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Equine herpesvirus type 1 enhances viral replication in CD172a⁺ monocytic cells upon adhesion to endothelial cells

Kathlyn Laval (UGent) , Herman Favoreel (UGent) , Katrien Poelaert (UGent) , Jolien Van Cleemput (UGent) and Hans Nauwynck (UGent)
(2015) JOURNAL OF VIROLOGY. 89(21). p.10912-10923
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Abstract
Equine herpesvirus type 1 (EHV-1) is a main cause of respiratory disease, abortion, and encephalomyelopathy in horses. Monocytic cells (CD172a(+)) are the main carrier cells of EHV-1 during primary infection and are proposed to serve as a "Trojan horse" to facilitate the dissemination of EHV-1 to target organs. However, the mechanism by which EHV-1 is transferred from CD172a(+) cells to endothelial cells (EC) remains unclear. The aim of this study was to investigate EHV-1 transmission between these two cell types. We hypothesized that EHV-1 employs specific strategies to promote the adhesion of infected CD172a(+) cells to EC to facilitate EHV-1 spread. Here, we demonstrated that EHV-1 infection of CD172a(+) cells resulted in a 3- to 5-fold increase in adhesion to EC. Antibody blocking experiments indicated that alpha(4)beta(1), alpha(L)beta(2), and alpha(V)beta(3) integrins mediated adhesion of infected CD172a(+) cells to EC. We showed that integrin-mediated phosphatidylinositol 3-kinase (PI3K) and ERK/MAPK signaling pathways were involved in EHV-1-induced CD172a(+) cell adhesion at early times of infection. EHV-1 replication was enhanced in adherent CD172a(+) cells, which correlates with the production of tumor necrosis factor alpha (TNF-alpha). In the presence of neutralizing antibodies, approximately 20% of infected CD172a(+) cells transferred cytoplasmic material to uninfected EC and 0.01% of infected CD172a(+) cells transmitted infectious virus to neighboring cells. Our results demonstrated that EHV-1 infection induces adhesion of CD172a(+) cells to EC, which enhances viral replication, but that transfer of viral material from CD172a(+) cells to EC is a very specific and rare event. These findings give new insights into the complex pathogenesis of EHV-1. IMPORTANCE Equine herpesvirus type 1 (EHV-1) is a highly prevalent pathogen worldwide, causing frequent outbreaks of abortion and myeloencephalopathy, even in vaccinated horses. After primary replication in the respiratory tract, EHV-1 disseminates via cell-associated viremia in peripheral blood mononuclear cells (PBMC) and subsequently infects the endothelial cells (EC) of the pregnant uterus or central nervous system, leading in some cases to abortion and/or neurological disorders. Recently, we demonstrated that CD172a(+) monocytic carrier cells serve as a "Trojan horse" to facilitate EHV-1 spread from blood to target organs. Here, we investigated the mechanism underlying the transmission of EHV-1 from CD172a(+) cells to EC. We demonstrated that EHV-1 infection induces cellular changes in CD172a(+) cells, promoting their adhesion to EC. We found that both cell-to-cell contacts and the secretion of soluble factors by EC activate EHV-1 replication in CD172a(+) cells. This facilitates transfer of cytoplasmic viral material to EC, resulting mainly in a nonproductive infection. Our findings give new insights into how EHV-1 may spread to EC of target organs in vaccinated horses.
Keywords
L-SELECTIN, BLOOD MONONUCLEAR-CELLS, EHV-1, PSEUDORABIES VIRUS, HUMAN CYTOMEGALOVIRUS, INFECTION, EXPRESSION, ACTIVATION, INTEGRINS, MYELOENCEPHALOPATHY

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Chicago
Laval, Kathlyn, Herman Favoreel, Katrien Poelaert, Jolien Van Cleemput, and Hans Nauwynck. 2015. “Equine Herpesvirus Type 1 Enhances Viral Replication in CD172a+ Monocytic Cells Upon Adhesion to Endothelial Cells.” Journal of Virology 89 (21): 10912–10923.
APA
Laval, K., Favoreel, H., Poelaert, K., Van Cleemput, J., & Nauwynck, H. (2015). Equine herpesvirus type 1 enhances viral replication in CD172a+ monocytic cells upon adhesion to endothelial cells. JOURNAL OF VIROLOGY, 89(21), 10912–10923.
Vancouver
1.
Laval K, Favoreel H, Poelaert K, Van Cleemput J, Nauwynck H. Equine herpesvirus type 1 enhances viral replication in CD172a+ monocytic cells upon adhesion to endothelial cells. JOURNAL OF VIROLOGY. 2015;89(21):10912–23.
MLA
Laval, Kathlyn et al. “Equine Herpesvirus Type 1 Enhances Viral Replication in CD172a+ Monocytic Cells Upon Adhesion to Endothelial Cells.” JOURNAL OF VIROLOGY 89.21 (2015): 10912–10923. Print.
@article{7081379,
  abstract     = {Equine herpesvirus type 1 (EHV-1) is a main cause of respiratory disease, abortion, and encephalomyelopathy in horses. Monocytic cells (CD172a(+)) are the main carrier cells of EHV-1 during primary infection and are proposed to serve as a "Trojan horse" to facilitate the dissemination of EHV-1 to target organs. However, the mechanism by which EHV-1 is transferred from CD172a(+) cells to endothelial cells (EC) remains unclear. The aim of this study was to investigate EHV-1 transmission between these two cell types. We hypothesized that EHV-1 employs specific strategies to promote the adhesion of infected CD172a(+) cells to EC to facilitate EHV-1 spread. Here, we demonstrated that EHV-1 infection of CD172a(+) cells resulted in a 3- to 5-fold increase in adhesion to EC. Antibody blocking experiments indicated that alpha(4)beta(1), alpha(L)beta(2), and alpha(V)beta(3) integrins mediated adhesion of infected CD172a(+) cells to EC. We showed that integrin-mediated phosphatidylinositol 3-kinase (PI3K) and ERK/MAPK signaling pathways were involved in EHV-1-induced CD172a(+) cell adhesion at early times of infection. EHV-1 replication was enhanced in adherent CD172a(+) cells, which correlates with the production of tumor necrosis factor alpha (TNF-alpha). In the presence of neutralizing antibodies, approximately 20% of infected CD172a(+) cells transferred cytoplasmic material to uninfected EC and 0.01% of infected CD172a(+) cells transmitted infectious virus to neighboring cells. Our results demonstrated that EHV-1 infection induces adhesion of CD172a(+) cells to EC, which enhances viral replication, but that transfer of viral material from CD172a(+) cells to EC is a very specific and rare event. These findings give new insights into the complex pathogenesis of EHV-1.
IMPORTANCE
Equine herpesvirus type 1 (EHV-1) is a highly prevalent pathogen worldwide, causing frequent outbreaks of abortion and myeloencephalopathy, even in vaccinated horses. After primary replication in the respiratory tract, EHV-1 disseminates via cell-associated viremia in peripheral blood mononuclear cells (PBMC) and subsequently infects the endothelial cells (EC) of the pregnant uterus or central nervous system, leading in some cases to abortion and/or neurological disorders. Recently, we demonstrated that CD172a(+) monocytic carrier cells serve as a "Trojan horse" to facilitate EHV-1 spread from blood to target organs. Here, we investigated the mechanism underlying the transmission of EHV-1 from CD172a(+) cells to EC. We demonstrated that EHV-1 infection induces cellular changes in CD172a(+) cells, promoting their adhesion to EC. We found that both cell-to-cell contacts and the secretion of soluble factors by EC activate EHV-1 replication in CD172a(+) cells. This facilitates transfer of cytoplasmic viral material to EC, resulting mainly in a nonproductive infection. Our findings give new insights into how EHV-1 may spread to EC of target organs in vaccinated horses.},
  author       = {Laval, Kathlyn and Favoreel, Herman and Poelaert, Katrien and Van Cleemput, Jolien and Nauwynck, Hans},
  issn         = {0022-538X},
  journal      = {JOURNAL OF VIROLOGY},
  keywords     = {L-SELECTIN,BLOOD MONONUCLEAR-CELLS,EHV-1,PSEUDORABIES VIRUS,HUMAN CYTOMEGALOVIRUS,INFECTION,EXPRESSION,ACTIVATION,INTEGRINS,MYELOENCEPHALOPATHY},
  language     = {eng},
  number       = {21},
  pages        = {10912--10923},
  title        = {Equine herpesvirus type 1 enhances viral replication in CD172a⁺ monocytic cells upon adhesion to endothelial cells},
  url          = {http://dx.doi.org/10.1128/JVI.01589-15},
  volume       = {89},
  year         = {2015},
}

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