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November 2021; 8 (6) ArticleOpen Access

Targeted RNA Sequencing of Formalin-Fixed, Paraffin-Embedded Temporal Arteries From Giant Cell Arteritis Cases Reveals Viral Signatures

Andrew N. Bubak, Teresa Mescher, Michael Mariani, Seth E. Frietze, James E. Hassell, Christy S. Niemeyer, Christina N. Como, Anna M. Burnet, View ORCID ProfilePrem S. Subramanian, Randall J. Cohrs, Ravi Mahalingam, Maria A. Nagel
First published September 7, 2021, DOI: https://doi.org/10.1212/NXI.0000000000001078
Andrew N. Bubak
From the Department of Neurology (A.N.B., T.M., J.E.H., C.S.N., C.N.C., A.M.B., P.S.S., R.J.C., R.M., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Medical Laboratory Sciences (M.M., S.E.F.), University of Vermont, Burlington; Department of Ophthalmology (P.S.S., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Neurosurgery (P.S.S.), University of Colorado School of Medicine, Aurora; and Department of Immunology and Microbiology (R.J.C.), University of Colorado School of Medicine, Aurora.
PhD
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  • For correspondence: andrew.bubak@cuanschutz.edu
Teresa Mescher
From the Department of Neurology (A.N.B., T.M., J.E.H., C.S.N., C.N.C., A.M.B., P.S.S., R.J.C., R.M., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Medical Laboratory Sciences (M.M., S.E.F.), University of Vermont, Burlington; Department of Ophthalmology (P.S.S., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Neurosurgery (P.S.S.), University of Colorado School of Medicine, Aurora; and Department of Immunology and Microbiology (R.J.C.), University of Colorado School of Medicine, Aurora.
BS
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  • For correspondence: teresa.mescher@cuanschutz.edu
Michael Mariani
From the Department of Neurology (A.N.B., T.M., J.E.H., C.S.N., C.N.C., A.M.B., P.S.S., R.J.C., R.M., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Medical Laboratory Sciences (M.M., S.E.F.), University of Vermont, Burlington; Department of Ophthalmology (P.S.S., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Neurosurgery (P.S.S.), University of Colorado School of Medicine, Aurora; and Department of Immunology and Microbiology (R.J.C.), University of Colorado School of Medicine, Aurora.
PhD
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  • For correspondence: michael.mariani@uvm.edu
Seth E. Frietze
From the Department of Neurology (A.N.B., T.M., J.E.H., C.S.N., C.N.C., A.M.B., P.S.S., R.J.C., R.M., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Medical Laboratory Sciences (M.M., S.E.F.), University of Vermont, Burlington; Department of Ophthalmology (P.S.S., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Neurosurgery (P.S.S.), University of Colorado School of Medicine, Aurora; and Department of Immunology and Microbiology (R.J.C.), University of Colorado School of Medicine, Aurora.
PhD
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  • For correspondence: seth.frietze@med.uvm.edu
James E. Hassell Jr
From the Department of Neurology (A.N.B., T.M., J.E.H., C.S.N., C.N.C., A.M.B., P.S.S., R.J.C., R.M., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Medical Laboratory Sciences (M.M., S.E.F.), University of Vermont, Burlington; Department of Ophthalmology (P.S.S., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Neurosurgery (P.S.S.), University of Colorado School of Medicine, Aurora; and Department of Immunology and Microbiology (R.J.C.), University of Colorado School of Medicine, Aurora.
PhD
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  • For correspondence: james.hasselljr@cuanschutz.edu
Christy S. Niemeyer
From the Department of Neurology (A.N.B., T.M., J.E.H., C.S.N., C.N.C., A.M.B., P.S.S., R.J.C., R.M., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Medical Laboratory Sciences (M.M., S.E.F.), University of Vermont, Burlington; Department of Ophthalmology (P.S.S., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Neurosurgery (P.S.S.), University of Colorado School of Medicine, Aurora; and Department of Immunology and Microbiology (R.J.C.), University of Colorado School of Medicine, Aurora.
PhD
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  • For correspondence: christy.niemeyer@cuanschutz.edu
Christina N. Como
From the Department of Neurology (A.N.B., T.M., J.E.H., C.S.N., C.N.C., A.M.B., P.S.S., R.J.C., R.M., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Medical Laboratory Sciences (M.M., S.E.F.), University of Vermont, Burlington; Department of Ophthalmology (P.S.S., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Neurosurgery (P.S.S.), University of Colorado School of Medicine, Aurora; and Department of Immunology and Microbiology (R.J.C.), University of Colorado School of Medicine, Aurora.
BA
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  • For correspondence: christina.como@cuanschutz.edu
Anna M. Burnet
From the Department of Neurology (A.N.B., T.M., J.E.H., C.S.N., C.N.C., A.M.B., P.S.S., R.J.C., R.M., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Medical Laboratory Sciences (M.M., S.E.F.), University of Vermont, Burlington; Department of Ophthalmology (P.S.S., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Neurosurgery (P.S.S.), University of Colorado School of Medicine, Aurora; and Department of Immunology and Microbiology (R.J.C.), University of Colorado School of Medicine, Aurora.
BS
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  • For correspondence: anna.burnet@cuanschutz.edu
Prem S. Subramanian
From the Department of Neurology (A.N.B., T.M., J.E.H., C.S.N., C.N.C., A.M.B., P.S.S., R.J.C., R.M., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Medical Laboratory Sciences (M.M., S.E.F.), University of Vermont, Burlington; Department of Ophthalmology (P.S.S., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Neurosurgery (P.S.S.), University of Colorado School of Medicine, Aurora; and Department of Immunology and Microbiology (R.J.C.), University of Colorado School of Medicine, Aurora.
MD, PhD
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  • ORCID record for Prem S. Subramanian
  • For correspondence: prem.subramanian@cuanschutz.edu
Randall J. Cohrs
From the Department of Neurology (A.N.B., T.M., J.E.H., C.S.N., C.N.C., A.M.B., P.S.S., R.J.C., R.M., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Medical Laboratory Sciences (M.M., S.E.F.), University of Vermont, Burlington; Department of Ophthalmology (P.S.S., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Neurosurgery (P.S.S.), University of Colorado School of Medicine, Aurora; and Department of Immunology and Microbiology (R.J.C.), University of Colorado School of Medicine, Aurora.
PhD
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  • For correspondence: randall.cohrs@cuanschutz.edu
Ravi Mahalingam
From the Department of Neurology (A.N.B., T.M., J.E.H., C.S.N., C.N.C., A.M.B., P.S.S., R.J.C., R.M., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Medical Laboratory Sciences (M.M., S.E.F.), University of Vermont, Burlington; Department of Ophthalmology (P.S.S., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Neurosurgery (P.S.S.), University of Colorado School of Medicine, Aurora; and Department of Immunology and Microbiology (R.J.C.), University of Colorado School of Medicine, Aurora.
PhD
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  • For correspondence: ravi.mahalingam@cuanschutz.edu
Maria A. Nagel
From the Department of Neurology (A.N.B., T.M., J.E.H., C.S.N., C.N.C., A.M.B., P.S.S., R.J.C., R.M., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Medical Laboratory Sciences (M.M., S.E.F.), University of Vermont, Burlington; Department of Ophthalmology (P.S.S., M.A.N.), University of Colorado School of Medicine, Aurora; Department of Neurosurgery (P.S.S.), University of Colorado School of Medicine, Aurora; and Department of Immunology and Microbiology (R.J.C.), University of Colorado School of Medicine, Aurora.
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Full PDF
Citation
Targeted RNA Sequencing of Formalin-Fixed, Paraffin-Embedded Temporal Arteries From Giant Cell Arteritis Cases Reveals Viral Signatures
Andrew N. Bubak, Teresa Mescher, Michael Mariani, Seth E. Frietze, James E. Hassell, Christy S. Niemeyer, Christina N. Como, Anna M. Burnet, Prem S. Subramanian, Randall J. Cohrs, Ravi Mahalingam, Maria A. Nagel
Neurol Neuroimmunol Neuroinflamm Nov 2021, 8 (6) e1078; DOI: 10.1212/NXI.0000000000001078

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Abstract

Background and Objectives Varicella zoster virus (VZV) antigen has been detected in temporal arteries (TAs) of individuals with giant cell arteritis (GCA), the most common systemic vasculitis in older adults. Thus, we explored the contribution of VZV to GCA pathogenesis.

Methods Formalin-fixed, paraffin-embedded TA sections from biopsy-positive GCA participants with VZV antigen (GCA/VZV-positive; n = 20) and without (GCA/VZV-negative, n = 20) and from normal participants with VZV antigen (control/VZV-positive, n = 11) and without (control/VZV-negative, n = 20) were analyzed by targeted RNA sequencing of the whole human transcriptome (BioSpyder TempO-Seq). Ingenuity pathway analysis and R-computational program were used to identify differentially expressed genes and pathways between groups.

Results Compared with control/VZV-negative TAs, GCA/VZV-negative and GCA/VZV-positive TAs were significantly enriched for human transcripts specific for pathways involved in viral infections, including viral entry, nuclear factor kappa B activation by viruses, and other pathogen-related immune activation pathways. Similarly, human gene sets supporting viral infection were found in control/VZV-positive TAs that showed no morphological signs of inflammation, suggesting that the enriched pathways were not nonspecific signatures of infiltrating immune cells. All GCA TAs and control/VZV-positive TAs showed enrichment of transcripts involved in vascular remodeling, including smooth muscle cell migration.

Discussion The detection of viral and immune activation pathways in GCA TAs supports a role for virus infection in GCA pathogenesis. In addition, the detection of viral pathways in control/VZV-positive TAs, along with vascular remodeling pathways, suggests that these samples may represent early infection with progression to clinical disease, depending on host and other environmental factors.

Glossary

COMIRB=
Colorado Multiple Institutional Review Board;
FFPE=
formalin-fixed, paraffin-embedded;
GCA=
giant cell arteritis;
gE=
glycoprotein E;
GSEA=
Gene Set Enrichment Analysis;
HSV=
herpes simplex virus;
IFN=
interferon;
IHC=
immunohistochemistry;
IL=
interleukin;
TA=
temporal artery;
TLR=
toll-like receptor;
TNF=
tumor necrosis factor;
VZV=
varicella zoster virus

Footnotes

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • Received April 20, 2021.
  • Accepted in final form June 28, 2021.
  • Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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