Allelic Variation in CXCL16 Determines CD3+ T Lymphocyte Susceptibility to Equine Arteritis Virus Infection and Establishment of Long-Term Carrier State in the Stallion

被引:14
作者
Sarkar, Sanjay [1 ]
Bailey, Ernest [1 ]
Go, Yun Young [1 ,3 ]
Cook, R. Frank [1 ]
Kalbfleisch, Ted [2 ]
Eberth, John [1 ]
Chelvarajan, R. Lakshman [1 ]
Shuck, Kathleen M. [1 ]
Artiushin, Sergey [1 ]
Timoney, Peter J. [1 ]
Balasuriya, Udeni B. R. [1 ]
机构
[1] Univ Kentucky, Dept Vet Sci, Maxwell H Gluck Equine Res Ctr, Lexington, KY 40506 USA
[2] Univ Louisville, Sch Med, Dept Biochem & Mol Genet, Louisville, KY 40292 USA
[3] Korea Res Inst Chem Technol, Div Drug Discovery Res, Virus Res & Testing Grp, Daejeon, South Korea
来源
PLOS GENETICS | 2016年 / 12卷 / 12期
基金
美国食品与农业研究所;
关键词
VIRULENT BUCYRUS STRAIN; SCAVENGER RECEPTOR; ENDOTHELIAL-CELLS; PERSISTENT INFECTION; VIRAL ARTERITIS; SR-PSOX; ENVELOPE PROTEINS; CHEMOKINE CXCL16; CDNA-CLONE; EXPRESSION;
D O I
10.1371/journal.pgen.1006467
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Equine arteritis virus (EAV) is the causative agent of equine viral arteritis (EVA), a respiratory, systemic, and reproductive disease of horses and other equid species. Following natural infection, 10-70% of the infected stallions can become persistently infected and continue to shed EAV in their semen for periods ranging from several months to life. Recently, we reported that some stallions possess a subpopulation(s) of CD3(+) T lymphocytes that are susceptible to in vitro EAV infection and that this phenotypic trait is associated with long-term carrier status following exposure to the virus. In contrast, stallions not possessing the CD3(+) T lymphocyte susceptible phenotype are at less risk of becoming long-term virus carriers. A genome wide association study (GWAS) using the Illumina Equine SNP50 chip revealed that the ability of EAV to infect CD3(+) T lymphocytes and establish long-term carrier status in stallions correlated with a region within equine chromosome 11. Here we identified the gene and mutations responsible for these phenotypes. Specifically, the work implicated three allelic variants of the equine orthologue of CXCL16 (EqCXCL16) that differ by four non-synonymous nucleotide substitutions (XM_00154756; c.715 A -> T, c.801 G -> C, c.804 T -> A/G, c.810 G -> A) within exon 1. This resulted in four amino acid changes with EqCXCL16S (XP_001504806.1) having Phe, His, Ile and Lys as compared to EqCXL16R having Tyr, Asp, Phe, and Glu at 40, 49, 50, and 52, respectively. Two alleles (EqCXCL 16Sa, EqCXCL16Sb) encoded identical protein products that correlated strongly with long-term EAV persistence in stallions (P<0.000001) and are required for in vitro CD3(+) T lymphocyte susceptibility to EAV infection. The third (EqCXCL16R) was associated with in vitro CD3(+) T lymphocyte resistance to EAV infection and a significantly lower probability for establishment of the long-term carrier state (viral persistence) in the male reproductive tract. EqCXCL16Sa and EqCXCL16Sb exert a dominant mode of inheritance. Most importantly, the protein isoform EqCXCL16S but not EqCXCL16R can function as an EAV cellular receptor. Although both molecules have equal chemoattractant potential, EqCXCL16S has significantly higher scavenger receptor and adhesion properties compared to EqCXCL16R.
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页数:34
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