Equine arteritis virus long-term persistence is orchestrated by CD8+ T lymphocyte transcription factors, inhibitory receptors, and the CXCL16/CXCR6 axis

PLoS Pathog. 2019 Jul 29;15(7):e1007950. doi: 10.1371/journal.ppat.1007950. eCollection 2019 Jul.


Equine arteritis virus (EAV) has the unique ability to establish long-term persistent infection in the reproductive tract of stallions and be sexually transmitted. Previous studies showed that long-term persistent infection is associated with a specific allele of the CXCL16 gene (CXCL16S) and that persistence is maintained despite the presence of local inflammatory and humoral and mucosal antibody responses. Here, we performed transcriptomic analysis of the ampullae, the primary site of EAV persistence in long-term EAV carrier stallions, to understand the molecular signatures of viral persistence. We demonstrated that the local CD8+ T lymphocyte response is predominantly orchestrated by the transcription factors eomesodermin (EOMES) and nuclear factor of activated T-cells cytoplasmic 2 (NFATC2), which is likely modulated by the upregulation of inhibitory receptors. Most importantly, EAV persistence is associated with an enhanced expression of CXCL16 and CXCR6 by infiltrating lymphocytes, providing evidence of the implication of this chemokine axis in the pathogenesis of persistent EAV infection in the stallion reproductive tract. Furthermore, we have established a link between the CXCL16 genotype and the gene expression profile in the ampullae of the stallion reproductive tract. Specifically, CXCL16 acts as a "hub" gene likely driving a specific transcriptional network. The findings herein are novel and strongly suggest that RNA viruses such as EAV could exploit the CXCL16/CXCR6 axis in order to modulate local inflammatory and immune responses in the male reproductive tract by inducing a dysfunctional CD8+ T lymphocyte response and unique lymphocyte homing in the reproductive tract.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arterivirus Infections / genetics
  • Arterivirus Infections / immunology
  • Arterivirus Infections / veterinary
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology*
  • Carrier State / immunology
  • Carrier State / veterinary
  • Carrier State / virology
  • Chemokine CXCL16 / genetics
  • Chemokine CXCL16 / immunology
  • Equartevirus / immunology*
  • Equartevirus / pathogenicity*
  • Gene Expression Profiling
  • Genitalia, Male / immunology
  • Genitalia, Male / pathology
  • Genitalia, Male / virology
  • Horse Diseases / genetics
  • Horse Diseases / immunology
  • Horse Diseases / virology
  • Horses
  • Host Microbial Interactions / genetics
  • Host Microbial Interactions / immunology
  • Male
  • Receptors, CXCR6 / genetics
  • Receptors, CXCR6 / immunology
  • Receptors, Virus / immunology
  • Transcription Factors / immunology
  • Virus Shedding / genetics
  • Virus Shedding / immunology


  • Chemokine CXCL16
  • Receptors, CXCR6
  • Receptors, Virus
  • Transcription Factors

Grants and funding

This study was supported by the Agriculture and Food Research Initiative competitive grant number 2013-68004-20360 from the USDA National Institute of Food and Agriculture. This work was also supported by the USDA National Institute of Food and Agriculture hatch project number KY014055 (College of Agriculture, Food and Environment, University of Kentucky), and partially supported by Louisiana State University, School of Veterinary Medicine start-up fund (PG 002165) to Dr. Udeni B. R. Balasuriya. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.