defenses to promote infection of new hosts through the respiratory tract remains unknown due to a lack of hostspecific 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 p-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.
Keywords
BLOOD MONONUCLEAR-CELLS, HUMAN ALPHA-DEFENSIN, HUMAN BETA-DEFENSIN-3, THETA-DEFENSINS, GLYCOPROTEIN-M, VIRUS, SEQUENCE, PEPTIDES, INNATE, HERPESVIRUS-1, beta-defensins, alphaherpesvirus, equine herpesvirus, immune evasion, respiratory tract

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MLA
Van Cleemput, Jolien, et al. “An Alphaherpesvirus Exploits Antimicrobial Beta-Defensins to Initiate Respiratory Tract Infection.” JOURNAL OF VIROLOGY, vol. 94, no. 8, 2020.
APA
Van Cleemput, J., Poelaert, K., Laval, K., Vanderheijden, N., Dhaenens, M., Daled, S., … Nauwynck, H. (2020). An alphaherpesvirus exploits antimicrobial beta-defensins to initiate respiratory tract infection. JOURNAL OF VIROLOGY, 94(8).
Chicago author-date
Van Cleemput, Jolien, Katrien Poelaert, Kathlyn Laval, Nathalie Vanderheijden, Maarten Dhaenens, Simon Daled, Filip Boyen, Frank Pasmans, and Hans Nauwynck. 2020. “An Alphaherpesvirus Exploits Antimicrobial Beta-Defensins to Initiate Respiratory Tract Infection.” JOURNAL OF VIROLOGY 94 (8).
Chicago author-date (all authors)
Van Cleemput, Jolien, Katrien Poelaert, Kathlyn Laval, Nathalie Vanderheijden, Maarten Dhaenens, Simon Daled, Filip Boyen, Frank Pasmans, and Hans Nauwynck. 2020. “An Alphaherpesvirus Exploits Antimicrobial Beta-Defensins to Initiate Respiratory Tract Infection.” JOURNAL OF VIROLOGY 94 (8).
Vancouver
1.
Van Cleemput J, Poelaert K, Laval K, Vanderheijden N, Dhaenens M, Daled S, et al. An alphaherpesvirus exploits antimicrobial beta-defensins to initiate respiratory tract infection. JOURNAL OF VIROLOGY. 2020;94(8).
IEEE
[1]
J. Van Cleemput et al., “An alphaherpesvirus exploits antimicrobial beta-defensins to initiate respiratory tract infection,” JOURNAL OF VIROLOGY, vol. 94, no. 8, 2020.
@article{8659150,
  abstract     = {beta-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 p-defensins during host invasion. We demonstrate how a central alphaherpesvirus, equine herpesvirus type 1 (EHV1), actually exploits p-defensins to invade its host and initiate viral spread. The equine beta-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. IMPORTANCE How herpesviruses circumvent mucosal defenses to promote infection of new hosts through the respiratory tract remains unknown due to a lack of hostspecific 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 p-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.},
  articleno    = {e01676-19},
  author       = {Van Cleemput, Jolien and Poelaert, Katrien and Laval, Kathlyn and Vanderheijden, Nathalie and Dhaenens, Maarten and Daled, Simon and Boyen, Filip and Pasmans, Frank and Nauwynck, Hans},
  issn         = {0022-538X},
  journal      = {JOURNAL OF VIROLOGY},
  keywords     = {BLOOD MONONUCLEAR-CELLS,HUMAN ALPHA-DEFENSIN,HUMAN BETA-DEFENSIN-3,THETA-DEFENSINS,GLYCOPROTEIN-M,VIRUS,SEQUENCE,PEPTIDES,INNATE,HERPESVIRUS-1,beta-defensins,alphaherpesvirus,equine herpesvirus,immune evasion,respiratory tract},
  language     = {eng},
  number       = {8},
  pages        = {23},
  title        = {An alphaherpesvirus exploits antimicrobial beta-defensins to initiate respiratory tract infection},
  url          = {http://dx.doi.org/10.1128/JVI.01676-19},
  volume       = {94},
  year         = {2020},
}

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