FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / PLoS Pathog / Equine arteritis virus long-term persistence is orchestrated...
PLoS pathogens2019; 15(7); e1007950; doi: 10.1371/journal.ppat.1007950

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

Abstract: 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.
Get Full Text
Publication Date: 2019-07-29 PubMed ID: 31356622PubMed Central: PMC6692045DOI: 10.1371/journal.ppat.1007950Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • Non-U.S. Gov't
  • Research Support
  • U.S. Gov't
  • Non-P.H.S.

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study examines the unique ability of Equine arteritis virus (EAV) to maintain persistent infections in the reproductive tract of stallions and reveals a complex interplay of immune responses and virus survival strategies, highlighting the role of the CXCL16/CXCR6 axis.

Understanding EAV Infections

  • The focus of the study is the Equine arteritis virus (EAV), which can establish a long-standing persistent infection within the reproductive tract of stallions, leading to sexual transmission.
  • EAV’s long-term persistence is believed to be related to an allele (variation) of the CXCL16 gene (specifically the CXCL16S allele).
  • EAV can continue to thrive even when there are manifested local inflammatory responses and the active involvement of humoral and mucosal antibodies.

A Detailed Look at EAV Persistence

  • To explore how EAV continues to persist, the researchers conducted a transcriptomic analysis of the ampullae, which is the primary location of EAV persistence in carrier stallions.
  • The analysis focused on understanding the identifying molecular markers associated with the long-term presence of the virus.
  • The findings suggest that the local CD8+ T lymphocyte response, significant in the immune defense against viruses, is regulated primarily by the transcription factors eomesodermin (EOMES) and nuclear factor of activated T-cells cytoplasmic 2 (NFATC2).
  • The study also indicates that the upregulated expression of inhibitory receptors tempers these T-cell responses.

Role of the CXCL16/CXCR6 Axis

  • The central discovery of the study is the association of EAV persistence with an increased display of CXCL16 and CXCR6 by infiltrating lymphocytes in the reproductive tract.
  • This association provides strong evidence implicating this chemokine axis (CXCL16/CXCR6) in the continuation of EAV infections within the reproductive tract of stallions.
  • The researchers believe that EAV exploits this axis to modulate local inflammatory and immune responses by promoting a deficient response from CD8+ T lymphocytes and enabling specific lymphocyte homing in the reproductive tract.
  • The genotype of CXCL16 also influences the gene expression pattern within the stallion reproductive tract; specifically, CXCL16 acts as a core or “hub” gene that may direct a particular transcriptional network.

Implications of the Findings

  • The study provides novel insights into our understanding of long-term viral persistence, specifically within the unique context of stallion reproductive physiology and EAV.
  • These findings could enhance our comprehension of how RNA viruses such as EAV evolve strategies to subvert host defenses and ensure their survival and propagation.

Cite This Article

APA
Carossino M, Dini P, Kalbfleisch TS, Loynachan AT, Canisso IF, Cook RF, Timoney PJ, Balasuriya UBR. (2019). Equine arteritis virus long-term persistence is orchestrated by CD8+ T lymphocyte transcription factors, inhibitory receptors, and the CXCL16/CXCR6 axis. PLoS Pathog, 15(7), e1007950. https://doi.org/10.1371/journal.ppat.1007950

Publication

PLoS pathogens
ISSN: 1553-7374
NlmUniqueID: 101238921
Country: United States
Language: English
Volume: 15
Issue: 7
Pages: e1007950

Researcher Affiliations

Carossino, Mariano
  • Louisiana Animal Disease Diagnostic Laboratory and Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States of America.
Dini, Pouya
  • Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY, United States of America.
  • Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Kalbfleisch, Theodore S
  • Department of Biochemistry and Molecular Genetics, School of Medicine, University of Louisville, Louisville, KY, United States of America.
Loynachan, Alan T
  • University of Kentucky Veterinary Diagnostic Laboratory, Department of Veterinary Science, University of Kentucky, Lexington, KY, United States of America.
Canisso, Igor F
  • Department of Veterinary Clinical Medicine, and Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL, United States of America.
Cook, R Frank
  • Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY, United States of America.
Timoney, Peter J
  • Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY, United States of America.
Balasuriya, Udeni B R
  • Louisiana Animal Disease Diagnostic Laboratory and Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States of America.

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

Conflict of Interest Statement

The authors have declared that no competing interests exist.

References

This article includes 74 references
  1. Cavanagh D. Nidovirales: a new order comprising Coronaviridae and Arteriviridae.. Arch Virol 1997;142(3):629–33.
    pubmed: 9349308
  2. Balasuriya U, MacLachlan NJ. Equine Viral Arteritis. Equine Infectious Diseases 2013;p. 169–81.
    doi: 10.1016/S1473-3099(13)70227-5google scholar: lookup
  3. Balasuriya UB, Go YY, MacLachlan NJ. Equine arteritis virus.. Vet Microbiol 2013;167(1–2):93–122.
    doi: 10.1016/j.vetmic.2013.06.015pmc: PMC7126873pubmed: 23891306google scholar: lookup
  4. Balasuriya UBR, Carossino M, Timoney PJ. Equine viral arteritis: a respiratory and reproductive disease of significant economic importance to the equine industry.. Equine Vet Educ 2016;In press.
    doi: 10.1111/eve.12566google scholar: lookup
  5. Timoney PJ. The increasing significance of international trade in equids and its influence on the spread of infectious diseases.. Ann N Y Acad Sci 2000;916:55–60.
    doi: 10.1111/j.1749-6632.2000.tb05274.xpubmed: 11193671google scholar: lookup
  6. Timoney PJ. Factors influencing the international spread of equine diseases.. Vet Clin North Am Equine Pract 2000;16(3):537–51.
    pubmed: 11219348
  7. Timoney PJ, McCollum WH. Equine viral arteritis: epidemiology and control.. J Equine Vet Sci 1988;8:54–9.
  8. Timoney PJ, McCollum WH. Equine viral arteritis.. Vet Clin North Am Equine Pract 1993;9(2):295–309.
    pmc: PMC7134676pubmed: 8395325
  9. Timoney PJ, McCollum WH. Equine viral arteritis: further characterization of the carrier state in stallions.. J Reprod Fertil Suppl 2000;56:3–11.
    pubmed: 20681110
  10. Timoney PJ, McCollum WH, Murphy TW, Roberts AW, Willard JG, Carswell GD. The carrier state in equine arteritis virus infection in the stallion with specific emphasis on the venereal mode of virus transmission.. J Reprod Fertil Suppl 1987;35:95–102.
    pubmed: 2824772
  11. Balasuriya U. Equine Viral Arteritis.. Vet Clin North Am Equine Pract 2014;30(3):543–60.
    doi: 10.1016/j.cveq.2014.08.011pubmed: 25441113google scholar: lookup
  12. Balasuriya UB, Snijder EJ, Heidner HW, Zhang J, Zevenhoven-Dobbe JC, Boone JD. Development and characterization of an infectious cDNA clone of the virulent Bucyrus strain of Equine arteritis virus.. J Gen Virol 2007;88(Pt 3):918–24.
    doi: 10.1099/vir.0.82415-0pubmed: 17325365google scholar: lookup
  13. Balasuriya UB, Snijder EJ, van Dinten LC, Heidner HW, Wilson WD, Hedges JF. Equine arteritis virus derived from an infectious cDNA clone is attenuated and genetically stable in infected stallions.. Virology 1999;260(1):201–8.
    doi: 10.1006/viro.1999.9817pubmed: 10405372google scholar: lookup
  14. Go YY, Cook RF, Fulgencio JQ, Campos JR, Henney P, Timoney PJ. Assessment of correlation between in vitro CD3+ T cell susceptibility to EAV infection and clinical outcome following experimental infection.. Vet Microbiol 2012;157(1–2):220–5.
    doi: 10.1016/j.vetmic.2011.11.031pubmed: 22177968google scholar: lookup
  15. MacLachlan NJ, Balasuriya UB, Rossitto PV, Hullinger PA, Patton JF, Wilson WD. Fatal experimental equine arteritis virus infection of a pregnant mare: immunohistochemical staining of viral antigens.. J Vet Diagn Invest 1996;8(3):367–74.
    doi: 10.1177/104063879600800316pubmed: 8844583google scholar: lookup
  16. McCollum WH, Timoney PJ, Tengelsen LA. Clinical, virological and serological responses of donkeys to intranasal inoculation with the KY-84 strain of equine arteritis virus.. J Comp Pathol 1995;112(2):207–11.
    pubmed: 7769149
  17. Vairo S, Vandekerckhove A, Steukers L, Glorieux S, Van den Broeck W, Nauwynck H. Clinical and virological outcome of an infection with the Belgian equine arteritis virus strain 08P178.. Vet Microbiol 2012;157(3–4):333–44.
    doi: 10.1016/j.vetmic.2012.01.014pubmed: 22306037google scholar: lookup
  18. Campos JR, Breheny P, Araujo RR, Troedsson MH, Squires EL, Timoney PJ. Semen quality of stallions challenged with the Kentucky 84 strain of equine arteritis virus.. Theriogenology 2014;82(8):1068–79.
    doi: 10.1016/j.theriogenology.2014.07.004pubmed: 25156969google scholar: lookup
  19. Vaala WE, Hamir AN, Dubovi EJ, Timoney PJ, Ruiz B. Fatal, congenitally acquired infection with equine arteritis virus in a neonatal thoroughbred.. Equine Vet J 1992;24(2):155–8.
    pubmed: 1316264
  20. Balasuriya UBR, Sarkar S, Carossino M, Go YY, Chelvarajan L, Cook RF. Host factors that contribute to equine arteritis virus persistence in the stallion: an update.. J Equine Vet Sci 2016;43:S11–S7.
  21. Timoney PJ, McCollum WH, Roberts AW, Murphy TW. Demonstration of the carrier state in naturally acquired equine arteritis virus infection in the stallion.. Res Vet Sci 1986;41(2):279–80.
    pubmed: 3022363
  22. McCollum WH, Little TV, Timoney PJ, Swerczek TW. Resistance of castrated male horses to attempted establishment of the carrier state with equine arteritis virus.. J Comp Pathol 1994;111(4):383–8.
    pubmed: 7884055
  23. Carossino M, Loynachan AT, Canisso IF, Campos JR, Nam B, Go YY. Equine Arteritis Virus has Specific Tropism for Stromal Cells and CD8+ T and CD21+ B Lymphocytes but not Glandular Epithelium at the Primary Site of Persistent Infection in the Stallion Reproductive Tract.. J Virol 2017;91(13):pii: e00418-17.
    pmc: PMC5469258pubmed: 28424285
  24. Carossino M, Wagner B, Loynachan AT, Cook RF, Canisso IF, Chelvarajan L. Equine Arteritis Virus Elicits a Mucosal Antibody Response in the Reproductive Tract of Persistently Infected Stallions.. Clin Vaccine Immunol 2017;24(10).
    pmc: PMC5629664pubmed: 28814389
  25. Balasuriya UB, Carossino M. Reproductive effects of arteriviruses: equine arteritis virus and porcine reproductive and respiratory syndrome virus infections.. Curr Opin Virol 2017;27:57–70.
    doi: 10.1016/j.coviro.2017.11.005pubmed: 29172072google scholar: lookup
  26. Sarkar S, Chelvarajan L, Go YY, Cook RF, Kalbfleisch T, Eberth J. Equine Arteritis Virus Uses Equine CXCL16 as an Entry Receptor.. J Virol 2016;90(7):3366–84.
    doi: 10.1128/JVI.02455-15pmc: PMC4794689pubmed: 26764004google scholar: lookup
  27. Go YY, Bailey E, Cook DG, Coleman SJ, Macleod JN, Chen KC. Genome-wide association study among four horse breeds identifies a common haplotype associated with in vitro CD3+ T cell susceptibility/resistance to equine arteritis virus infection.. J Virol 2011;85(24):13174–84.
    doi: 10.1128/JVI.06068-11pmc: PMC3233183pubmed: 21994447google scholar: lookup
  28. Go YY, Bailey E, Timoney PJ, Shuck KM, Balasuriya UB. Evidence that in vitro susceptibility of CD3+ T lymphocytes to equine arteritis virus infection reflects genetic predisposition of naturally infected stallions to become carriers of the virus.. J Virol 2012;86(22):12407–10.
    doi: 10.1128/JVI.01698-12pmc: PMC3486460pubmed: 22933293google scholar: lookup
  29. Sarkar S, Bailey E, Go YY, Cook RF, Kalbfleisch T, Eberth J. Allelic Variation in CXCL16 Determines CD3+ T Lymphocyte Susceptibility to Equine Arteritis Virus Infection and Establishment of Long-Term Carrier State in the Stallion.. PLoS Genet 2016;12(12):e1006467.
    doi: 10.1371/journal.pgen.1006467pmc: PMC5145142pubmed: 27930647google scholar: lookup
  30. Carossino M, Dini P, Kalbfleisch TS, Loynachan AT, Canisso IF, Shuck KM. Downregulation of microRNA eca-mir-128 in seminal exosomes and enhanced expression of CXCL16 in the stallion reproductive tract are associated with long-term persistence of equine arteritis virus.. J Virol 2018.
    pmc: PMC5899189pubmed: 29444949
  31. Go YY, Zhang J, Timoney PJ, Cook RF, Horohov DW, Balasuriya UB. Complex interactions between the major and minor envelope proteins of equine arteritis virus determine its tropism for equine CD3+ T lymphocytes and CD14+ monocytes.. J Virol 2010;84(10):4898–911.
    doi: 10.1128/JVI.02743-09pmc: PMC2863813pubmed: 20219931google scholar: lookup
  32. Mi H, Huang X, Muruganujan A, Tang H, Mills C, Kang D. PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements.. Nucleic Acids Res 2017;45(D1):D183–D9.
    doi: 10.1093/nar/gkw1138pmc: PMC5210595pubmed: 27899595google scholar: lookup
  33. Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.. Nat Protoc 2009;4(1):44–57.
    doi: 10.1038/nprot.2008.211pubmed: 19131956google scholar: lookup
  34. Jurikova M, Danihel L, Polak S, Varga I. Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer.. Acta Histochem 2016;118(5):544–52.
    doi: 10.1016/j.acthis.2016.05.002pubmed: 27246286google scholar: lookup
  35. Wilson JA, Prow NA, Schroder WA, Ellis JJ, Cumming HE, Gearing LJ. RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation.. PLoS Pathog 2017;13(2):e1006155.
    doi: 10.1371/journal.ppat.1006155pmc: PMC5312928pubmed: 28207896google scholar: lookup
  36. Vandenbon A, Dinh VH, Mikami N, Kitagawa Y, Teraguchi S, Ohkura N. Immuno-Navigator, a batch-corrected coexpression database, reveals cell type-specific gene networks in the immune system.. Proc Natl Acad Sci U S A 2016;113(17):E2393–402.
    doi: 10.1073/pnas.1604351113pmc: PMC4855614pubmed: 27078110google scholar: lookup
  37. Kahan SM, Wherry EJ, Zajac AJ. T cell exhaustion during persistent viral infections.. Virology 2015;479–480:180–93.
    doi: 10.1016/j.virol.2014.12.033pmc: PMC4424083pubmed: 25620767google scholar: lookup
  38. Wherry EJ. T cell exhaustion.. Nat Immunol 2011;12(6):492–9.
    pubmed: 21739672
  39. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion.. Nat Rev Immunol 2015;15(8):486–99.
    doi: 10.1038/nri3862pmc: PMC4889009pubmed: 26205583google scholar: lookup
  40. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V. Molecular signature of CD8+ T cell exhaustion during chronic viral infection.. Immunity 2007;27(4):670–84.
    doi: 10.1016/j.immuni.2007.09.006pubmed: 17950003google scholar: lookup
  41. Wang J, Lu Y, Wang J, Koch AE, Zhang J, Taichman RS. CXCR6 induces prostate cancer progression by the AKT/mammalian target of rapamycin signaling pathway.. Cancer Res 2008;68(24):10367–76.
    doi: 10.1158/0008-5472.CAN-08-2780pmc: PMC2884407pubmed: 19074906google scholar: lookup
  42. Doering TA, Crawford A, Angelosanto JM, Paley MA, Ziegler CG, Wherry EJ. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory.. Immunity 2012;37(6):1130–44.
    doi: 10.1016/j.immuni.2012.08.021pmc: PMC3749234pubmed: 23159438google scholar: lookup
  43. Novershtern N, Subramanian A, Lawton LN, Mak RH, Haining WN, McConkey ME. Densely interconnected transcriptional circuits control cell states in human hematopoiesis.. Cell 2011;144(2):296–309.
    doi: 10.1016/j.cell.2011.01.004pmc: PMC3049864pubmed: 21241896google scholar: lookup
  44. Han JD, Bertin N, Hao T, Goldberg DS, Berriz GF, Zhang LV. Evidence for dynamically organized modularity in the yeast protein-protein interaction network.. Nature 2004;430(6995):88–93.
    doi: 10.1038/nature02555pubmed: 15190252google scholar: lookup
  45. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis.. BMC Bioinformatics 2008;9:559.
    doi: 10.1186/1471-2105-9-559pmc: PMC2631488pubmed: 19114008google scholar: lookup
  46. Zhang B, Horvath S. A general framework for weighted gene co-expression network analysis.. Stat Appl Genet Mol Biol 2005;4:Article17.
    pubmed: 16646834
  47. Kommadath A, Bao H, Arantes AS, Plastow GS, Tuggle CK, Bearson SM. Gene co-expression network analysis identifies porcine genes associated with variation in Salmonella shedding.. BMC Genomics 2014;15:452.
    doi: 10.1186/1471-2164-15-452pmc: PMC4070558pubmed: 24912583google scholar: lookup
  48. Wang W, Jiang W, Hou L, Duan H, Wu Y, Xu C. Weighted gene co-expression network analysis of expression data of monozygotic twins identifies specific modules and hub genes related to BMI.. BMC Genomics 2017;18(1):872.
    doi: 10.1186/s12864-017-4257-6pmc: PMC5683603pubmed: 29132311google scholar: lookup
  49. Nam B, Mekuria Z, Carossino M, Li G, Zheng Y, Zhang J. Intra-host Selection Pressure Drives Equine Arteritis Virus Evolution during Persistent Infection in the Stallion Reproductive Tract.. J Virol 2019.
    pmc: PMC6613756pubmed: 30918077
  50. Trigunaite A, Dimo J, Jorgensen TN. Suppressive effects of androgens on the immune system.. Cell Immunol 2015;294(2):87–94.
    doi: 10.1016/j.cellimm.2015.02.004pubmed: 25708485google scholar: lookup
  51. Roved J, Westerdahl H, Hasselquist D. Sex differences in immune responses: Hormonal effects, antagonistic selection, and evolutionary consequences.. Horm Behav 2016.
    pubmed: 27956226
  52. Vom Steeg LG, Klein SL. Sex Steroids Mediate Bidirectional Interactions Between Hosts and Microbes.. Horm Behav 2017;88:45–51.
    doi: 10.1016/j.yhbeh.2016.10.016pmc: PMC6530912pubmed: 27816626google scholar: lookup
  53. Ye B, Liu X, Li X, Kong H, Tian L, Chen Y. T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance.. Cell Death Dis 2015;6:e1694.
    doi: 10.1038/cddis.2015.42pmc: PMC4385920pubmed: 25789969google scholar: lookup
  54. Martinez GJ, Pereira RM, Aijo T, Kim EY, Marangoni F, Pipkin ME. The transcription factor NFAT promotes exhaustion of activated CD8(+) T cells.. Immunity 2015;42(2):265–78.
    doi: 10.1016/j.immuni.2015.01.006pmc: PMC4346317pubmed: 25680272google scholar: lookup
  55. Man K, Gabriel SS, Liao Y, Gloury R, Preston S, Henstridge DC. Transcription Factor IRF4 Promotes CD8(+) T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection.. Immunity 2017;47(6):1129–41 e5.
    doi: 10.1016/j.immuni.2017.11.021pubmed: 29246443google scholar: lookup
  56. Klenerman P, Hill A. T cells and viral persistence: lessons from diverse infections.. Nat Immunol 2005;6(9):873–9.
    doi: 10.1038/ni1241pubmed: 16116467google scholar: lookup
  57. McLane LM, Banerjee PP, Cosma GL, Makedonas G, Wherry EJ, Orange JS. Differential localization of T-bet and Eomes in CD8 T cell memory populations.. J Immunol 2013;190(7):3207–15.
    doi: 10.4049/jimmunol.1201556pmc: PMC3608800pubmed: 23455505google scholar: lookup
  58. Buggert M, Tauriainen J, Yamamoto T, Frederiksen J, Ivarsson MA, Michaelsson J. T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection.. PLoS Pathog 2014;10(7):e1004251.
    doi: 10.1371/journal.ppat.1004251pmc: PMC4102564pubmed: 25032686google scholar: lookup
  59. Macian F, Lopez-Rodriguez C, Rao A. Partners in transcription: NFAT and AP-1.. Oncogene 2001;20(19):2476–89.
    doi: 10.1038/sj.onc.1204386pubmed: 11402342google scholar: lookup
  60. Olive AJ, Gondek DC, Starnbach MN. CXCR3 and CCR5 are both required for T cell-mediated protection against C. trachomatis infection in the murine genital mucosa.. Mucosal Immunol 2011;4(2):208–16.
    doi: 10.1038/mi.2010.58pmc: PMC3010299pubmed: 20844481google scholar: lookup
  61. Gunther C, Carballido-Perrig N, Kaesler S, Carballido JM, Biedermann T. CXCL16 and CXCR6 are upregulated in psoriasis and mediate cutaneous recruitment of human CD8+ T cells.. J Invest Dermatol 2012;132(3 Pt 1):626–34.
    pubmed: 22113484
  62. Kunkel EJ, Butcher EC. Plasma-cell homing.. Nat Rev Immunol 2003;3(10):822–9.
    doi: 10.1038/nri1203pubmed: 14523388google scholar: lookup
  63. van der Voort R, Verweij V, de Witte TM, Lasonder E, Adema GJ, Dolstra H. An alternatively spliced CXCL16 isoform expressed by dendritic cells is a secreted chemoattractant for CXCR6+ cells.. J Leukoc Biol 2010;87(6):1029–39.
    doi: 10.1189/jlb.0709482pmc: PMC3210559pubmed: 20181724google scholar: lookup
  64. van der Voort R, Volman TJ, Verweij V, Linssen PC, Maas F, Hebeda KM. Homing characteristics of donor T cells after experimental allogeneic bone marrow transplantation and posttransplantation therapy for multiple myeloma.. Biol Blood Marrow Transplant 2013;19(3):378–86.
    doi: 10.1016/j.bbmt.2012.12.014pubmed: 23266741google scholar: lookup
  65. Bryans JT, Crowe ME, Doll ER, McCollum WH. Isolation of a filterable agent causing arteritis of horses and abortion by mares; its differentiation from the equine abortion (influenza) virus.. Cornell Vet 1957;47(1):3–41.
    pubmed: 13397177
  66. Wade CM, Giulotto E, Sigurdsson S, Zoli M, Gnerre S, Imsland F. Genome sequence, comparative analysis, and population genetics of the domestic horse.. Science 2009;326(5954):865–7.
    doi: 10.1126/science.1178158pmc: PMC3785132pubmed: 19892987google scholar: lookup
  67. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform.. Bioinformatics 2009;25(14):1754–60.
    doi: 10.1093/bioinformatics/btp324pmc: PMC2705234pubmed: 19451168google scholar: lookup
  68. Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks.. Nat Protoc 2012;7(3):562–78.
    doi: 10.1038/nprot.2012.016pmc: PMC3334321pubmed: 22383036google scholar: lookup
  69. Huang da W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists.. Nucleic Acids Res 2009;37(1):1–13.
    doi: 10.1093/nar/gkn923pmc: PMC2615629pubmed: 19033363google scholar: lookup
  70. Ruijter JM, Ramakers C, Hoogaars WM, Karlen Y, Bakker O, van den Hoff MJ. Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data.. Nucleic Acids Res 2009;37(6):e45.
    doi: 10.1093/nar/gkp045pmc: PMC2665230pubmed: 19237396google scholar: lookup
  71. Carossino M, Loynachan AT, James MacLachlan N, Drew C, Shuck KM, Timoney PJ. Detection of equine arteritis virus by two chromogenic RNA in situ hybridization assays (conventional and RNAscope(R)) and assessment of their performance in tissues from aborted equine fetuses.. Arch Virol 2016;161(11):3125–36.
    doi: 10.1007/s00705-016-3014-5pubmed: 27541817google scholar: lookup
  72. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D. Cytoscape: a software environment for integrated models of biomolecular interaction networks.. Genome Res 2003;13(11):2498–504.
    doi: 10.1101/gr.1239303pmc: PMC403769pubmed: 14597658google scholar: lookup
  73. Abedi M, Gheisari Y. Nodes with high centrality in protein interaction networks are responsible for driving signaling pathways in diabetic nephropathy.. PeerJ 2015;3:e1284.
    doi: 10.7717/peerj.1284pmc: PMC4636410pubmed: 26557424google scholar: lookup
  74. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method.. Nat Protoc 2008;3(6):1101–8.
    pubmed: 18546601
Subscribe to our newsletter
Join 99,359 horse owners like you who receive our email updates on horse health and nutrition.