Table 1. Summary of recent tree shrew models for human diseases.

Disease / intervention	Modeling methods	Phenotypes and symptoms	Potential mechanism, drug efficacy, and limitations	References
We only compiled publications from January 2017 to May 2024, and summarized the main symptoms of each tree shrew model. Please refer to the original publication for additional details.
Naturally aging	Adult (mean age 3.8 years), old (mean age 6 years), and aged (mean age 7.5 years) tree shrews	Aged tree shrews showed increased activated microglia labeled with ferritin and dystrophic microglia labeled with Iba1, increased oxidative RNA damage, as revealed by 8-hydroxyguanine (8-OHG) staining in all hippocampal regions, enhanced Tau hyperphosphorylation in dentate gyrus (DG), CA3, and subiculum (SUB) subregions, and phagocytic inclusions of cellular debris or neurons containing tau aggregates and/or damaged RNA in activated M2 microglia. Adult and old tree shrews harbored increased hypertrophic astrocytes in hippocampal region, while aged animals contained significant atrophic astrocytes compared to younger animals.	Mechanism: Aged tree shrews showed increased oxidative stress, phosphorylated tau, and dystrophic microglia in hippocampus; S100A10, a protein overexpressed by neuroprotective-type astrocytes, occurred in the nucleus of hypertrophic astrocytes of young animals, but in the cytoplasmic compartment of atrophic astrocytes in aged animals. Aged tree shrews could be used to study brain and microglial alterations during aging process. Limitations: Only histochemical and immunofluorescence assays were performed, with no characterization of molecular mechanisms and potential targets.	Rodriguez-Callejas et al., 2020; 2024
	Adult (about 1 year old) and aged (6 years old or older) tree shrews	Aged tree shrews showed impaired cognitive performance, as revealed by pole-board and novel object recognition tests, increased Aβ accumulation and phosphorylated Tau protein, synaptic degeneration, neuronal loss, and gliosis in cortical and hippocampal tissues.	Mechanism: Aged tree shrews showed increased levels of Aβ40, Aβ42, total-Aβ, and phosphorylation of Tau at Ser202/Thr205 and Thr231, decreased levels of PSD95 and NeuN, and increased levels of GFAP and Iba1 in cortical and hippocampal tissues. Limitations: No characterization of natural aging pattern was performed at omics and single-cell levels.	Li et al., 2024
Alzheimer’s disease (AD)	Adult male tree shrews (15 months old) received an intracerebroventricular (icv) injection of Aβ1-40	Aβ1-40-treated tree shrews showed cognitive impairments, hippocampal atrophy, increased apparent diffusion coefficient (ADC) and fractional anisotropy (FA) based on diffusion tensor magnetic resonance imaging (DTI) analysis, thinner and smaller cells in hippocampal CA3 and DG subregions and reduced number of cells in DG, neurotic plaques and neurofibrillary tangles (NFTs) in hippocampus, and cell apoptosis.	Mechanism: Expression levels of apoptosis related genes, including Bad, IAP, and Cytochrome c, were down-regulated, expression level of TNF-R1 was up-regulated, differentially expressed genes were enriched in AD pathways and other biological processes. Limitations: Sample size was too small for robust conclusions and interpretation of molecular mechanism may be biased based on transcriptome analysis alone.	Lin et al., 2016
AD and donepezil	Adult male tree shrews (1–1.5 years old) received icv injection of Aβ1-40, followed by daily treatment with donepezil (1 mg/kg)	Aβ1-40-treated tree shrews showed spatial cognitive deficits, body weight loss, hippocampal atrophy with lateral ventricle enlargement, enlarged temporal horn and increased ADC in DTI analysis, Aβ deposits, neuronal loss, and glial activation. Donepezil ameliorated all symptoms.	Mechanism: Expression of choline acetyl transferase (ChAT) and BDNF and phosphorylation of TrkB were decreased, acetylcholinesterase (AChE) activity and fibrillary acid protein (GFAP) expression were increased, Aβ1-40 injection affected cholinergic system and BDNF/TrkB-signaling pathway. Drug efficacy: Donepezil rescued gene expression abnormalities caused by Aβ1-40, and showed a protective effect. Limitations: Detailed description of data analyses lacking, and independent validation still required.	Zheng et al., 2018
AD and Ginsenoside Rg1 (GRg1)	Adult male tree shrews (6 months old) received an Aβ25–35 injection in both hippocampal regions, with daily dose of D-galactose (D-gal) at 125 mg/kg; treatment groups included intragastric (ig) administration of donepezil daily (3 mg/kg) and GRg1	Aβ25–35-injected group showed impaired learning and memory in Morris water maze test, increased Tau expression in hippocampal and cortical tissues, altered bacterial communities, increased oxidative stress damage, microglial activation, inflammation, and apoptosis in hippocampal and cortical tissues. Donepezil and high concentrations of GRg1 ameliorated impaired learning and memory ability and related abnormalities in tree shrews treated with Aβ25–35 and D-gal. High concentrations of GRg1 reduced Tau-positive cells and changed abundances of Proteobacteria, Verrucomicrobia, and Lactobacillus in gut microbiota	Mechanism: Tree shrews treated with Aβ25–35 and D-gal showed increased tau expression and altered gut microbiota composition and abundance, increased Aβ1-42, BACE1, and phosphorylated Tau levels, enhanced oxidative stress injury, as revealed by increased nitrotyrosine and 8-OHG levels and decreased expression of SOD1, increased expression of Iba1 and IL-1, and decreased levels of MAP2, NeuN, β-catenin, and phosphorylated GSK-3β. Drug efficacy: Donepezil and high concentrations of GRg1 decreased Tau expression, reversed altered levels of related proteins, exerted a neuroprotective effect, and altered gut microbiota. Limitations: No detailed targets or mechanisms were tested.	Wang et al., 2020c; Yang et al., 2022
Parkinson’s disease (PD) induced by MPP+	Male tree shrews (1.5 years old) received a unilateral nigral injection of 50 μg MPP+	MPP+-treated tree shrews manifested PD clinical symptoms, including motor deficits (difficulties in forelimb use, loss of balance, stooped posture), bradykinesia, rest tremor, gait abnormalities, postural instability, and apomorphine-induced rotations; increased PD score based on improved Kurlan scale; marked dopaminergic neuron loss (up to 95%) in substantia nigra on lesioned side of the brain	Mechanism: Precise injection of MPP+ into substantia nigral region depleted local dopaminergic neurons and resulted in PD-like symptoms in tree shrews. Limitations: No test for Lewy body-like pathology and related changes in circuit; no test for treatments such as stem cell transplantation and related drugs.	Li et al., 2023d
Cerebral ischemia (CI)	Adult male tree shrews (6-months old) received permanent distal middle cerebral artery occlusion after anesthesia	Tree shrews in CI group exhibited a decline in aggressive behavior, seeking behavior, and voluntary activity, and showed no response to stimuli and increased neural behavior scores (higher scores represent more severe damage). Magnetic resonance imaging showed high signals at infarct area. 2,3,5-triphenyltetrazolium chloride (TTC) staining revealed a marked white infarction. Defective cortical structure and deep-stained nuclei were observed in cortex of CI group. Most neurons shrank in size, with a reduced number of NeuN- and GFAP-positive cells around lesion epicenter in the CI group relative to the sham group.	Mechanism: Cerebral ischemia in tree shrews was demonstrated by alterations in neural behavior score and pathological analyses for neural cell morphology and infarct area. Limitations: Drug efficacy was not tested and no molecular target was identified.	Wang et al., 2019c
Depression and clomipramine	Adult male tree shrews were subjected to chronic psychosocial stress induced by social defeat between dominant and subordinate animals	Socially defeated tree shrews exhibited a decrease in sucrose preference, exploration behaviors, locomotion distance, and social interaction. Oral clomipramine administration reversed almost all depression-like behaviors, but not motivational reduction.	Mechanism: Chronic social defeat induced a broad spectrum of behavioral changes, including anhedonia, motivation reduction, and social avoidance, with no report of potential mechanism. Drug efficacy: Clomipramine had a therapeutic effect on socially defeated animals, but no effect on rescuing motivational reduction. Limitations: No detailed target for clomipramine was analyzed and no molecular mechanism regarding why clomipramine had no effect on reversing reduced motivation in socially defeated tree shrews was provided.	Shen et al., 2018
Cocaine motivation	Adult male tree shrews were subjected to cocaine self-administration (SA)	Tree shrews were trained to acquire cocaine SA. Cocaine craving (as measured by number of active nose-pokes) gradually increased, then declined along cocaine withdrawal timeline; incubation of cue-induced cocaine craving occurred on withdrawal day (WD) 45. Knockdown of Cav1.2 inhibited cocaine craving on WD45.	Mechanism: Striatal dopamine D1 receptor (D1R), but not D2R, mediated up-regulation of Cav1.2, showing a time-dependent increase in nucleus accumbens (NAc) during incubation of cocaine craving. Drug efficacy: Injection of L-type calcium channels antagonist verapamil in NAc decreased cocaine-seeking behaviors. Limitations: D1R-Cav1.2 signaling underlying incubation of cocaine craving needs validation, especially in the context of cocaine relapse.	Duan et al., 2021
Cocaine-seeking habit	Adult male tree shrews were subjected to cocaine and sucrose SA, compared to sucrose-habitual behavior and cocaine-seeking habitual behavior	Habitual cocaine-seeking behaviors (HCSB) and habitual sucrose-seeking behaviors (HSSB) were established in tree shrews.	Mechanism: Animals with HCSB exhibited higher D1Rs and Cav1.2 expression but lower D2Rs and Cav1.3 expression in the putamen, while animals with HSSB exhibited lower membrane expression of D2R in the putamen than animals with non-habitual behavior. Limitations: Imbalanced function between putamen and nucleus caudate and the neural circuits need to be further determined.	Duan et al., 2022
Glaucoma / ocular hypertension	Adult tree shrews (1.7-7.7 years old) were injected with ferromagnetic beads (50 μL of a 25 mg/mL solution) into anterior chamber, which were then directed into iridocorneal angle by a magnet to block aqueous outflow	Tree shrews injected with ferromagnetic beads (treated group) showed significantly increased intraocular pressure (IOP) relative to control group during 12-week follow-up period, average of 22.7±3.6 mm Hg. Significant retinal nerve fiber layer (RNFL) was thinner and optic nerve axon counts and density were reduced in treated group, along with progressive bowing of lamina cribrosa and posterior displacement of anterior laminar surface in tree shrews with increasing severity of experimental glaucoma	Mechanism: Reductions in RNFL thickness and optic nerve axon counts and density were associated with IOP elevation. Optic nerves in the treated group showed histopathology consistent with glaucomatous optic neuropathy Limitations: No drug efficacy was tested	Samuels et al., 2018
Hyperopia	Starting at 24±1 days of visual experience, juvenile tree shrews (6 weeks old) received light treatment through amber filters (BPI 500/550 dyed acrylic) either atop cage (Filter group, 300–400 lux) or through amber-dyed lenses fitted into a goggle frame (Goggle group). Age-matched animals raised in standard lighting (100–300 lux) were used as the control group	Animals in Filter group became progressively more hyperopic, whereas animals in the Goggle and control groups showed continued normal emmetropization during 11-day treatment period. Significant hyperopia (mean [SE] = 3.5 [0.6] D) was observed in Filter group compared to Goggle (0.2 [0.8] D) and control groups (1.0 [0.2] D). Filter group had significantly thicker choroid at the end of 11-day treatment. Vitreous chamber depth in Filter group decreased with increasing hyperopia, whereas that in the Goggle and control groups was similar. End-of-treatment vitreous chamber depth was significantly smaller than that in the other two groups.	Mechanism: Exposure to ambient amber light caused substantial hyperopia in tree shrews but had no effect on refractive error in Goggle group. Limitations: No drug efficacy or prophylactics was tested.	Khanal et al., 2021
Choroidal neovascularization (CNV)	Adult tree shrews (2 years old) were subjected to CNV by laser photocoagulation	Retinal edema and damaged Haller’s layer in choroid occurred 7 days after photocoagulation; after day 14, neovascularization in retina destroyed ganglion cell layer, disrupted nerve fiber layer, loosened Haller’s and Sattler’s layers, with neovascularization surrounded by neutrophils, macrophages, and fibroblasts; microvessel density increased.	Mechanism: Choroid and retinal transcriptomic data were used to identify differentially expressed genes during CNV; signaling pathways, including fatty acid metabolic pathway and cell adhesion molecular signaling, and genes in ribosomal protein family and complement system were involved in tree shrew CNV. Limitations: No drug efficacy was tested and no molecular target was verified.	Jia et al., 2021
Chronic experimental autoimmune uveitis (EAU)	Adult tree shrews (4–8 months old) were subcutaneously immunized at tail base and both thighs with six inter-photoreceptor retinoid-binding proteins (IRBPs) of tree shrews (R14, IRBP1197-1211, R16 and IRBP1041-1071) and bovines (R14 and R16)	IRBP1197–1211 and R14 induced ocular inflammation and chronic EAU (including conjunctival hyperemia, ciliary injections, whitish hypopyon spots, and corneal ulcers and edema), with subretinal deposits and retinal damage. Inflammatory infiltration of innate immune cells and adaptive immune cells into conjunctiva, cornea, anterior chamber, ciliary processes, choroid, and retina, and retinal lesions were main histopathological changes. Subretinal deposits positively expressed Aβ, CD8, and P2RY12. RGS4 inhibitor CCG203769 and dihydroartemisinin significantly alleviated retinal pathological damage of IRBP1197-1211-induced EAU by decreasing expression of CD4 T-cells.	Mechanism: Chronic EAU in tree shrews was elicited by bovine R14 and tree shrew IRBP1197-1211, characterized by retinal degeneration, retinal damage with subretinal Aβ deposits and microglial/macrophage infiltration, and T-cell response, likely by altering multiple signaling pathways including mitogen-activated protein kinase (MAPK) signaling. Limitations: No molecular target was experimentally verified.	Hu et al., 2022
Diabetic retinopathy	Male adult tree shrews received a single intraperitoneal injection of streptozotocin (STZ; 175 mg/kg)	In total, 75% of animals developed type 1 diabetes with sustained hyperglycemia; islet β cells were almost lost in the pancreas of diabetic animals; serum levels of glycated hemoglobin, free fatty acids, total cholesterol, high- and low-density lipoproteins, and triglycerides were increased; cone photoreceptor function was compromised as shown by diminished A- and B-wave photopic electroretinogram amplitudes; retinal function was lost; retinal ganglion cell (RGC) function was compromised, with loss of RGCs and peripheral short-wave sensitivity (SWS) cones.	Mechanism: SWS cones and RGCs were lost after STZ injection, with increased expression of TRIB3, VEGF, and p-AKT/p-mTOR axis, but reduced levels of ISR-1 protein in diabetic retinas. Limitations: No drug efficacy was tested.	Gorbatyuk et al., 2022
Diabetic cerebral ischemia	Adult male tree shrews fed a high-fat diet for 8 weeks received an intravenous injection of 2% STZ (100 mg/kg body weight), with photochemically induced cortical thrombotic cerebral ischemia	STZ application resulted in a relatively high ratio (up to 77%) of successful diabetes modeling. Diabetic animals showed polydipsia, polyphagia, polyuria, thinned retina layers with disordered structures, with pathological retinal changes aggravated after cerebral ischemia. Ischemic postconditioning reduced pathological changes in diabetic retinopathy and alleviated retinopathy.	Mechanism: Diabetes and cerebral ischemia increased retinal VEGF expression, which was reduced by ischemic postconditioning. Limitations: No drug efficacy was tested for diabetic retinopathy; molecular mechanisms of the ameliorating effects of ischemic postconditioning were not determined.	Zhao et al., 2020a
Ischemia stroke and diabetes mellitus	Adult male tree shrews were treated with STZ (Zhao et al., 2020a), and thrombotic cerebral ischemic stroke was induced using photochemical treatment	Tree shrews with diabetes mellitus (DM) and DM ischemic stroke (DMIS) showed increased water intake, urine volume, serum glucose levels, altered biochemical indicators, and abnormal ultrastructure of cellular organelles; DMIS group exhibited a larger infarct size. Transcriptomic analysis of infarct tissues identified differentially expressed genes and enriched pathways.	Mechanism: DM tree shrews showed increased IL-8 expression and activation of inflammatory status relative to healthy controls; DMIS group showed increased expression of CCL7, ATP-binding cassette sub-family A member 12, and adhesion G protein-coupled receptor E2 relative to DM group. Limitations: No drug efficacy was tested and no molecular target was verified.	Zhao et al., 2021b
		Ischemic postconditioning reduced infarct size and reduced nerve cell injury in tree shrews with DMIS. Transcriptomic analysis of ischemic cerebral tissues identified differentially expressed genes and enriched pathways.	Mechanism: Ischemic postconditioning reduced inflammation and stress responses by decreasing activity of TNF and NF-κB signaling, and Fc gamma R-mediated phagocytosis. Limitations: No drug efficacy was tested and no molecular target was experimentally verified.	Zhao et al., 2021c
Diabetes and regeneration of islet β-cells	Male tree shrews (8 weeks old) were intraperitoneally injected with STZ (150 mg/kg)	Increased fasting blood glucose and mean serum insulin levels after STZ treatment for 3 days; islets were smaller and deformed, with visible cell necrosis and degeneration, and number of islets was reduced; intra-islet cell regeneration was only scattered at day 7 after STZ treatment, with no regeneration of centroacinar cells	Mechanism: Proportion and expression of insulin-positive cells in islets were decreased after STZ treatment; positive PDX-1 expression was observed in pancreatic interstitial cells and dendritic cells of pancreatic lymph; repair mechanism of STZ-injured islet β-cells in tree shrews was similar to that of humans. Limitations: No drug efficacy or stem cell transplantation therapy was tested.	Zhao et al., 2018
Diabetes mellitus and mesenchymal stem cell (MSC) transplantation	Male tree shrews were intraperitoneally injected (lower right quadrant of abdomen) with STZ (170 mg/kg), with intraportal transplantation of insulin-producing cells (IPCs) derived from human MSCs	Tree shrews showed increased blood glucose levels, loss of body weight, and no intact islets in the pancreas after STZ treatment; after IPC transplantation (which expressed islet-related genes and secreted high levels of insulin) one week after STZ treatment, blood glucose levels decreased to normal levels in diabetic animals and body weight recovered; liver tissues of diabetic animals with IPC transplantation showed extensive and diffuse edema and scattered insulin-positive cells in hepatic sinusoids.	Mechanism: Transplantation of IPCs expressing insulin, NGN3, and PDX1, derived from MSCs, reversed hyperglycemia and weight loss in diabetic tree shrews induced by STZ. Limitations: Recovery of pancreatic islets in STZ-induced diabetes model was not examined, with a different mechanism compared to human diabetes; no follow-up study was conducted to monitor the fate and potential risk of malignancy of transplanted cells.	Zhu et al., 2023
Chronic stomach mucosal injury	Adult tree shrews (2-3 years old) were administered a daily intraperitoneal injection of MPTP (2 mg/kg/day) for 13 weeks	Tree shrews showed local congestion or diffuse hemorrhagic spots on the gastric mucosa, multiple regions of redness and bleeding on inner wall covered with white moss, or partial slight shedding of gastric mucosa; H&E staining of gastric mucosa showed immune cell infiltrations.	Mechanism: Integration of transcriptomic and proteomic data revealed changes in mRNA and proteins in gastric mucosa, and identified several genes (e.g., RPL4, ANXA1, GAST, and DDC) involved in MPTP-induced mucosal injury. Limitations: No experimental assays to characterize the highlighted genes in MPTP-induced mucosal injury and affected signaling pathways were conducted.	Wang et al., 2024a
Asthenoteratozoospermia	Adult male tree shrews (6 months old or older) were injected with TR-AAV9-Ssx1-shRNA (each 80 μL, dose of 1.5×1012 vector genome/mL) into seminiferous tubules of bilateral testes via rete testis for 60 days	Levels of Ssx1 mRNA and protein were significantly reduced in the testes of tree shrews with TR-AAV9-Ssx1-shRNA injection. Tree shrews with Ssx1 knockdown displayed reduced testis weight, impaired spermatogenesis or loss of germ cells in seminiferous tubules, abnormal sperm morphologies (absent, coiled, or angulated flagella; absence of peripheral or central microtubules at midpiece and principal piece of sperm flagella), and reduced sperm motility.	Mechanism: Expression of multiple spermatogenesis-associated factors was dysregulated in testes of tree shrews with Ssx1 deficiency, and these factors were enriched in multiple biological processes involved in spermatogenesis Limitations: No detailed mechanism regarding SSX1 deficiency in spermatogenesis was determined and no drug efficacy was tested.	Liu et al., 2023
Breast cancer	Female tree shrews (6 months to 1 year old) were administered an intraductal injection of PI3KCA-H1047R or H-RAS-Q61L lentiviruses at different titers (3×107 TU/mL and 1.4×106 TU/mL, respectively) into 3rd pair of mammary glands	Incidence of breast tumor in tree shrews injected with PI3KCA-H1047R lentivirus was 41.7%–58.3% within 3–10 weeks after infection, but no breast tumors were detected in animals injected with H-RAS-Q61L lentivirus within 10 weeks. Dominant pathological type was intraductal papilloma and atypical hyperplasia, with only one case of invasive ductal carcinoma. Tumor sections were positive for progesterone receptor (PR) but negative for human epidermal growth factor receptor-2 (HER-2) staining and had weak or no staining for estrogen receptor-α (ERα). PI3K inhibitor alpelisib inhibited growth of transplanted tumors in NOD-SCID mice.	Mechanism: Common PI3KCA-H1047R mutation caused a high incidence of breast tumor in tree shrews, which were hormone receptor-positive and HER2 negative. PI3K pathway was involved in development of breast tumors. Limitations: Precise reason why PI3KCA-H1047R and H-RAS-Q61L lentiviruses behaved differently in mammary tumor induction in tree shrews and FVB mice was not determined, with this species-specific pattern having important implications regarding development of breast cancer in humans.	Zeng et al., 2023
	Female tree shrews (10–12-months old) were injected with DMBA (10 mg/kg) in one side of lumbar mammary fatty pad four times (once per week for 2 weeks and suspended for one week), with or without intramuscularly injection of MPA (100 mg/kg) once per 2 weeks five times from 1st DMBA injection	Around 10% of tree shrews with DMBA treatment and 50% of tree shrews with DMPA and MPA developed breast lesions. All induced breast lesions were intraductal papilloma and atypical ductal hyperplasia, with almost equal incidence. Breast lesions were highly vascular and had regular morphology, clear margins, and heterogeneous enhancement. Breast lesions were positive for ERα, PR, and cytokeratin 5/6 (CK5/6) staining, but negative for HER-2 staining.	Mechanism: Combination of DMBA and MPA effectively established breast precancerous lesions including intraductal papilloma and atypical ductal hyperplasia in tree shrews. Tissues of atypical ductal hyperplasia showed a higher expression of B cell lymphoma-extra-large (Bcl-xl) and lower expression of B cell lymphoma 2 associated X protein (Bax) than those with intraductal papilloma. Limitations: No detailed mechanism was studied for induced breast lesions and no drug effects were tested.	Chen et al., 2019
Spontaneous mammary gland tumor	Female tree shrews of different ages	Spontaneous mammary tumors usually occurred in virgin tree shrews at 2–3 years old, with an incidence rate of 24.6% (15/61). Simultaneous or metachronous multiplex tumor rate was 60%. Familial mammary gland tumor incidence was observed for some pedigrees. Intraductal papillary adenomas were predominant and tubulopapillary carcinomas were also found but at a lower frequency. All tumors were PR-positive, nearly all were negative for HER-2 staining (4.3%), and 91.3% were positive for ERα staining.	Mechanism: No PTEN and PIK3CA mutations were observed in mammary tumors after sequencing. Most simultaneous or metachronous multiplex tumors exhibited possible origins from multiple sites. More than 25% of mammary tumor cells expressed Nectin-4. Limitations: Genetic aspects of familial inheritance of mammary tumors were not determined and no drug effects were tested.	Chi et al., 2020
Glioblastoma	Adult tree shrews (1–2 years old) were intracranially injected with pTomo-H-RasV12-shp53 lentivirus (3×1011/ml titer, expressing HRasV12 and shRNA targeting tree shrew Tp53) into hippocampus	Tree shrews showed slight neurological symptoms, including ataxia, imbalance, and emaciation after lentivirus delivery for 4 weeks. Induced gliomas exhibited aggressive behavior and relatively short latency, with reduced animal survival. Gliomas showed increased cell density, necrosis and pseudopalisades, vascular hyperplasia, and active cellular proliferation, and resembled human high-grade gliomas.	Mechanism: Transcriptomic profiling of tree shrew gliomas indicated that tumors belonged to mesenchymal subgroup of human glioblastoma multiforme. Limitations: No drug effects were tested.	Tong et al., 2017
Pancreatic cancer	Adult male tree shrews (2–3 years old) were injected with lentiviral vectors containing mutant oncogene KRASG12D and shRNAs targeting Tp53, Cdkn2a, Cdkn2b, and Cdkn2a/b in head of pancreas	Pancreatic tumors with full penetrance were observed at 3–7 weeks after lentivirus injection. Tumors were moderately differentiated ductal adenocarcinomas and expressed several well-established markers of human pancreatic cancer, including CK19, Muc5, MMP7, and Hes1. Tree shrews showed gross morphological changes associated with pancreatic cancer, including intestinal darkening, colorectal inflation, gall bladder dilatation, and blockage of bile overflow. Induced pancreatic cancer originated from malignant transformation of acinar cells.	Mechanism: Induced pancreatic cancer resembled human pancreatic ductal adenocarcinoma based on transcriptomic profiling; expression of oncogenic Kras along with loss of Tp53, Cdkn2a, and Cdkn2b expression were essential for transformation of acinar cells and induction of tree shrew pancreatic cancer. Rb1 signaling pathway was actively involved in this process. Limitations: No drug effects were tested.	Tu et al., 2019
Basal cell carcinoma (BCC)	Adult male tree shrews were intracutaneously injected with pCDH-mSmoA1 lentivirus (5.6×105 TU) and shRNA targeting tree shrew Tp53 lentivirus (shp53, 2×105 TU) in dorsum and tail skin	Tree shrews with pCDH-SmoA1 lentivirus injection exhibited human BCC-like pathological characteristics, including hyperplasia of skin cells with hair follicle disruption, pigmentation, and nuclear explosion expansion. Around 40% of tree shrews presented with BCC-like phenotypes after 4 weeks following delivery of pCDH-SmoA1 lentivirus, which reached 60% after 6–8 weeks. Injection of pCDH-mSmoA1 and shp53 lentiviruses resulted in BCC-like phenotypes in 70% of tree shrews at 2 weeks, which reached 100% after 4 weeks.	Mechanism: Activation of Hh signaling pathway by SmoA1 overexpression induced tree shrew BCC, which was further accelerated by knockdown of tumor suppressor p53. Limitations: No characterization of related molecular markers of BCC was conducted and no drug effects were tested.	Jiang et al., 2017
Acute respiratory distress syndrome (ARDS)	Lipopolysaccharide (LPS, 180–200 mg/kg) was administered to tree shrews via intratracheal instillation	LPS-treated tree shrews demonstrated symptoms of respiratory failure between days 3 and 5, and exhibited behavioral abnormalities (less activity, piloerection, and tachypnea) from day 3. LPS-treated animals showed a PaO2 to FiO2 (P/F) ratio of 160–200 mmHg, suggesting moderate ARDS. LPS treatment caused bilateral patchy infiltrates, typical diffuse alveolar damage, pulmonary inflammation, and lung tissue injury (e.g., thickened alveolar septum, hemorrhage, edema, proteinaceous debris, massive neutrophils accumulation, and infiltration).	Mechanism: One-hit intratracheal instillation of LPS led to symptoms resembling acute phase of human ARDS. Limitations: No detailed mechanism of this LPS-induced model was determined and no drug effects were tested.	He et al., 2024
Chronic pulmonary inflammation (CPI)	Adult male tree shrews (4–6 months old) were subcutaneously injected with 0.25 mL of solution (2 mg/mL of bovine type II collagen, 0.1 mol/L acetic acid, emulsified in complete Freund’s adjuvant) to induce arthritis	Joint inflammation severity worsened over two weeks and peaked at day 21, followed by remission and slow recovery. Swollen soft tissue, narrowed joint spaces, marginal erosions, denser and abnormal lymphoid infiltrates, and cartilage damage were observed in bone joints, including forelimb joint. Diffused lymphoid infiltrates in lung tissue were detected at day 21. Typical CPI but no fibrosis developed pathologically in the collagen-induced arthritis associated CPI model.	Mechanism: Abnormal up-regulation of pulmonary chemokine CXCL10 was associated with lung damage, and CXCL10-CXCR3 chemotaxis mediated joint inflammation in this model. Treatment with CXCR3 antagonist NBI74330 down-regulated inflammatory infiltrates and expression of inflammatory factors and chemokines. Limitations: No experimental assays were conducted to reveal the initiation and role of CXCL10-CXCR3 chemotaxis.	Gao et al., 2018
Idiopathic pulmonary fibrosis	Tree shrews (3–5 months old) were administered bleomycin (1.75 U/kg body weight) via intratracheal catheter	After bleomycin exposure for 21 days, fibrotic responses were observed in a significant portion of the lungs, with increased levels of fibrotic collagen area and hydroxyproline relative to control animals. Bleomycin exposure induced myofibroblast differentiation, increased extracellular matrix proteins, and activated FAK signaling in lung tissues, indicating increased pro-fibrotic responses and fibrotic remodeling. During fibrosis, monocyte-derived macrophages were significantly recruited and polarized to a profibrotic phenotype. Macrophage-derived profibrotic mediators from bleomycin-exposed tree shrews promoted fibroblast activation.	Mechanism: FAK signaling was actively mediated pro-fibrotic responses in lungs of bleomycin-exposed tree shrews. Monocyte-derived macrophage-fibroblast crosstalk induced fibrosis. Limitations: No drug effects were tested.	Che et al., 2021; Larson-Casey et al., 2020
Systemic sclerosis	Adult tree shrews (10–12 months old) were subcutaneously injected with different doses of bleomycin (0.4, 2, and 4 ng/mL; 100 µL of solution) for 21 days	Long-term injection of bleomycin caused ulcers in the skin injection site of tree shrews and induced inflammation and/or fibrosis in skin and internal organs. Medium to high doses of bleomycin caused markedly thickened dermis, infiltration of inflammatory cells, increased collagen fibers and collagen volume fraction in skin, pulmonary septal thickening, and fibrosis and inflammatory cells infiltration in the lung. Increased expression of α-SMA in skin and presence of serum autoantibodies (antinuclear antibodies and anti-scleroderma-70) were observed in bleomycin-treated animals.	Mechanism: Bleomycin-treated tree shrews showed similar pathological and serological changes to human systemic sclerosis. Ten hub genes (KIF20A, KIF11, UBE2C, BUB1B, CDK1, CCNB2, AURKB, TOP2A, PLK1, and NCAPG) were identified based on transcriptomic profiling; immune cell infiltrations in the skin may play a key role. Limitations: No drug effects were tested.	Zheng et al., 2024
Periodontitis	Adult male tree shrews (2–6 months old) were modeled using a 2-0 ligature through the mandibular space between the first and second molars, with tightening on the subgingival surface of first molar crown	Tree shrews showed ligature-induced inflammatory reactions, e.g., swelling, redness, and tissue softening in the gingiva at week 2. Redness and swelling of the gums continued in weeks 3 and 4, and spontaneous bleeding of the gingiva was observed at week 4, followed by gradual reduction of swelling and redness and disappearance of hemorrhaging at weeks 5–8. Severe bone destruction and significantly increased molar root exposure were observed after induction of periodontitis, along with substantial inflammatory infiltrates, apical migration of junctional epithelium, and alveolar bone loss.	Mechanism: Inflammatory infiltrates and transition from acute to chronic inflammation were involved in development of gingival swelling, redness, spontaneous bleeding, and bone loss after induction of periodontitis Limitations: No drug effects were tested.	Ma et al., 2023
Osteonecrosis	Adult male tree shrews (6 months old) were intravenously injected with LPS (300 μg/kg), followed by three intraperitoneal injections of methylprednisolone (MPS; 130 mg/kg) over a 24 h interval, with subsequent delivery of MPS two times per week until 12 weeks	Treated tree shrews showed increased levels of bone alkaline phosphatase, bone GLA protein, N-terminal propeptide of type I collagen, and C-terminal propeptide of type I collagen relative to control animals, with subchondral trabecular bone deterioration of femoral heads, including cortical bone partial collapse, trabecular fracture, trabecular sparseness, thinning, and increased intercellular spacing. Increased cell apoptosis and fused adipose cells into vacuoles, and decreased bone quality were observed.	Mechanism: Administration of low-dose LPS combined with high-dose MPS resulted in femoral head necrosis in tree shrews. Limitations: No drug efficacy was tested and no detailed target or mechanism was studied.	Chen et al., 2020
Osteoporosis	Bilateral ovaries were removed in healthy female tree shrews (6 months old; ovariectomy (OVX) group) after anesthesia, with animals euthanized at 6 months after surgery	Animals in the OVX group showed a significantly low level of serum estradiol, high bone turnover and bone loss, increased body weight, and reduced uterus weight and uterus coefficient compared to the sham group. OVX group exhibited a decreased in number and connections of trabeculae in the third lumbar vertebra, decreased structural stiffness, and fewer osteoblasts but more osteoclasts relative to the sham group.	Mechanism: Osteoporosis was induced in tree shrews by ovariectomy. Transcriptomic analysis of first lumbar vertebra identified several differentially expressed genes associated with osteoporosis. Limitations: No drug efficacy was tested and no detailed target or mechanism was studied.	Wang et al., 2019b
SARS-CoV-2 infection	Adult (1-year old) and aged (5–6 years old) tree shrews were infected with 107 TCID50 SARS-CoV-2 strain 107 by oral, intranasal, and ocular routes	Lung infiltrates were visible from 3 days post-infection (dpi) in 85% of infected animals. Most lung lobes had high viral RNA copies, which peaked at 3 dpi and decreased to undetectable levels at 14 dpi. Sporadic or massive pulmonary punctate hemorrhage, thickened alveolar septa, and interstitial hemorrhage were observed. Viral antigens were present in a small number of pneumocytes in infected lung tissues. Elevated white blood cell, lymphocyte, monocyte, and granulocyte counts were detected, as well as increased aspartate aminotransferase after infection in the adult group and decreased monocytes in the old group.	Mechanism: Tree shrews were susceptible to SARS-CoV-2 infection, displaying viral shedding, lung lesions, and alterations in blood biochemical indices. Limitations: No vaccine or drug efficacy was tested, no data about host immune response were provided, and no intra- or inter-species transmission study was performed.	Xu et al., 2020a
	Young (6–12 months old), adult (2–4 years old), and old (5–7 years old) tree shrews were infected nasally with 106 PFU SARS-CoV-2	Some infected animals showed an increased body temperature. Low viral shedding and replication in tissues occurred in all three groups. Pathological changes included pulmonary abnormalities, widened pulmonary septum, interstitial hyperemia, airway obstruction, consolidation of lung margin, local hemorrhagic necrosis, and infiltration of inflammatory cells. Mild histopathological changes were observed in brain, heart, liver, and pancreas.	Mechanism: Tree shrews were less susceptible to SARS-CoV-2 infection but may be a potential intermediate host. Limitations: No data about host immune response were provided and no intra- or inter-species transmission study was performed.	Zhao et al., 2020b
Zika virus (ZIKV) infection	Tree shrews (5 months old) were infected with 105 or 106 PFU of ZIKV strain GZ01 via subcutaneous injection; neonatal tree shrews (1-day old) were inoculated via the intracerebral route with 105 PFU of ZIKV	Tree shrews showed ZIKV infection and replication in primary kidney, testis, and peripheral blood cells. ZIKV-infected tree shrews developed transient viremia and skin rash at 2 dpi (which disappeared at 3 dpi), with the abdomen and chest being the main sites of dermatological manifestations. Apparent cutaneous lesions characterized by massive hemorrhage and inflammatory cell infiltration were observed in the hypodermis, along with in situ viral replication. ZIKV caused systemic infection involving multiple organs, including the brain. Testes had the highest viral load. ZIKV infection had a protection against secondary homologous infection. ZIKV was neurovirulent and replicated in neonatal animals, leading to a 75% mortality rate within 21 dpi.	Mechanism: Genes with antiviral immunity and inflammatory response were up-regulated by ZIKV infection in tree shrews. Both innate and adaptive immune responses were induced by ZIKV infection. Limitations: Exact mechanism underlying dermatological manifestations was not examined and no vaccine or drug efficacy was tested.	Zhang et al., 2019b
	Sexually mature tree shrews were infected with 105 or 106 PFU ZIKV GZ01 strain via the vaginal route	No dermatological manifestations were observed in tree shrews after ZIKV vaginal infection. Viral RNA loads were detected in blood, saliva, urine, and vaginal douching, with ZIKV viremia in vaginal lavage peaking at 1 dpi and persisting until 10 dpi in several animals. ZIKV vaginal infection led to systemic multi-tissue and multi-organ infections.	Mechanism: Female tree shrews were infected with ZIKV via the vaginal route. Expression levels of key inflammatory genes, including IL6, IL8, TNFα, CCL5, and CXCL9, were increased in the spleen of ZIKV-infected tree shrews. Limitations: No vaccine or drug efficacy was tested.	Baloch et al., 2021
Dengue virus (DENV) infection	Adult tree shrews were infected with 1×104 PFU DENV-2 or DENV-3 through intravenous injection or multisite subcutaneous injection	DENV-3 productively proliferated in tree shrew bone marrow mesenchymal stem cells at 4 dpi. Half of the animals presented with viremia, and most presented with high neutralizing antibody titers at 7 and 15 dpi. Alterations in some hematological and biochemical parameters, including modest thrombocytopenia, slight decrease in white blood cell count, and increased levels of aspartate transaminase, alanine aminotransferase, and alkaline phosphatase were observed in tree shrews after DENV infection. Viral RNA was barely detectable in the liver at 48 dpi but was detectable in the brain. Intra-brain bleeding lesions were more severe in animals with an intravenous injection of DENV than those with subcutaneous infection.	Mechanism: Tree shrews displayed fever, viremia, abnormal aminotransferase levels, and death after DENV infection, resembling clinical manifestations in humans. Limitations: Potential mechanism regarding vascular leakage and central nervous system impairment after DENV infection was not determined and no drug efficacy was tested.	Jiang et al., 2021a
	Tree shrew fibroblast cells were infected with DENV-1, DENV-2, DENV-3, and DENV-4	DENV serotypes 1–4 replicated in tree shrew fibroblast cells, with a linear increase in viral load at 24–96 h post-infection in both cells and culture supernatants. DENV-2 had the highest viral growth among all serotypes. Different DENV serotypes showed variable viral replication kinetics and TLR and cytokine expression profiles in fibroblast cells.	Mechanism: TLR8 mRNA was induced during DENV infection. Knockdown of TLR8 led to an increase in DENV-1 viral load. Limitations: No drug efficacy was tested, no detailed mechanism was studied, and no in vivo infection of DENV was performed.	Kayesh et al., 2017c
Kaposi’s sarcoma-associated herpesvirus (KSHV)	Tree shrews (4–5 months old) were infected with 5×107 GFU rKSHV.219 via the intravenous route	Tree shrew kidney epithelial cells were the most susceptible cells to KSHV infection, with KSHV genomic DNA, mRNA, and KSHV-specific proteins detected in this cell type up to 32 dpi. KSHV DNA and mRNA were detected in peripheral blood mononuclear cells and various tissues of KSHV-infected tree shrews. Lymphocyte infiltration, lymphoid tissue focal aggregation, alveolar wall thickening, hepatocyte edema, and hepatic necrosis were observed in the spleen, lung, and liver of a certain proportion of KSHV-infected animals.	Mechanism: Tree shrews exhibited a robust innate immune response against KSHV infection. Limitations: No transcriptomic profiling was performed in tissues upon KSHV infection and no drug efficacy was tested.	Li et al., 2021a
Herpes simplex virus-1 (HSV-1)	Adult female tree shrews (6 months old) were infected with 106 PFU HSV-1 strain McKrae by dropping on each eye without ocular scarification (McKrae group) and HSV-1 17+ strain with ocular scarification (17+ group). Trigeminal ganglia (TG) were collected from 17+ group at 58 dpi	Herpes simplex keratitis was induced in McKrae group, and eyes recovered at 33 dpi. The 17+ group exhibited more pronounced scarring and opaqueness in cornea and inflammation in eye lids during acute infection stage between 5 and 15 dpi compared to McKrae group. Thickening cornea, inflammatory infiltration, weakened luminousness, rough cornea surface, and deciduous corneal epithelial cells were observed during weeks 1 and 3 post-infection, with corneas showing recovery by 33 dpi. Titer of active virus peaked at 5 and 10 dpi, then reduced to the lowest level at 13 dpi, with persistent infection or spontaneous reactivation. Viral protein was detected in the cornea epithelial layer and retina neuronal ganglion cells at 5–20 dpi. Cornea supernatants and ciliary ganglion homogenates from the McKrae group at 46 dpi induced a cytopathic effect at 3 days post co-cultivation in RS1 cells. HSV-1 efficiently infected tree shrew eyes and persisted during latency period.	Mechanism: Decreased transcript levels of ICP0, ICP4, and LAT were detected after the acute infection stage, but LAT increased at 46 dpi, indicating latency of HSV-1 in tree shrew eyes (ciliary ganglion). Comparison of transcriptomes of infected TGs from tree shrews, mice, and humans showed that HSV-1 transcription in acutely infected TGs differed dramatically between mice and tree shrews. HSV-1 transcripts were detected in mouse TGs during acute infection but had an abortive infectious cycle in tree shrew TGs. During latency, LAT was detected in mouse, tree shrew, and human TGs but ICP0 transcripts were only found in tree shrew and human TGs. Infected human and tree shrew TGs exhibited a more similar LAT region transcription peak. Limitations: No detailed molecular mechanism regarding HSV-1 latency in tree shrews was uncovered and no drug efficacy was tested.	Li et al., 2020; Wang et al., 2020b
Influenza A viruses (IAVs)	Healthy adult tree shrews were infected with 105 TCID50/mL swine influenza virus subtype H3N2 (SW2783 group) and avian influenza virus subtype H6N6 (ZZ346 group) through nasal drip, conjunctiva drip, and pharyngeal tonsil drip	Tree shrews presented with decreased appetite, reduced activity, and increased nasopharyngeal secretions at 1 dpi which lasted 8 days, with severe symptoms in the SW2783 group. Both viruses replicated and spread, with SW2783 showing stronger replication capacity than ZZ346. Infection was restricted to the upper respiratory tract, and nucleoprotein expression peaked at 3–5 dpi and gradually recovered at 7–14 dpi. Various histopathological changes were observed in respiratory tract tissues, with limited cell necrosis and infiltration of inflammatory cells in mucosal epithelium of nasal turbinate. Both viruses were transmissible in tree shrews, and SW2783 could transmit from tree shrews to guinea pigs.	Mechanism: Swine SW2783 and avian ZZ346 strains infected tree shrews, induced effective innate and adaptive immune responses, and regulated response degrees. In total, 14 differentially expressed miRNAs were identified in turbinate tissues from SW2783-infected tree shrews, including some miRNAs involved in viral replication and proliferation by regulating signal transduction, and others playing an antiviral role via regulating immune response. Limitations: No vaccine or drug efficacy was tested.	Wang et al., 2023b, 2024c
	Adult tree shrews were infected with 106 PFU avian H5N1 (highly virulent) and H7N9 (lowly pathogenic) into nostrils and trachea by aerosolized administration and onto tonsils and conjunctivae with pipette	H5N1 group showed elevated body temperature, body weight loss, and decreased locomotor activity starting from 2 dpi, with one of four infected animals dying. Tree shrews infected with H7N9 exhibited no clinical symptoms. Both viruses were continuously detected in nasal, oral, tracheal, and conjunctival swab samples and lung tissues, peaking at 1–2 dpi and replicating in lung tissues. Animals infected with H5N1, but not H7N9, displayed severe diffuse pneumonia, with focal inflammation around bronchioles. Antibody responses were detected in infected animals.	Mechanism: H5N1-infected tree shrews had higher expression levels of cytokine genes (IFNG, IL6, TNFA) compared to those without infection or with H7N9 infection, and severity of pneumonia was correlated with mRNA expression of proinflammatory cytokines. Limitations: Reasons for significant differences in symptoms between H5N1 infection and H7N9 infection were not determined and no vaccine or drug efficacy was tested.	Sanada et al., 2019c
	Tree shrews were infected intranasally with 106 TCID50 H9N2 viruses (Y280-wt and Y280 virus with mammalian adaptation mutation PB2-E627K). For ex vivo cultures of nasal turbinate, trachea, and lung tissues, tissue blocks were infected with 106 TCID50 H9N2 (Y280-wt and Y280-PB2-E627K) for 2 h, then cultured with fresh medium to 72 h dpi	Viral shedding was found in nasal washes of tree shrews, with longer persistence of PB2-E627K mutant virus up to 6 dpi. Tree shrews infected by PB2-E627K exhibited increased body temperature and body weight loss. H9N2 virus replicated in nasal turbinate and lungs. Animals with Y208-wt infection showed infiltration of inflammatory cells and focal edema on submucosal layer of nasal turbinate at 2 dpi, while those infected with PB2-E627K showed increased severity of lesions characterized by necrotic and sloughed epithelial cells and increased lymphocytic infiltration. Lung tissues showed similar lesion patterns. PB2-E627K virus replicated more efficiently than Y280-wt virus in ex vivo culture model of nasal turbinate, trachea, and lung tissues.	Mechanism: mRNA expression levels of cytokines, including TNF-α, IFN-β, IL-8, IL-13, and IL-6, were increased in infected tree shrews and respiratory tissues. PB2-E627K virus mutant had a higher induction effect than Y280-wt virus. Limitations: No transcriptomic profiling was performed for tissues infected with two viruses of different virulence and no vaccine or drug efficacy was tested.	Li et al., 2018a
	Tree shrews (1–4 months old) were infected intranasally with 106 EID50 pandemic H1N1 (pdmH1N1), avian H5N1, and human H7N9, respectively. Contact infection between tree shrews and guinea pigs was also tested	Three influenza viruses efficiently replicated in tree shrew primary renal cells and lung cells, and induced expression of IFNβ, IFIT2, and OASL. Tree shrews showed subclinical symptoms after infection with three viruses, with viral tropism in respiratory tract. Lung lesions, including obvious alveolar edema, interstitial edema, hemorrhage, and inflammatory cell infiltration, were observed at 3 dpi, with pdmH1N1 infection showing more severe lesions than H5N1 and G7N9. Influenza viruses induced protective responses against homologous challenge in tree shrews. PdmH1N1 and H7N9, but not H5N1, were transmissible in tree shrews. H7N9, but not pdmH1N1, was transmissible from tree shrews to guinea pigs.	Mechanism: Tree shrews were infected by different subtypes of influenza viruses, which induced a humoral immune response upon infection. Limitations: No detailed mechanisms were studied and no vaccine or drug efficacy was tested.	Xu et al., 2019
Influenza B viruses (IBVs)	Male tree shrews were intranasally inoculated with 106 TCID50 IBV V0215 or Y12. Infected tree shrews were compared with infected ferrets and mice	IBVs replicated in the respiratory tract of tree shrews, ferrets, and mice, with peak viral titers in nasal washes at 2 dpi. Infected tree shrews, but not ferrets, exhibited weight loss. Seroconversion was observed in tree shrews, with higher antibody titer in animals inoculated with V0215 compared to Y12. Clinical signs and pathological changes were mild. Elevated levels of cytokines and inflammation were detected in respiratory tract of all three infected animals. Infected tree shrews presented with rhinitis and pneumonia, and Y12 infection caused more disease severity relative to V0215 infection in tree shrews.	Mechanism: Peak and period of respiratory IBV viral shedding in tree shrews was similar to those in humans. IBV infection led to elevated levels of cytokines in respiratory tract of tree shrews. Limitations: No mechanism was reported for different virulence and tissue tropism of V0215 and Y12 in tree shrews and between tree shrews and ferrets or mice. No intra- or inter-species transmission was performed and no vaccine or drug efficacy was tested.	Yuan et al., 2019
Human adenovirus (HAdV) species B	Male tree shrews were intranasally infected with 5×106 TCID50 HAdV-55. For HAdV-55 vaccine evaluation, tree shrews were intramuscularly vaccinated with 2×1010 of inactivated HAdV-55 VPs, and two booster vaccinations on days 14 and 28	HAdV species B (HAdV-55, HAdV-7, HAdV-14) replicated in tree shrew primary cells from the kidney, lung, and trachea and caused the cytopathic effect (CPE). HAdV-55 infection led to rapid weight loss and increased body temperature. HAdV-55 was detected in respiratory tract and lung of infected tree shrews with interstitial pneumonia. Pre-vaccination provided a protective effect against homologous infection. HAdV-55 transmitted among tree shrews.	Mechanism: HAdV-55 infection induced cytokine gene expression in peripheral blood mononuclear cells (PBMCs) of tree shrews. Pre-vaccination inhibited HAdV-55 replication in vivo. Limitations: No mechanisms for pathological alterations and HAdV-55 distribution in respiratory tract and other organs were investigated.	Li et al., 2021c
Epstein-Barr virus (EBV)	Adult tree shrews (1–1.5 years old) were inoculated with 3.9×108 copies of EBV by intravenous injection	Most tree shrews (8/10) showed evidence of EBV infection, with intermittent or transient increases in EBV copy number and expression of EBV genes in PBMCs post-infection. Anti-EBV capsid antigen IgG increased by varying degrees in tree shrews with increasing EBV copy number. Splenic corpuscle hyperplasia, inflammatory cell infiltration in liver, and extensive lymphocyte proliferation in mesenteric lymph node enlargement were observed in some infected animals, but none had obvious abnormalities in lungs or nasopharynx.	Mechanism: Tree shrews were infected by EBV via intravenous infusion and presented with different patterns concerning EBV copy number. EBV-related gene expression was detected after infection. Lymphocytes and spleen were primary targets of EBV infection Limitations: No study on the mechanisms of EBV entry into the nasopharynx was conducted and no drug or vaccine efficacy was tested.	Wang et al., 2017
	Primary tree shrew PBMCs were infected with 1×107 copies of EBV. Adult tree shrews were injected with 2×107 copies of EBV via femoral vein. Daily intraperitoneal injection of cyclosporine A (CsA, 25 mg/kg) was used for immunosuppression at 5 weeks post-infection after two consecutive negative results of EBV-DNA	Tree shrew PBMCs supported EBV replication and proliferation. EBV-infected tree shrews displayed fever and weight loss, increased white blood cell count and total cell counts, and decreased neutrophils after infection. Immune organs (spleen and lymph nodes) had higher viral loads. Tree shrews acted as asymptomatic carriers of EBV, with viral protein detectable in blood and tissues. EBV infection increased percentage of immature neutrophils (rod-shaped nucleus) and neutrophils containing specific cytoplasmic intoxication particles. EBV infection altered gut microflora in composition and metabolome profile, peaking at 7 dpi. Autophagy and ferroptosis signaling pathways were activated by EBV infection, along with alterations in the competing endogenous RNA (ceRNA) network that regulates EBV-host interactions. CsA increased the proliferation ability of EBV-infected PBMCs, promoted transformation into immortalized cells, and caused EBV reactivation in infected animals.	Mechanism: Tree shrews possessed the same key residues in the complement C3d receptor 2 (CR2) that binds to the gp350 protein as humans, which facilitates viral entry. EBV infection led to dynamic transcriptomic changes in tree shrew blood cells. Neutropenia in EBV-infected animals at early infection may affect EBV immune escape and long-term latency. Changes in gut microflora during EBV infection were correlated with fecal metabolic profile. EBV infection caused alterations in ceRNA networks that remodel the immune microenvironment. Immunosuppression caused EBV reactivation in latency. Limitations: No study on the mechanisms underlying the proposed neutrophil suppression hypothesis or alterations in gut microbiota and ceRNA network during EBV infection was conducted and no drug or vaccine efficacy was tested.	Xia et al., 2022, 2023, 2024; Shi et al., 2023
Hepatitis B virus (HBV)	Adult tree shrews (>2 months old) were treated with triamcinolone steroid (5 mg/kg) for 2 days, followed by intraperitoneal inoculation with 108 copies of HBV in 1 mL of human serum	Infected animals displayed enhanced serum HBV and viral proteins were synthesized de novo in hepatocytes, with hepatitis B surface antigen (HBsAg) and hepatitis Be antigen (HBeAg) titers, and HBV DNA and covalently closed circular DNA (cccDNA) copies peaking at day 9, declining at days 15 and 21, and becoming undetectable at day 42. HBV infection led to elevated alanine transaminase levels and inflammatory infiltration and hepatocyte ballooning degeneration in liver.	Mechanism: A complete and natural process from HBV infection, replication, to elimination was modulated in tree shrews, with a noncytopathic-mediated control of cccDNA content during acute viral hepatitis Limitations: No characterization for host immune response during HBV infection and elimination was performed and no vaccine efficacy was tested.	Li et al., 2021b
	Newborn tree shrews were subcutaneously administered with 106 copies of HBV genotype A (HBV-A) or C (HBV-C) per animal; Adult tree shrews (1-year old) were intraperitoneally injected with 106-7 copies of HBV-A	HBV-A showed higher intrahepatic replication than HBV-C in newborn tree shrews, leading to abnormal architecture of liver cell cords and mitotic figures at 8 dpi. HBV-DNA and HBsAg were detected in liver tissues of adult animals at 28 dpi. HBV infection caused expression alterations in IFN-β, TLR1, TLR3, TLR9, and cGAS, and suppression of NTCP expression during chronic phase of infection.	Mechanism: Suppression of IFN-β may have contributed to establishment of chronic HBV infection in tree shrews. Limitations: No precise mechanisms for signaling pathways activated by HBVinfection and host immune response during chronic HBV infection were determined and no vaccine efficacy was tested.	Kayesh et al., 2017a
Hepatitis C virus (HCV)	Tree shrew bone marrow-derived mesenchymal stem cells (BM-MSCs) overexpressing human CD81, OCLN, and miR-122 were infected with 0.5 MOI HCVcc derived from J6/JFH1 (HCV2a)	HCV viral copies and core protein were detected in culture supernatants of infected BM-MSCs overexpressing human CD81/OCLN or CD81/OCLN/miR-122. VEGF treatment increased BM-MSC infectivity to HCV.	Mechanism: BM-MSCs overexpressing human CD81, OCLN, and miR-122 supported HCV replication and infectious virus production, and VEGF enhanced HCV infectivity in these cells. Limitations: No data on host immune response or the exact mechanisms underlying HCV replication and production of infectious particles were provided and no drug efficacy was tested.	Lu et al., 2020
	Adult tree shrews (1-year old) were infected intraperitoneally with HCV (genotypes 1a, 1b, 4a, and 2a (JFH1)) for 41 weeks	All HCV genotypes established infections and showed intermittent HCV propagation. Infected animals produced anti-core and anti-NS3 antibodies and had increased levels of reactive oxygen species (ROS) in serum and liver. Pathological changes, including lymphocytic infiltration, disturbance of hepatic cords, and initiation of fibrosis, were observed in livers of infected tree shrews.	Mechanism: Intrahepatic levels of TLR3, TLR7, and TLR9 were significantly increased upon HCV infection. Increased levels of IFNβ in tree shrews with HCV genotypes 1a and 2a infection were detected, along with a decrease in NTCP. Humoral and innate immune responses and ROS were involved in HCV infection. Limitations: No detailed mechanism was studied and no drug or vaccine efficacy was tested.	Kayesh et al., 2017b
	Tree shrews (6 months old) were infected intravenously with 1×107 copies of HCVcc (J6/JFH1) in the tail	Nearly half of the tree shrews were infected, with intermittent HCV viremia and mild hepatitis. HCV-specific proteins (Core, E2, NS3/4, and NS5A) were detected in hepatocytes of infected tree shrews. Various degrees of microvesicular fat accumulation, vacuolar degeneration, hepatic edema, and lymphocytic infiltration were observed in the livers of infected animals.	Mechanism: HCV infection led to mild hepatitis in tree shrews. Limitations: No validation for sample infectivity of infected tree shrews was conducted, no data on host immune response was provided, and no drug or vaccine efficacy was tested.	Feng et al., 2017