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Rodents are widely used in immunology but do not always recapitulate human immune functions. The tree shrew ( Tupaia belangeri ) is phylogenetically closer to primates than rodents and may help bridge this gap, yet its immune system has not been comprehensively characterised at single-cell resolution. Here, we present a single-cell transcriptomic atlas of the tree shrew immune system, profiling 39 cell types across 12 tissues. We uncover human-like tonsillar structures and two transcriptionally distinct splenic macrophage subsets: an NR1H3 + immunoregulatory subset and an IRF8 + pro-inflammatory subset. During acute Epstein-Barr virus infection, NR1H3 + macrophages undergo pronounced inflammatory reprogramming and emerge as a major intercellular signalling hub. Cross-species integration of single-cell datasets from seven vertebrate species indicates that NR1H3 + macrophage gene programmes are evolutionarily conserved. Functional analyses further support a shared anti-inflammatory programme mediated by NR1H3-dependent suppression of the non-canonical NF-κB pathway in both tree shrew and human macrophages. Together, these findings provide a reference resource for tree shrew immunology and support the tree shrew as a complementary model alongside rodent and primate systems. Rodents are frequently used as models of the human immune system, but not all immune functions are shared between the two evolutionary families. Here the authors provide evidence that the immune system of the tree shrew (Tupaia belangeri) is closer to humans than that of rodents and the single cell immune atlas they assemble support the wider employment of the tree shrew as immunological model.

The northern tree shrew ( Tupaia belangeri ) possesses high potential as an animal model of human diseases and biology, given its genetic similarity to primates. Although genetic information on the tree shrew has already been published, some of the entire coding sequences (CDSs) of tree shrew genes remained incomplete, and the reliability of these CDSs remained difficult to determine. To improve the determination of tree shrew CDSs, we performed sequencing of the whole-genome, mRNA, and total RNA and integrated the resulting data. Additionally, we established criteria for the selection of reliable CDSs and annotated these sequences by comparison to the human transcriptome, resulting in the identification of complete CDSs for 12,612 tree shrew genes and yielding a more accurate tree shrew genome database (TupaiaBase: http://tupaiabase.org ). Transcriptome profiles in hepatitis B virus infected tree shrew livers were analyzed for validation. Gene ontology analysis showed enriched transcriptional regulation at 1 day post-infection, namely in the “type I interferon signaling pathway”. Moreover, a negative regulator of type I interferon, SOCS3 , was induced. This work, which provides a tree shrew CDS database based on genomic DNA and RNA sequencing, is expected to serve as a powerful tool for further development of the tree shrew model.

A new species of Moniliformis, M. tupaia n. sp. is described using integrated morphological methods (light and scanning electron microscopy) and molecular techniques (sequencing and analysing the nuclear 18S, ITS, 28S regions and mitochondrial cox1 and cox2 genes), based on specimens collected from the intestine of the northern tree shrew Tupaia belangeri chinensis Anderson (Scandentia: Tupaiidae) in China. Phylogenetic analyses show that M. tupaia n. sp. is a sister to M. moniliformis in the genus Moniliformis, and also challenge the systematic status of Nephridiacanthus major. Moniliformis tupaia n. sp. represents the third Moniliformis species reported from China.

Chinese tree shrews ( Tupaia belangeri chinensis ) possess many features valuable in animals used as experimental models in biomedical research. Currently, there are numerous attempts to employ tree shrews as models for a variety of human disorders: depression, myopia, hepatitis B and C virus infections, and hepatocellular carcinoma, to name a few. Here we present a publicly available annotated genome sequence for the Chinese tree shrew. Phylogenomic analysis of the tree shrew and other mammalians highly support its close affinity to primates. By characterizing key factors and signalling pathways in nervous and immune systems, we demonstrate that tree shrews possess both shared common and unique features, and provide a genetic basis for the use of this animal as a potential model for biomedical research. The Chinese tree shrew, Tupaia belangeri chinensis , has been proposed as a potential animal model in biomedical research and drug safety testing. This study presents the full genome of the Chinese tree shrew, identifying common features between the tree shrew and primates.

Rationale: Substance P and its preferred receptor, the neurokinin 1 receptor (NK sub(1)R), have been proposed as possible targets for new antidepressant therapies, although results of a recently completed phase III trial failed to demonstrate that the NK sub(1)R antagonist MK-869 is more effective than placebo in the treatment of depression. Methods: In the present study, we compared the effects of the NK sub(1)R antagonist L-760735 with the tricyclic antidepressant clomipramine on endocrine and behavioral parameters in chronically stressed tree shrews. Animals were subjected to a 7-day period of psychosocial stress before receiving daily oral administration of L-760735 (10 mg/kg/day) or clomipramine (50 mg/kg/day). The psychosocial stress continued throughout the treatment period of 21 days. Daily morning urine was collected to measure cortisol and norepinephrine levels. All animals were videotaped daily and three types of behavior were analyzed. Results: Chronic psychosocial stress resulted in a significant increase of urinary cortisol and norepinephrine concentrations. Moreover, stressed animals displayed decreased marking behavior and locomotor activity, while grooming remained unaffected. Neither treatment with clomipramine nor L-760735 was able to normalize the stress-induced elevation of cortisol or norepinephrine. On the behavioral parameters, L-760735 had a time-dependent restorative influence on marking behavior close to normal levels, without affecting locomotor activity. Grooming behavior was significantly increased by the 3 weeks of drug treatment. Conclusions: These results suggest that L-760735 was able to counteract certain stress-induced behavioral alterations in an animal model of depression.

BACKGROUND: Hepatitis B virus (HBV) infection has been believed as a major cause of hepatocellular carcinoma (HCC) for a long time, however, the evidences of which are mostly from clinical and epidemiological investigations while there is no evidence from animal experiments. Tree shrew (Tupaia) is a small animal closely related to primates evolutionarily, with about 8 years of lifespan. Our previous study proved that tree shrews can be chronically HBV-infected after being inoculated neonatally with HBV. The present study reports the further results from the longer-term observation of these animals. METHODS: Neonatal tree shrews were inoculated with sera from HBV-infected patient or tree shrew. Their serum samples and liver biopsies were collected periodically for detection of HBV markers as well as for histopathological and immunohistochemical examinations. Group A consisted of six tree shrews with chronic HBV-infection, and group B consisted of nine tree shrews without chronic HBV infection. RESULTS: Periodical examinations on serum and liver biopsies of the animals in group A showed the progress of HBV infection, and two cases of HCC occurred at their late stage of life. The courses of HBV infection and the hepatic histopathological and immunohistochemical changes in the tree shrews were similar to those in humans. In contrast, neither HCC nor obvious hepatitis histopathological change was found among the tree shrews in group B. CONCLUSIONS: The course of HBV infection and the features of HCC discovered in tree shrews are similar to those of chronically HBV-infected humans. The tree shrew model might be used to investigate the underlying mechanisms favoring susceptibility for chronic HBV infection and disease progression.

Background The Niemann-Pick C1-Like 1 protein, a multi-transmembrane domain molecule, is critical for intestinal cholesterol absorption, and is the entry factor for hepatitis C virus (HCV). The Chinese tree shrew ( Tupaia belangeri chinensis ) is closer to primates in terms of genetic evolution than rodents. Previous studies indicated that the tree shrew was suitable for HCV research; however, little is known about tree shrew NPC1L1. Methods and results TsNPC1L1 cDNA was amplified by rapid amplification of cDNA ends (RACE) technology. The cDNA sequence, its encoded protein structure, and expression profile were analyzed. Results indicated that the tsNPC1L1 mRNA is 4948 bp in length and encodes a 1326 amino acid protein. TsNPC1L1 possesses 84.97% identity in homology to human NPC1L1 which is higher than both mouse (80.37%) and rat (81.80%). The protein structure was also similar to human with 13 conserved transmembrane helices, and a sterol-sensing domain (SSD). Like human NPC1L1, the tsNPC1L1 mRNA transcript is highly expressed in small intestine, but it was also well-expressed in the lung and pancreas of the tree shrew. Conclusion The homology of tree shrew NPC1L1 was closer to human than that of rodent NPC1L1. The expression of tsNPC1L1 was the highest in small intestine, and was detectable in lung and pancreas. These results may be useful in the study of tsNPC1L1 function in cholesterol absorption and HCV infection.

Two of the most-studied ecogeographical rules describe patterns of body size variation within species. Bergmann’s rule predicts that individuals have larger body sizes in colder climates (typically at higher latitudes), and the island rule predicts that island populations of small-bodied species average larger in size than their mainland counterparts (insular gigantism). These rules are rarely tested in conjunction or assessed across space and time simultaneously. We investigated these patterns in the Northern Treeshrew ( Tupaia belangeri ) using museum specimens collected across a wide spatial and temporal range. Contrary to Bergmann’s rule, size increases with temperature in T. belangeri , a signal that is highly consistent across space and time. We also show that these rules are intertwined: Bergmann’s rule is reversed on the mainland but holds on islands, and therefore the island rule is upheld at higher, but not lower, latitudes. Moreover, we demonstrate a rapid reversal of both rules over time. The mechanism behind these inversions remains unclear, though temperature and precipitation are significant predictors of body size. Ecogeographical rules rely on the assumption of a constant relationship between size and the factors driving its variation. Our results highlight the need to question this assumption and reevaluate these rules in the context of accelerating and uneven climate change.

The relationship of food comminution and individual age in Tupaia belangeri is investigated. It is hypothesized that with increasing age the performance of the molar dentition decreases due to progressive tooth wear. While this relationship is well-documented for herbivores, age-related test series are largely lacking for insectivorous mammals. 15 individuals of Tupaia belangeri were fed exclusively with mealworms, and their faeces were analyzed for the number and size of chitin particles. The exoskeleton of a mealworm is resistant to digestive fluids in the gastrointestinal tract, and the size of individual chitin particles indicates the effectiveness of mechanical comminution that occurs in the oral cavity during mastication. It is hypothesized that a more precise occlusion of the dentition results in smaller particle size. Although individuals of all ages (juvenile, adult, and senile) were able to effectively process mealworms with their dentition prior to digestion, a larger area of very large chitin particles (98% quantile of all particles in senile animals as compared to in the same quantile in adults) in the feces of senile animals was detected. Even though the particle size of indigestible material is irrelevant for the digestive process, these findings either document somatic senescence in the functionality of the teeth, or alternatively a change in chewing behaviour with age.

The p53 protein is a transcriptional regulatory factor and many of its functions require that it forms a tetrameric structure. Although the tetramerization domain of mammalian p53 proteins (p53TD) share significant sequence similarities, it was recently shown that the tree shrew p53TD is considerably more thermostable than the human p53TD. To determine whether other mammalian species display differences in this domain, we used biophysical, functional, and structural studies to compare the properties of the p53TDs from six mammalian model organisms (human, tree shrew, guinea pig, Chinese hamster, sheep, and opossum). The results indicate that the p53TD from the opossum and tree shrew are significantly more stable than the human p53TD, and there is a correlation between the thermostability of the p53TDs and their ability to activate transcription. Structural analysis of the tree shrew and opossum p53TDs indicated that amino acid substitutions within two distinct regions of their p53TDs can dramatically alter hydrophobic packing of the tetramer, and in particular substitutions at positions corresponding to F341 and Q354 of the human p53TD. Together, the results suggest that subtle changes in the sequence of the p53TD can dramatically alter the stability, and potentially lead to important changes in the functional activity, of the p53 protein.