Tree Shrew as an Emerging Small Animal Model for Human Viral Infection: A Recent Overview

Abstract

Viral infection is a global public health threat causing millions of deaths. A suitable small animal model is essential for viral pathogenesis and host response studies that could be used in antiviral and vaccine development. The tree shrew (Tupaia belangeri or Tupaia belangeri chinenesis), a squirrel-like non-primate small mammal in the Tupaiidae family, has been reported to be susceptible to important human viral pathogens, including hepatitis viruses (e.g., HBV, HCV), respiratory viruses (influenza viruses, SARS-CoV-2, human adenovirus B), arboviruses (Zika virus and dengue virus), and other viruses (e.g., herpes simplex virus, etc.). The pathogenesis of these viruses is not fully understood due to the lack of an economically feasible suitable small animal model mimicking natural infection of human diseases. The tree shrew model significantly contributes towards a better understanding of the infection and pathogenesis of these important human pathogens, highlighting its potential to be used as a viable viral infection model of human viruses. Therefore, in this review, we summarize updates regarding human viral infection in the tree shrew model, which highlights the potential of the tree shrew to be utilized for human viral infection and pathogenesis studies.

In vivo Delivery Tools for Clustered Regularly Interspaced Short Palindromic Repeat/Associated Protein 9-Mediated Inhibition of Hepatitis B Virus Infection: An Update

“…We observed that AAV2-WJ11/Cas9 significantly inhibited HBV DNA replication and reduced cccDNA levels both in vitro and in vivo (Kayesh et al, 2020); however, the effect required high multiplicity of genome (MOG) copies of the AAV2 vector, suggesting low transduction efficiency of the AAV2 vector. Using an immunocompetent tree shrew model of HBV infection (Kayesh et al, 2021), we observed a much lower transduction efficiency of the AAV2 vector in liver tissues (unpublished data) than in humanized chimeric mice (Kayesh et al, 2020). Stone et al demonstrated the antiviral efficacy of SaCas9 in humanized FRG mice chronically infected with HBV genotype C, which resulted in decreased total liver HBV DNA and cccDNA levels (Stone et al, 2021).…”

The Hepatitis B Virus Nucleocapsid—Dynamic Compartment for Infectious Virus Production and New Antiviral Target

“…The discovery of NTCP as HBV entry receptor has meanwhile allowed to engineer NTCP-expressing HepG2 cells that are susceptible to HBV infection, albeit infection efficiency is very limited, with no net amplification of the input virus. There are also no convenient small animal models for infection with human HBV; in vivo infection of tree shrews is inefficient [ 207 ] and mice, by necessity immunodeficient, need to be xenotransplanted with human hepatocytes to become susceptible. Improvements are under way on various levels [ 208 , 209 , 210 ] but not yet widely available.…”

An Update on Animal Models for Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Countermeasure Development

“…For tree shrew infection experiments, the SARS-CoV-2 strain was usually inoculated by oral, intranasal and intraocular routes ( Xu L. et al, 2020 ; Zhao et al, 2020 ; Kayesh et al, 2021 ). After infection, viral RNA was detected in different organs and tissues (e. g. conjunctiva, kidney, bladder, small intestine, testis and ovary) of adult tree shrews, and the peak of viral RNA in lung tissues appeared at day 3 post-infection.…”

“…Additionally, the virus exudation and replication levels were relatively low in tree shrews (6–12 months old), adult tree shrews (2–4 years old) and aged tree shrews (5–7 years old). According to the comparison of the two studies ( Zhao et al, 2020 ; Kayesh et al, 2021 ), the different concentrations of injected virus and the different routes of infection led to above differences, which need further study to clarify. Notably, young tree shrews did not experience a significant increase in body temperature for 6 days after inoculation, but virus shedding was detected from the nose, throat, anus and serum.…”