Human cytomegalovirus-encoded receptor US28 is expressed in renal allografts and facilitates viral spreading in vitro.

Wouter T Lollinga; Raymond H de Wit; Afsar Rahbar; Gwenda F Vasse; Belghis Davoudi; Arjan Diepstra; Annelies Riezebos-Brilman; Martin C Harmsen; Jan-Luuk Hillebrands; Cecilia Söderberg-Naucler; Willem J van Son; Martine J Smit; Jan-Stephan Sanders; Jacob van den Born

doi:10.1097/TP.0000000000001289

Human cytomegalovirus-encoded receptor US28 is expressed in renal allografts and facilitates viral spreading in vitro.

Wouter T Lollinga, Raymond H de Wit, Afsar Rahbar, Gwenda F Vasse, Belghis Davoudi, Arjan Diepstra, Annelies Riezebos-Brilman, Martin C Harmsen, Jan-Luuk Hillebrands, Cecilia Söderberg-Naucler, Willem J van Son, Martine J Smit, Jan-Stephan Sanders, Jacob van den Born

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

BACKGROUND: Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling.

METHODS: Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro.

RESULTS: Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells.Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller.

CONCLUSIONS: In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.

Original language	English
Pages (from-to)	531-540
Number of pages	10
Journal	Transplantation
Volume	101
Issue number	3
Early online date	1 Mar 2017
DOIs	https://doi.org/10.1097/TP.0000000000001289
Publication status	Published - Mar 2017

Bibliographical note

pmid 27362315

Keywords

Adult
Aged
Allografts
Antibodies, Viral
Biomarkers
Biopsy
Cells, Cultured
Cytomegalovirus
Cytomegalovirus Infections
Epithelial Cells
Female
Humans
Immunoglobulin G
Immunohistochemistry
Journal Article
Kidney
Kidney Transplantation
Male
Middle Aged
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Receptors, Chemokine
Retrospective Studies
Time Factors
Tissue Donors
Viral Proteins
Virulence
Young Adult

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lollinga, W. T., de Wit, R. H., Rahbar, A., Vasse, G. F., Davoudi, B., Diepstra, A., Riezebos-Brilman, A., Harmsen, M. C., Hillebrands, J-L., Söderberg-Naucler, C., van Son, W. J., Smit, M. J., Sanders, J-S., & van den Born, J. (2017). Human cytomegalovirus-encoded receptor US28 is expressed in renal allografts and facilitates viral spreading in vitro. Transplantation, 101(3), 531-540. https://doi.org/10.1097/TP.0000000000001289

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title = "Human cytomegalovirus-encoded receptor US28 is expressed in renal allografts and facilitates viral spreading in vitro.",

abstract = "BACKGROUND: Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling.METHODS: Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro.RESULTS: Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells.Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller.CONCLUSIONS: In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.",

keywords = "Adult, Aged, Allografts, Antibodies, Viral, Biomarkers, Biopsy, Cells, Cultured, Cytomegalovirus, Cytomegalovirus Infections, Epithelial Cells, Female, Humans, Immunoglobulin G, Immunohistochemistry, Journal Article, Kidney, Kidney Transplantation, Male, Middle Aged, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Receptors, Chemokine, Retrospective Studies, Time Factors, Tissue Donors, Viral Proteins, Virulence, Young Adult",

author = "Lollinga, {Wouter T} and {de Wit}, {Raymond H} and Afsar Rahbar and Vasse, {Gwenda F} and Belghis Davoudi and Arjan Diepstra and Annelies Riezebos-Brilman and Harmsen, {Martin C} and Jan-Luuk Hillebrands and Cecilia S{\"o}derberg-Naucler and {van Son}, {Willem J} and Smit, {Martine J} and Jan-Stephan Sanders and {van den Born}, Jacob",

note = "pmid 27362315",

year = "2017",

month = mar,

doi = "10.1097/TP.0000000000001289",

language = "English",

volume = "101",

pages = "531--540",

journal = "Transplantation",

issn = "0041-1337",

publisher = "Lippincott Williams and Wilkins",

number = "3",

}

Lollinga, WT, de Wit, RH, Rahbar, A, Vasse, GF, Davoudi, B, Diepstra, A, Riezebos-Brilman, A, Harmsen, MC, Hillebrands, J-L, Söderberg-Naucler, C, van Son, WJ, Smit, MJ, Sanders, J-S & van den Born, J 2017, 'Human cytomegalovirus-encoded receptor US28 is expressed in renal allografts and facilitates viral spreading in vitro.', Transplantation, vol. 101, no. 3, pp. 531-540. https://doi.org/10.1097/TP.0000000000001289

TY - JOUR

T1 - Human cytomegalovirus-encoded receptor US28 is expressed in renal allografts and facilitates viral spreading in vitro.

AU - Lollinga, Wouter T

AU - de Wit, Raymond H

AU - Rahbar, Afsar

AU - Vasse, Gwenda F

AU - Davoudi, Belghis

AU - Diepstra, Arjan

AU - Riezebos-Brilman, Annelies

AU - Harmsen, Martin C

AU - Hillebrands, Jan-Luuk

AU - Söderberg-Naucler, Cecilia

AU - van Son, Willem J

AU - Smit, Martine J

AU - Sanders, Jan-Stephan

AU - van den Born, Jacob

N1 - pmid 27362315

PY - 2017/3

Y1 - 2017/3

N2 - BACKGROUND: Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling.METHODS: Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro.RESULTS: Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells.Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller.CONCLUSIONS: In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.

AB - BACKGROUND: Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling.METHODS: Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro.RESULTS: Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells.Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller.CONCLUSIONS: In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.

KW - Adult

KW - Aged

KW - Allografts

KW - Antibodies, Viral

KW - Biomarkers

KW - Biopsy

KW - Cells, Cultured

KW - Cytomegalovirus

KW - Cytomegalovirus Infections

KW - Epithelial Cells

KW - Female

KW - Humans

KW - Immunoglobulin G

KW - Immunohistochemistry

KW - Journal Article

KW - Kidney

KW - Kidney Transplantation

KW - Male

KW - Middle Aged

KW - Muscle, Smooth, Vascular

KW - Myocytes, Smooth Muscle

KW - Receptors, Chemokine

KW - Retrospective Studies

KW - Time Factors

KW - Tissue Donors

KW - Viral Proteins

KW - Virulence

KW - Young Adult

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UR - http://www.scopus.com/inward/citedby.url?scp=84976549753&partnerID=8YFLogxK

U2 - 10.1097/TP.0000000000001289

DO - 10.1097/TP.0000000000001289

M3 - Article

C2 - 27362315

SN - 0041-1337

VL - 101

SP - 531

EP - 540

JO - Transplantation

JF - Transplantation

IS - 3

ER -

Human cytomegalovirus-encoded receptor US28 is expressed in renal allografts and facilitates viral spreading in vitro.

Abstract

Bibliographical note

Keywords

UN SDGs

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