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Genome-wide profiling of RNAs reveals novel insights into the immune response between infectious bronchitis virus and avian dendritic cells

ABSTRACT: Background: Avian infectious bronchitis virus (IBV) was an major respiratory disease-causing agents that lead to significant losses in birds. Dendritic cells (DCs), an major antigen-presenting cells, influence viruses pathogenicity as well as host immune response. Expression of host non-coding mRNA changes markedly during infectious bronchitis virus (IBV) infection of avian, but their role in regulating host immune function to defend IBV infection has not been explored. Here, microarray, including mRNAs, miRNAs and lncRNAs, were analysed to better understand the interaction between IBV and avian DCs. Results: Firstly, we found that IBV infection can effectively induce avian DCs to become mature. Interestingly, inactivated IBV possess high ability in inducing DC maturation and activating lymphocytes than that in actived IBV stimulated group. Then, result identified that IBV infection induced 1093 upregulated and 845 downregulated mRNAs in avian DCs. Analysis of Gene Ontology suggested that celluar macromolecule and protein location (GO-BP), as well as transcription factor binding (GO-MF) were abundance in IBV infected group. Whilst, pathway analyses suggested that oxidative phosphorylation and T cell receptor signalling pathways might activated in IBV group. Moreover, microRNA (miRNA) and long non-coding RNA (lncRNA) alterations in IBV-stimulated avian DCs were observed. A total of 19 significantly altered (7 up and 12 down) miRNAs and 101 (75 up and 26 down) lncRNAs were identified in IBV-stimulated DCs. Furtherly insight analyses not only gain that regulation of actin cytoskeleton and MAPK signal pathway were contributed to IBV stimulated miRNAs target genes, but also build an regulatory networks based on co-expressed lncRNA and mRNA. Finally, our study identified 2 TF-miRNA (CEBPA-miR1772 and CEBPA-miR21), which we based on to constructed 53 transcription factor (TF)–miRNA–mRNA interactions involving 1 TF, 2 miRNAs, and 53 mRNAs in IBV-stimulated avian DCs.

ORGANISM(S): Gallus gallus

PROVIDER: GSE100802 | GEO | 2017/12/01

SECONDARY ACCESSION(S): PRJNA393114

REPOSITORIES: GEO

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Project description:Human SARS-CoV-2 and avian IBV are highly contagious and deadly coronaviruses causing devastating respiratory diseases in human and chicken, respectively. Lacking effective therapies exacerbates the disease associated with SARS-CoV-2 and IBV infections. Thus, novel therapeutic agents are in demand for controlling viral transmission and disease progression. Mesenchymal stem cells secreted factors (secretome) proven to be safe and highly efficient alternative to stem cells in mesenchymal stem cell-based therapy (MSCT). The most favorable advantage of secretome is the bypass of the side effects of MSCT that include but not limited to tumorigenesis, immune rejection, and infection. In this study, we aimed to investigate the antiviral activities of human Wharton’s jelly mesenchymal stem cells secretome against SARS-CoV-2 and IBV infection. The half-maximal inhibitory concentrations (IC50), and cytotoxic concentration (CC50) values of hWJ-MSC secretome (hWJ-MSC-S) were determined in Vero-E6 cells. Virucidal, anti-adsorption, and anti-replication mechanisms of hWJ-MSC-S against SARS-CoV-2 and IBV infection were evaluated in vitro. In Ovo anti-IBV activity of hWJ-MSC-S was estimated using Specific pathogen-free (SPF) embryonated chicken eggs (ECEs). The antiviral efficacy of hWJ-MSC-S was determined in terms of reduction in viral infection. Protein composition of hWJ-MSC-S was analyzed by mass spectrometry analysis, and gene ontology of secretome proteins was evaluated. Our data showed hWJ-MSC-S to significantly inhibits infection of human SARS-CoV-2 and avian IBV with very low cytotoxicity and embryotoxicity profile. CC50 value of hWJ-MSC-S in Vero-E6 was 39200 µg/ml. IC50, SI values of hWJ-MSC secretome against SARS-CoV-2 were 166.6 µg/ml, and 235.29, respectively. Similarly, IC50, SI values of hWJ-MSC-S against IBV were 439.9 µg/ml, and 89.11, respectively. hWJ-MSC-S reduced PFU/ml of SARS-CoV-2 and IBV by > 90%. Antiviral mechanistic studies demonstrated that hWJ-MSC-S had >95% and >90% virucidal effects on SARS-CoV-2 and IBV infections, respectively. The anti-replication effect was approximately 87.33% against SARS-CoV-2 infection, and >90% against IBV infection. In ovo model, hWJ-MSC-S significantly inhibited IBV infection. At a concentration of 1000 µg/ml, hWJ-MSC-S reduced IBV titre from 763000 ± 32638 to 38.333 ± 6.0093 EID50/ml (>99% inhibition). Similarly, hWJ-MSC-S reduced IBV titer from 763000 ± 32638 to 1896 ± 926.1 EID50/ml (>97% inhibition) at a concentration of 500 µg/ml. In addition, 250 µg/ml concentration of hWJ-MSC-S reduce IBV titer from 763000 ± 32638 to 20380 ± 2885 EID50/ml (>96% inhibition). LC/MS-MS analysis revealed that biological processes of hWJ-MSC-S proteins were mostly related to Immunomodulatory effect. Collectively, our results not only uncovered the antiviral potency of hWJ-MSC-S against SARS-CoV-2 and IBV, but also described the mechanism by which hWJ-MSC-S inhibit viral infection. These findings could be utilized in future pre-clinical and clinical studies to develop an effective therapeutic against human COVID-19 and avian IB respiratory diseases using hWJ-MSC-S.

Project description:Background: Avian infectious bronchitis (IB) is an acute and highly contagious disease of the upper-respiratory tract caused by infectious bronchitis virus (IBV). Understanding the molecular mechanisms involved in the interaction between innate and adaptive immune responses to IBV infection is a crucial element for further improvements in strategies to control IB. To this end, two chicken lines, selected for high and low serum concentration of mannose-binding lectin (MBL), a soluble pattern recognition receptor, were studied. In total, 32 birds from each line (designated L10H for high and L10L for low MBL serum concentration, respectively) were used. Sixteen birds from each line were infected with IBV at 3 weeks of age and sixteen birds were left uninfected. Eight uninfected and eight infected birds from each line were euthanized at 1 and 3 weeks post infection. RNA sequencing was performed on spleen samples from all 64 birds used in the experiment. Differential gene expression analysis was performed for four comparisons: L10L line versus L10H line for uninfected birds at weeks 1 and 3, respectively, and L10L line versus L10H line for infected birds at weeks 1 and 3, respectively. Functional analysis based on the differentially expressed genes was performed using Gene Ontology (GO) Immune System Process terms specific for Gallus gallus. Results: Comparing uninfected L10H and L10L birds, we identified 1698 and 1424 differentially expressed (DE) genes at weeks 1 and 3, respectively. For the IBV-infected birds, 1934 and 866 DE genes were identified between the two lines at weeks 1 and 3, respectively. In both cases DE genes had FDR-adjusted p-value <0.05. The two most enriched GO terms emerging from the comparison of uninfected birds between the two lines were “Lymphocyte activation involved in immune response” (GO:0002285) and “Somatic recombination of immunoglobulin genes involved in immune response” (GO:0002204) at weeks 1 and 3, respectively. When comparing IBV-infected birds between the two lines, the most enriched GO terms were “Alpha-beta T cell activation” (GO:0046631) and “Positive regulation of leukocyte activation” (GO:0002696) at weeks 1 and 3, respectively. Conclusion: Healthy birds from the two lines showed significant differences in expression profiles for subsets of both adaptive and innate immunity-related genes, whereas comparison of the IBV-infected birds from the two lines showed differences in expression of immunity-related genes involved in T cell activation and proliferation. The observed transcriptome differences between the two lines indicate that selection for MBL had a much wider effect than solely on serum MBL concentration, and in addition influenced the innate and adaptive immune responses. Future research will focus on identifying signatures of selection in order to further understand molecular pathways be responsible for differences between the two lines as well as for efficient IBV immune protection.

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Genome-wide profiling of RNAs reveals novel insights into the immune response between infectious bronchitis virus and avian dendritic cells

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