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Thymus Transcriptome Reveals Novel Pathways in Response to Avian Pathogenic Escherichia coli (APEC) Infection

ABSTRACT: Purpose: This study would be useful to characterize the molecular mechanisms of an effective anti-bacterial response of chicken immune system. Methods: meat-type chickens were either infected with APEC O1 or given saline as a control. Thymii were collected on 1 and 5 days post-infection (dpi). The infected birds were classified based upon necropsy findings as having mild or severe pathology, representing resistant and susceptible phenotypes, respectively. Data from RNA sequencing experiments were analyzed using the R package, edgR, to identify the significantly differentially expressed (DE) genes. GO and pathway analysis using the R package GOseq identified many immune-related pathways. Results: Thousands of genes were DE at 5 dpi in susceptible vs. non-infected birds and in susceptible vs. resistant birds, as well as in susceptible birds at 1 vs. 5 dpi. In the contrast of susceptible birds with resistant or non-challenged birds, many immune response and signal transduction pathways were strongly induced, whereas the TCR signaling pathway was deeply suppressed to affect T cell development, differentiation, proliferation, and maturation. The transcriptomes of resistant and non-challenged birds were similar. Conclusions: These results provide the first comprehensive assessment of global gene networks and biological functionalities of DE genes in thymus in response to APEC infection, thus providing novel insights into key molecular genetic mechanisms that differentiate host resistance from susceptibility in this primary lymphoid tissue. These findings are foundational to the development of strategies to enhance host resistance to APEC infection.

ORGANISM(S): Gallus gallus

PROVIDER: GSE69014 | GEO | 2017/02/09

SECONDARY ACCESSION(S): PRJNA284293

REPOSITORIES: GEO

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Project description:Purpose: This study is to more comprehensively understand the genome-wide host response to avian pathogen E. coli (APEC). Methods: Male broiler chicks were challenged with APEC (or mock-challenged as controls), and bone marrow was harvested at 1 and 5 days post-infection (dpi). Based upon necropsy-scored lesions on liver, pericardium, and air sacs, the challenged birds were assigned to mild or severe pathology categories, representing resistant and susceptible phenotypes, respectively. RNA sequence data were first analyzed using the R package EdgeR to identify differentially expressed genes.GO and pathway analysis using the R package GOseq identified many immune-related pathways. Results: RNA sequencing resulted in 11 to 40 million single-end raw reads of 100 bp per sample. After alignment, an average of 80 % of the reads, with 5 % representing multiple mapping, were mapped to the chicken reference transcriptome. Among these detected unique transcripts, there were 2,404 novel genes mainly distributed on chromosomes 1, 2, 4, 3, Z, 5 in decreasing number. Genes were detected as differentially expressed (DE) between treatments (susceptible, resistant, and mock-challenged) at a given time point, or DE between 1 and 5 dpi within the same treatment group. Compared to mock-challenged birds on 5 dpi, susceptible birds exhibited extensive enhancement of their T cell and B cell development, as well as innate and adaptive immune response. However, for the 1 dpi group, susceptible birds exhibited a decreased gene expression of T and B cell development. The differences between the two phenotypes, susceptible and resistant birds, at 5 dpi showed that susceptible birds had increased gene expression of B-cell development and adaptive immune response. Conclusions: This is the first report to our knowledge examining the role of bone marrow cells in responding to APEC infection in broilers. This transcriptome study provides insight and global overview into the response of genes involved in the earliest phases of the immune response to APEC infection. Our data indicate a dynamic interaction between the innate and adaptive immune responses to APEC infection in susceptible birds, providing flexibility and redundancy in the host’s induction of cytokines and chemokines. Additionally, B cell and T cell development are also extensively affected by APEC infection for susceptible birds, resulting in drastic host impairment in early response to infection. The findings of present study shed light on the underlying chicken immune modulation against APEC infection. Also, this study will build a solid foundation for identifying host genetic variation that may be manipulated to enhance resistance to infection and may be useful as colibacillosis control targets.

Project description:Avian pathogenic Escherichia coli (APEC) is considered one of the most common infectious bacterial diseases resulting in significant economic losses in poultry industry worldwide. In order to investigate the association between host immune resistance and miRNA expression in the pathogenic process induced by APEC, miRNA expression profiles in broilers spleen were performed by Solexa deep sequencing from three different treatment groups including non-challenged (NC), challenged-mild pathology (MD), and challenged-severe pathology (SV).In total, 3 462 706, 3 586 689, and 3 591 027 clean reads were obtained for NC, MD, and SV, respectively. After comparing the miRNA expression patterns, 27 differentially expressed miRNAs were identified among the three response groups, which included 13 miRNAs between NC and MD, 17 between NC and SV, and 14 between MD and SV. For these miRNAs, different expression in MD and SV suggested they may have resistance activity in APEC infection. Through integrated analysis of miRNA and mRNA expression patterns, 43 negative pairs between miRNA and mRNA (r < -0.80) were obtained. 4 miRNAs were validated to be significant negatively correlated to targets by quantitative real time PCR: gga-miR-21 (CLEC3B and GGTLA1), gga-miR-429 (TMEFF2, CDC20, SHISA2 and NOX4), gga-miR-146b (LAT2 and WNK1), and gga-miR-215 (C7 and ASL2). Additionally, the expression of gga-miR-21 and gga-miR-146b was significantly up-regulated by LPS induced in HD11 macrophage cell. In contrast, gga-miR-429 has no significant change. In summary, we present the first report that characterized the miRNA profiles of chicken spleen in response to APEC infection, and identified several candidate miRNAs which might accelerate host immune response through down-regulating their specific target genes. Through the intra-air sac route into the left thoracic air sac, 240 non-vaccinated males at 4 weeks of age were challenged with 0.1 ml APEC O1 (10^8 colony forming units) and another 120 non-vaccinated males were non-challenged but treated with 0.1 ml PBS. Detailed information on the APEC O1 strain and challenge process was described by previously described study. Necropsy was performed at 1 day post challenge, and a summarized lesion ranging from 0 to 7 was determined for each APEC-challenged bird. Birds with lesions scoring 0-2 were regarded as mild infection, and those scoring 4-7 were designated as severe infection. The mild and severe pathology meant that birds were resistant and susceptible to APEC infection, respectively. Then, spleens from three groups, consisting of non-challenged, challenged-mild pathology and challenged-severe pathology were subjected to Solexa deep sequencing to investigate the dynamics of chicken miRNA expression.

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Thymus Transcriptome Reveals Novel Pathways in Response to Avian Pathogenic Escherichia coli (APEC) Infection

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