Infection of central nervous system endothelial cells by cell-associated EHV-1

Goehring, Lutz S.; Hussey, Gisela Soboll; Ashton, Laura V.; Schenkel, Alan R.; Lunn, D.P.

doi:10.1016/j.vetmic.2010.08.030

Cited by 27 publications

(28 citation statements)

References 21 publications

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“…We could confirm that cell-associated EHV-1 was able to infect EC through direct cell-to-cell contact, as previously reported by Goehring et al (18). Strikingly, we saw that cell-associated EHV-4 was not able to infect EC in the presence of neutralizing antibody.…”

Section: Figsupporting

confidence: 91%

“…A recent study reported on virus transfer from PBMC to EC, where EHV-1-infected PBMC were cocultured on top of an EC monolayer in the presence of neutralizing antibodies. This demonstrated the potential importance of this mode of transfer during EHV-1 infection (18). There are certain viral proteins that likely play key roles during the transfer from PBMC to EC.…”

Section: Importancementioning

confidence: 90%

“…The "no-contact" situation was used to evaluate the efficacy of the citrate treatment of PBMC to inactivate nonpenetrated virus. In the "contact" situation, experiments were done in the presence of a 1:100 dilution of an EHV-1/ EHV-4-neutralizing antiserum (VNA) with a titer of 1:2,048 (18). All cells were incubated for 24 h prior to counting GFP-positive plaques on the EC monolayer using an inverted fluorescence microscope (Zeiss Axiovert 100).…”

Section: Methodsmentioning

confidence: 99%

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Role of gB and pUS3 in Equine Herpesvirus 1 Transfer between Peripheral Blood Mononuclear Cells and Endothelial Cells: a DynamicIn VitroModel

Spiesschaert

Goldenbogen

Taferner

et al. 2015

J Virol

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Infected peripheral blood mononuclear cells (PBMC) effectively transport equine herpesvirus type 1 (EHV-1), but not EHV-4, to endothelial cells (EC) lining the blood vessels of the pregnant uterus or central nervous system, a process that can result in abortion or myeloencephalopathy. We examined, using a dynamic in vitro model, the differences between EHV-1 and EHV-4 infection of PBMC and PBMC-EC interactions. In order to evaluate viral transfer between infected PBMC and EC, cocultivation assays were performed. Only EHV-1 was transferred from PBMC to EC, and viral glycoprotein B (gB) was shown to be mainly responsible for this form of cell-to-cell transfer. For addressing the more dynamic aspects of PBMC-EC interaction, infected PBMC were perfused through a flow channel containing EC in the presence of neutralizing antibodies. By simulating capillary blood flow and analyzing the behavior of infected PBMC through live fluorescence imaging and automated cell tracking, we observed that EHV-1 was able to maintain tethering and rolling of infected PBMC on EC more effectively than EHV-4. Deletion of US3 reduced the ability of infected PBMC to tether and roll compared to that of cells infected with parental virus, which resulted in a significant reduction in virus transfer from PBMC to EC. Taking the results together, we conclude that systemic spread and EC infection by EHV-1, but not EHV-4, is caused by its ability to infect and/or reprogram mononuclear cells with respect to their tethering and rolling behavior on EC and consequent virus transfer. IMPORTANCEEHV-1 is widespread throughout the world and causes substantial economic losses through outbreaks of respiratory disease, abortion, and myeloencephalopathy. Despite many years of research, no fully protective vaccines have been developed, and several aspects of viral pathogenesis still need to be uncovered. In the current study, we investigated the molecular mechanisms that facilitate the cell-associated viremia, which is arguably the most important aspect of EHV-1 pathogenesis. The newly discovered functions of gB and pUS3 add new facets to their previously reported roles. Due to the conserved nature of cell-associated viremia among numerous herpesviruses, these results are also very relevant for viruses such as varicella-zoster virus, pseudorabies virus, human cytomegalovirus, and others. In addition, the constructed mutant and recombinant viruses exhibit potent in vitro replication but have significant defects in certain stages of the disease course. These viruses therefore show much promise as candidates for future live vaccines. E quine herpesvirus type 1 (EHV-1) and EHV-4 are members of the Herpesviridae family and Alphaherpesvirinae subfamily (1, 2). After initial replication in the upper respiratory tract, EHV-1 infects immune cells and migrates past the epithelial basement membrane to the lymph nodes and bloodstream (1-4). As a result, EHV-1 is able to spread throughout the body, where it infects endothelial cells (EC), causing vascular lesions an...

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Section: Figsupporting

confidence: 91%

Section: Importancementioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Role of gB and pUS3 in Equine Herpesvirus 1 Transfer between Peripheral Blood Mononuclear Cells and Endothelial Cells: a DynamicIn VitroModel

Spiesschaert

Goldenbogen

Taferner

et al. 2015

J Virol

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“…During acute infection, EHV-1 generally penetrates by the respiratory route and replicates in the epithelium of the respiratory tract, spreading to regional lymph nodes and promoting cellassociated viremia [8,9]. Viremia is important for virus spread to target organs.…”

Section: Introductionmentioning

confidence: 99%

Respiratory and neurological disease in rabbits experimentally infected with equid herpesvirus 1

Kanitz

Cargnelutti

Anziliero

et al. 2015

Microbial Pathogenesis

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“…Studies have shown that the infection of EC located in the vasculature of the late-gravid uterus or CNS was mediated by cellto-cell contacts between infected PBMC and EC and occurred even in the presence of virus-neutralizing antibodies (18,19). In addition, Smith et al (18) provided evidence that activation of EC adhesion molecules may be involved in the transfer of virus from infected PBMC to EC and may determine the restricted tissue specificity of EHV-1.…”

mentioning

confidence: 99%

Equine Herpesvirus Type 1 Enhances Viral Replication in CD172a ⁺ Monocytic Cells upon Adhesion to Endothelial Cells

Laval

Favoreel

Poelaert

et al. 2015

J Virol

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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 ␣ 4 ␤ 1 , ␣ L ␤ 2 , and ␣ V ␤ 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-␣). 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. IMPORTANCEEquine 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. E quine herpesvirus type 1 (EHV-1), a member of the subfamily Alphaherpesvirinae, is a ubiquitous pathogen in horses, causing...

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Infection of central nervous system endothelial cells by cell-associated EHV-1

Cited by 27 publications

References 21 publications

Role of gB and pUS3 in Equine Herpesvirus 1 Transfer between Peripheral Blood Mononuclear Cells and Endothelial Cells: a DynamicIn VitroModel

Role of gB and pUS3 in Equine Herpesvirus 1 Transfer between Peripheral Blood Mononuclear Cells and Endothelial Cells: a DynamicIn VitroModel

Respiratory and neurological disease in rabbits experimentally infected with equid herpesvirus 1

Equine Herpesvirus Type 1 Enhances Viral Replication in CD172a ⁺ Monocytic Cells upon Adhesion to Endothelial Cells

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Infection of central nervous system endothelial cells by cell-associated EHV-1

Cited by 27 publications

References 21 publications

Role of gB and pUS3 in Equine Herpesvirus 1 Transfer between Peripheral Blood Mononuclear Cells and Endothelial Cells: a DynamicIn VitroModel

Role of gB and pUS3 in Equine Herpesvirus 1 Transfer between Peripheral Blood Mononuclear Cells and Endothelial Cells: a DynamicIn VitroModel

Respiratory and neurological disease in rabbits experimentally infected with equid herpesvirus 1

Equine Herpesvirus Type 1 Enhances Viral Replication in CD172a + Monocytic Cells upon Adhesion to Endothelial Cells

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Equine Herpesvirus Type 1 Enhances Viral Replication in CD172a ⁺ Monocytic Cells upon Adhesion to Endothelial Cells