Abstract
Very virulent plus Marek’s disease (MD) virus (vv + MDV) induces tumors in relatively resistant lines of chickens and early mortality in highly susceptible lines of chickens. The vv + MDV also triggers a series of cellular responses in both types of chickens. We challenged birds sampled from a highly inbred chicken line (line 63) that is relatively resistant to MD and from another inbred line (line 72) that is highly susceptible to MD with a vv + MDV. RNA-sequencing analysis was performed with samples extracted from spleen tissues taken at 10-day and 21-day post infection (dpi). A total of 64 and 106 differentially expressed genes was identified in response to the vv + MDV challenge at latent phase in the resistant and susceptible lines of chickens, respectively. Direct comparisons between samples of the two lines identified 90 and 126 differentially expressed genes for control and MDV challenged groups, respectively. The differentially expressed gene profiles illustrated that intensive defense responses were significantly induced by vv + MDV at 10 dpi and 21 dpi but with slight changes in the resistant line. In contrast, vv + MDV induced a measurable suppression of gene expression associated with host defense at 10 dpi but followed by an apparent activation of the defense response at 21 dpi in the susceptible line of chickens. The observed difference in gene expression between the two genetic lines of chickens in response to MDV challenge during the latent phase provided a piece of indirect evidence that time points for MDV reactivation differ between the genetic lines of chickens with different levels of genetic resistance to MD. Early MDV reactivation might be necessary and potent to host defense system readiness for damage control of tumorigenesis and disease progression, which consequently results in measurable differences in phenotypic characteristics including early mortality (8 to 20 dpi) and tumor incidence between the resistant and susceptible lines of chickens. Combining differential gene expression patterns with reported GO function terms and quantitative trait loci, a total of 27 top genes was selected as highly promising candidate genes for genetic resistance to MD. These genes are functionally involved with virus process (F13A1 and HSP90AB1), immunity (ABCB1LB, RGS5, C10ORF58, OSF-2, MMP7, CXCL12, GAL1, GAL2, GAL7, HVCN1, PDE4D, IL4I1, PARP9, EOMES, MPEG1, PDK4, CCLI10, K60 and FST), and tumor suppression (ADAMTS2, LXN, ARRDC3, WNT7A, CLDN1 and HPGD). It is anticipated that these findings will facilitate advancement in the fundamental understanding on mechanisms of genetic resistance to MD. In addition, such advancement may also provide insights on tumor virus-induced tumorigenesis in general and help the research community recognize MD study may serve as a good model for oncology study involving tumor viruses.
Highlights
Marek’s disease (MD) is a neoplastic disease of chickens caused by an oncogenic alpha-herpesvirus, commonly known as MD virus (MDV)
To further identify key genes that may confer genetic resistance to MD from all the unique differentially expressed genes (DEGs), we focused on the followings: (1) DEGs located within reported QTL regions of MD resistance; (2) DEGs with large fold change (FC >2) in one line but not in the other (FC < 0.5); (3) DEGs differentially expressed between the two lines regardless of MDV challenge; (4) MDV induced DEGs with differential expression between infected line 63 and line 72 birds (Fig. 3E–H)
We have carried out a comprehensive gene expression study using RNA-Seq analysis and identified hundreds of differentially expressed genes in response to a vv + MDV challenge in two highly inbred lines of chickens at 10 and 21 days post MDV infection
Summary
Marek’s disease (MD) is a neoplastic disease of chickens caused by an oncogenic alpha-herpesvirus, commonly known as MD virus (MDV). When challenged with a partially attenuated very virulent plus strain of MDV (648A passage 40), up to 100% of the line 72 chickens developed MD while over 90% of line 63 chickens remained MD free 8 weeks post MDV inoculation[19] These inbred lines of chickens are commonly considered as ideal resources for investigating the mechanisms of genetic resistance to MD and MD tumor progression[15,20]. Since the establishment of the genetic lines, a variety of differences in response to MDV infection between the two lines of chickens have been investigated, which include the aggregate number of target lymphocytes for virus infection and transformation[21,22], expressed antigens on T-cell surface[23], the number of infected lymphocytes during the early lytic phase of infection[24], viral load during latent phase of infection[25,26], the expression of Interferon (INF) genes[27] and cytokine genes[26]. Public web server tools for high-throughput genomics data analyses were employed to dissect the identified DEGs for functional interpretations and to select candidate DEGs functionally relevant to MD resistance, which was anticipated to provide some insights on the mechanisms of genetic resistance to MD
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