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Objective: Systemic sclerosis (SSc) is a chronic systemic disease characterized by immune dysregulation and fibrosis for which there is no effective treatment. Animal models are crucial for advancing SSc research. Tree shrews are genetically, anatomically, and immunologically closer to humans than rodents. Thus, the tree shrew model provides a unique opportunity for translational research in SSc. Methods: In this study, a SSc tree shrew model was constructed by subcutaneous injection of different doses of bleomycin (BLM) for 21 days. We assessed the degree of inflammation and fibrosis in the skin and internal organs, and antibodies in serum. Furthermore, RNA sequencing and a series of bioinformatics analyses were performed to analyze the transcriptome changes, hub genes and immune infiltration in the skin tissues of BLM induced SSc tree shrew models. Multiple sequence alignment was utilized to analyze the conservation of selected target genes across multiple species. Results: Subcutaneous injection of BLM successfully induced a SSc model in tree shrew. This model exhibited inflammation and fibrosis in skin and lung, and some developed esophageal fibrosis and secrum autoantibodies including antinuclear antibodies and anti-scleroderma-70 antibody. Using RNA sequencing, we compiled skin transcriptome profiles in SSc tree shrew models. 90 differentially expressed genes (DEGs) were identified, which were mainly enriched in the PPAR signaling pathway, tyrosine metabolic pathway, p53 signaling pathway, ECM receptor interaction and glutathione metabolism, all of which are closely associated with SSc. Immune infiltration analysis identified 20 different types of immune cells infiltrating the skin of the BLM-induced SSc tree shrew models and correlations between those immune cells. By constructing a protein-protein interaction (PPI) network, we identified 10 hub genes that were significantly highly expressed in the skin of the SSc models compared to controls. Furthermore, these genes were confirmed to be highly conserved in tree shrews, humans and mice. Conclusion: This study for the first time comfirmed that tree shrew model of SSc can be used as a novel and promising experimental animal model to study the pathogenesis and translational research in SSc. [ABSTRACT FROM AUTHOR]

Background: Previous studies have established several animal models for experimental autoimmune uveitis (EAU) in rodents without the fovea centralis in the human retina. This study aimed to develop and explore the application of a novel EAU model in tree shrews with a cone-dominated retina resembling the human fovea. Methods: Tree shrews were clinically and pathologically evaluated for the development and characteristics of EAU immunized with six inter-photoreceptor retinoid-binding proteins (IRBPs). IRBP-specific T-cell proliferation and serum cytokine of tree shrews were evaluated to determine the immune responses. Differentially expressed genes (DEGs) were identified in the eyes of tree shrews with EAU by RNA-sequencing. The disruptive effects of the DEG RGS4 inhibitor CCG 203769 and dihydroartemisinin on the EAU were investigated to evaluate the potential application of tree shrew EAU. Results: IRBP1197–1211 and R14 successfully induced chronic EAU with subretinal deposits and retinal damage in the tree shrews. The immunological characteristics presented the predominant infiltration of microglia/macrophages, dendritic cells, and CD4-T-cells into the uvea and retina and pathogenic T helper (Th) 1 and Th17 responses. The subretinal deposits positively expressed amyloid β-protein (Aβ), CD8, and P2Y purinoceptor 12 (P2RY12). The crucial DEGs in R14-induced EAU, such as P2RY2 and adenylate cyclase 4 (ADCY4), were enriched for several pathways, including inflammatory mediator regulation of transient receptor potential (TRP) channels. The upregulated RGS4 in IRBP-induced EAU was associated with mitogen-activated protein kinase (MAPK) activity. RGS4 inhibition and dihydroartemisinin could significantly alleviate the retinal pathological injuries of IRBP1197-1211-induced EAU by decreasing the expression of CD4 T-cells. Conclusion: Our study provides a novel chronic EAU in tree shrews elicited by bovine R14 and tree shrew IRBP1197-1211 characterized by retinal degeneration, retinal damage with subretinal Aβ deposits and microglia/macrophage infiltration, and T-cell response, probably by altering important pathways and genes related to bacterial invasion, inflammatory pain, microglial phagocytosis, and lipid and glucose metabolism. The findings advance the knowledge of the pathogenesis and therapeutics of the fovea-involved visual disturbance in human uveitis. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is a human herpesvirus that latently infects approximately 95% of adults and is associated with a spectrum of human diseases including Infectious Mononucleosis and a variety of malignancies. However, understanding the pathogenesis, vaccines and antiviral drugs for EBV-associated disease has been hampered by the lack of suitable animal models. Tree shrew is a novel laboratory animal with a close phylogenetic relationship to primates, which is a critical advantage for many animal models for human disease, especially viral infections. Herein, we first identified the key residues in the CR2 receptor that bind the gp350 protein and facilitate viral entry. We found that tree shrew shares 100% sequence identity with humans in these residues, which is much higher than rabbits (50%) and rats (25%). In vitro analysis showed that B lymphocytes of tree shrews are susceptible to EBV infection and replication, as well as EBV-enhanced cell proliferation. Moreover, results of in vivo experiments show that EBV infection in tree shrews resembles EBV infection in humans. The infected animals exhibited transient fever and loss of weight accompanied by neutropenia and high viremia levels during the acute phase of the viral infection. Thereafter, tree shrews acted as asymptomatic carriers of the virus in most cases that EBV-related protein could be detected in blood and tissues. However, a resurgence of EBV infection occurred at 49 dpi. Nanopore transcriptomic sequencing of peripheral blood in EBV-infected animals revealed the dynamic changes in biological processes occurring during EBV primary infection. Importantly, we find that neutrophil function was impaired in tree shrew model as well as human Infectious Mononucleosis datasets (GSE85599 and GSE45918). In addition, retrospective case reviews suggested that neutropenia may play an important role in EBV escaping host innate immune response, leading to long-term latent infection. Our findings demonstrated that tree shrew is a suitable animal model to evaluate the mechanisms of EBV infection, and for developing vaccines and therapeutic drugs against EBV.

Dengue virus is a significant public health threat worldwide; however, the pathogenesis of dengue disease remains poorly understood due to lack of appropriate small animal models. Tree shrews are an emerging experimental animal model for the study of human diseases due to their resemblance of genetic characteristics to primate animals. Herein we report that dengue infection in tree shrews elicits resemble clinical symptoms as in humans. Dengue fever (△2°C> normal body temperature) developed in ~22% healthy Chinese tree shrews from 2 through 33 days after infection with a low dose (1 ∗ 104 PFU/animal) of dengue virus serotype 2 or 3 intravenously or subcutaneously. The dengue genomic RNA and neutralizing antibodies were detected in ~78% of animals at days 7 and 15 post infection respectively. The serum levels of liver enzymes including aspartate transaminase, alanine aminotransferase and alkaline phosphatase were elevated with peaks at day 7 after infection. Modest thrombocytopenia and a slight decrease in the white blood cell count were observed. Intriguingly, although viral RNA was barely detectable in the liver by 48 days after infection, it was still evident in the brain. The intra-brain bleeding lesions in the intravenous infection group were more severe than those in the subcutaneous infection group. Our data demonstrate that primary dengue virus infection in tree shrews causes resemble clinical disease as in humans and thus tree shrews may be a suitable model for the study of dengue disease pathogenesis.

Dengue virus is a significant public health threat worldwide; however, the pathogenesis of dengue disease remains poorly understood due to lack of appropriate small animal models. Tree shrews are an emerging experimental animal model for the study of human diseases due to their resemblance of genetic characteristics to primate animals. Herein we report that dengue infection in tree shrews elicits resemble clinical symptoms as in humans. Dengue fever (△2°C> normal body temperature) developed in ~22% healthy Chinese tree shrews from 2 through 33 days after infection with a low dose (1 ∗ 104 PFU/animal) of dengue virus serotype 2 or 3 intravenously or subcutaneously. The dengue genomic RNA and neutralizing antibodies were detected in ~78% of animals at days 7 and 15 post infection respectively. The serum levels of liver enzymes including aspartate transaminase, alanine aminotransferase and alkaline phosphatase were elevated with peaks at day 7 after infection. Modest thrombocytopenia and a slight decrease in the white blood cell count were observed. Intriguingly, although viral RNA was barely detectable in the liver by 48 days after infection, it was still evident in the brain. The intra-brain bleeding lesions in the intravenous infection group were more severe than those in the subcutaneous infection group. Our data demonstrate that primary dengue virus infection in tree shrews causes resemble clinical disease as in humans and thus tree shrews may be a suitable model for the study of dengue disease pathogenesis. [ABSTRACT FROM AUTHOR]