Equid herpesvirus 1 (EHV1) infection of equine mesenchymal stem cells induces a pUL56-dependent downregulation of select cell surface markers

Claessen, Christophe; Favoreel, Herman; Ma, Guanggang; Osterrieder, Nikolaus; Schauwer, Catharina De; Piepers, Sofie; Walle, Gerlinde R. Van de

doi:10.1016/j.vetmic.2014.12.013

Cited by 15 publications

(8 citation statements)

References 33 publications

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“…In addition, the US11 protein utilized by CMV for immune evasion can also downregulate MHC class I expression on human MSCs, making them vulnerable to NK cell-mediated lysis [ 45 ]. This same effect was described in horse MSCs after equid herpesvirus-1 (EHV-1) infection [ 20 ].…”

Section: Viral Infection Of Mscs Potential Outcomes and Safetysupporting

confidence: 69%

Multipotent Stromal Cells and Viral Interaction: Current Implications for Therapy

Taechangam

Kol

Arzi

et al. 2021

Stem Cell Rev and Rep

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Multipotent stromal cells (MSCs) are widely utilized in therapy for their immunomodulatory properties, but their usage in infectious viral diseases is less explored. This review aimed to collate the current novel use of MSCs in virus-associated conditions, including MSC’s susceptibility to virus infection, antiviral properties of MSCs and their effects on cell-based immune response and implementation of MSC therapy in animal models and human clinical trials of viral diseases. Recent discoveries shed lights on MSC’s capability in suppressing viral replication and augmenting clearance through enhancement of antiviral immunity. MSC therapy may maintain a crucial balance between aiding pathogen clearance and suppressing hyperactive immune response. Graphical Abstract

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Section: Viral Infection Of Mscs Potential Outcomes and Safetysupporting

confidence: 69%

Multipotent Stromal Cells and Viral Interaction: Current Implications for Therapy

Taechangam

Kol

Arzi

et al. 2021

Stem Cell Rev and Rep

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“…9 The absence of clinical signs has been confirmed in our study, both in broodmares and newborn foals, and in other horses from the same barns. Subclinical infection of apparently healthy broodmares must therefore be considered, and risks of exogenous or endogenous (stress-induced viral reactivation) introduction of EHV-1 should be closely monitored in the context UC-MSC banking, especially as susceptibility of equine blood-derived MSCs for EHV-1 has been demonstrated in vitro, 25 even if no EHV-1 sequence could be detected in paired UC-MSC samples in our study. In a similar approach, despite EHV-4 low prevalence (confirmed by its absence of detection), we recommend testing this agent whose variants present genetic similarities with EHV-1, since it is regularly found in respiratory diseases and is sporadically responsible for abortion (1-2 cases reported in France per year, RESPE data).…”

Section: Discussionmentioning

confidence: 89%

Biosafety Evaluation of Equine Umbilical Cord-Derived Mesenchymal Stromal Cells by Systematic Pathogen Screening in Peripheral Maternal Blood and Paired UC-MSCs

Denys

Léon

Robert³

et al. 2020

Biopreservation and Biobanking

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Background: The growing interest in mesenchymal stromal cells (MSCs) in equine medicine, together with the development of MSC biobanking for allogeneic use, raises concerns about biosafety of such products. MSCs derived from umbilical cord (UC) carry an inherent risk of contamination by environmental conditions and vertical transmission of pathogens from broodmares. There is yet no report in the scientific literature about horses being contaminated by infected MSC products, and no consensus about systematic infectious screening of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) to ensure microbiological safety of therapeutic products. Objectives: To develop a standard protocol to ensure UC-MSC microbiological safety and to assess the risk of vertical transmission of common intracellular pathogens from broodmares to paired UC-MSCs. Study Design and Methods: Eighty-four UC and paired peripheral maternal blood (PMB) samples were collected between 2014 and 2016. Sterility was monitored by microbiological control tests. Maternal contamination was tested by systematical PMB PCR screening for 14 pathogens and a Coggins test. In case of a PCR-positive result regarding one or several pathogen(s) in PMB, a PCR analysis for the detected pathogen(s) was then conducted on the associated UC-MSCs. Results: Ten out of 84 UC samples were contaminated upon extraction and 6/84 remained positive in primo culture. The remaining 78/84 paired PMB & UC-MSC samples were evaluated for vertical transmission; 37/78 PMB samples were PCR positive for Equid herpesvirus (EHV)-1, EHV-2, EHV-5, Theileria equi, Babesia caballi, and/or Mycoplasma spp. Hepacivirus was detected in 2/27 cases and Theiler Diseases Associated Virus in 0/27 cases (not performed on all samples due to late addition). All paired UC-MSC samples tested for the specific pathogen(s) detected in PMB were negative (37/37). Main Limitations: More data are needed regarding MSC susceptibility to most pathogens detected in PMB. Conclusions: In-process microbiological controls combined with PMB PCR screening provide a comprehensive assessment of UC-MSC exposure to infectious risk, vertical transmission risk appearing inherently low.

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“…In contrast, RacL11 or other strains lacking pUL56 and/or pUL43 are unable to adopt this immune evasion strategy. Apart from MHC-I, a variety of cell surface molecules might be affected by the cooperation of pUL43 with pUL56, as pUL56 was recently shown to modulate a selection of cell surface markers in equine mesenchymal stem cells after EHV-1 infection (39). In the future, we will address questions on the involvement of pUL43 in MHC-I downregulation by various EHV-1 strains and the spectrum and functional consequences of the pUL43-pUL56 interaction.…”

Section: Discussionmentioning

confidence: 98%

Equine Herpesvirus 1 Multiply Inserted Transmembrane Protein pUL43 Cooperates with pUL56 in Downregulation of Cell Surface Major Histocompatibility Complex Class I

Huang

Osterrieder

2015

J Virol

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Herpesviruses have evolved an array of strategies to counteract antigen presentation by major histocompatibility complex class I (MHC-I). Previously, we identified pUL56 of equine herpesvirus 1 (EHV-1) as one major determinant of the downregulation of cell surface MHC-I (G. Ma, S. Feineis, N. Osterrieder, and G. R. Van T he interplay between viruses and their hosts has led to the evolution of a number of strategies that facilitate evasion from the recognition and clearance of virus infection by the host immune system. Upon successful entry into the cell, viruses are uncoated. Structural components of the invading virus as well as newly produced proteins are polyubiquitinated and then fragmented into peptides by the proteasome (1). The processed antigenic peptides are transported into the endoplasmic reticulum (ER) and presented by major histocompatibility complex class I (MHC-I) molecules on the cell surface. Cytotoxic CD8 ϩ T lymphocytes (CTL), whose T-cell receptor (TCR) specifically recognizes small peptides bound in the groove of MHC-I, ultimately eliminate the infected cell (2, 3). However, CTL-mediated immunity may fail or be delayed, because many viruses encode specific inhibitors that interfere with various stages of MHC-I antigen presentation (4). As a consequence, infected cells have reduced MHC-I expression and become less sensitive to patrolling CTL.Equine herpesvirus 1 (EHV-1) is an important veterinary pathogen that poses a severe risk to the health of horse populations around the world. EHV-1 infection results in various clinical syndromes involving upper respiratory ailments, miscarriage, death of neonates, and neurological disease (5). Classified as a member of the Alphaherpesvirinae subfamily, EHV-1 is a double-stranded DNA virus featuring a large genome of ϳ150 kbp. The EHV-1 genome contains at least 80 open reading frames (ORFs), of which at least 4 ORFs are duplicated in the inverted-repeat regions (6). Historically, the EHV-1 genome has been annotated in accordance with those of herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV), prototype viruses of the Alphaherpesvirinae. This approach has also been applied to other closely related viruses, e.g., EHV-4 and pseudorabies virus (PRV) (7,8). Hence, the role of a particular EHV-1 gene product can be deduced on the basis of its HSV-1 or VZV counterpart and extended to predict the function of the orthologues that are conserved in the genus, subfamily, or even family. Nevertheless, several genes and/or gene functions are unique to HSV-1, VZV, or EHV-1. For instance, HSV-1 ICP47 was the first protein identified in the Alphaherpesvirinae to induce down-

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Equid herpesvirus 1 (EHV1) infection of equine mesenchymal stem cells induces a pUL56-dependent downregulation of select cell surface markers

Cited by 15 publications

References 33 publications

Multipotent Stromal Cells and Viral Interaction: Current Implications for Therapy

Multipotent Stromal Cells and Viral Interaction: Current Implications for Therapy

Biosafety Evaluation of Equine Umbilical Cord-Derived Mesenchymal Stromal Cells by Systematic Pathogen Screening in Peripheral Maternal Blood and Paired UC-MSCs

Equine Herpesvirus 1 Multiply Inserted Transmembrane Protein pUL43 Cooperates with pUL56 in Downregulation of Cell Surface Major Histocompatibility Complex Class I

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