Teaching a new mouse old tricks: Humanized mice as an infection model for Variola virus

Smallpox, caused by the solely human pathogen Variola virus (VARV), was declared eradicated in 1980. While known VARV stocks are secure, smallpox remains a bioterrorist threat agent. Recent U.S. Food and Drug Administration approval of the first smallpox anti-viral (tecovirimat) therapeutic was a successful step forward in smallpox preparedness; however, orthopoxviruses can become resistant to treatment, suggesting a multi-therapeutic approach is necessary. Animal models are required for testing medical countermeasures (MCMs) and ideally MCMs are tested directly against the pathogen of interest. Since VARV only infects humans, a representative animal model for testing therapeutics directly against VARV remains a challenge. Here we show that three different humanized mice strains are highly susceptible to VARV infection, establishing the first small animal model using VARV. In comparison, the non-humanized, immunosuppressed background mouse was not susceptible to systemic VARV infection. Following an intranasal VARV challenge that mimics the natural route for human smallpox transmission, the virus spread systemically within the humanized mouse before mortality (~ 13 days post infection), similar to the time from exposure to symptom onset for ordinary human smallpox. Our identification of a permissive/representative VARV animal model can facilitate testing of MCMs in a manner consistent with their intended use.

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Serum Metabolomics Investigation of Humanized Mouse Model of Dengue Virus Infection

Journal of Virology ◽

10.1128/jvi.00386-17 ◽

2017 ◽

Vol 91 (14) ◽

Cited By ~ 11

Author(s):

Liang Cui ◽

Jue Hou ◽

Jinling Fang ◽

Yie Hou Lee ◽

Vivian Vasconcelos Costa ◽

...

Keyword(s):

Fatty Acids ◽

Animal Model ◽

Bile Acid ◽

Dengue Virus ◽

Metabolic Pathways ◽

Dengue Infection ◽

Small Animal ◽

Humanized Mice ◽

Small Animal Model ◽

Serum Metabolomics

ABSTRACT Dengue is an acute febrile illness caused by dengue virus (DENV) and a major cause of morbidity and mortality in tropical and subtropical regions of the world. The lack of an appropriate small-animal model of dengue infection has greatly hindered the study of dengue pathogenesis and the development of therapeutics. In this study, we conducted mass spectrometry-based serum metabolic profiling from a model using humanized mice (humice) with DENV serotype 2 infection at 0, 3, 7, 14, and 28 days postinfection (dpi). Forty-eight differential metabolites were identified, including fatty acids, purines and pyrimidines, acylcarnitines, acylglycines, phospholipids, sphingolipids, amino acids and derivatives, free fatty acids, and bile acid. These metabolites showed a reversible-change trend—most were significantly perturbed at 3 or 7 dpi and returned to control levels at 14 or 28 dpi, indicating that the metabolites might serve as prognostic markers of the disease in humice. The major perturbed metabolic pathways included purine and pyrimidine metabolism, fatty acid β-oxidation, phospholipid catabolism, arachidonic acid and linoleic acid metabolism, sphingolipid metabolism, tryptophan metabolism, phenylalanine metabolism, lysine biosynthesis and degradation, and bile acid biosynthesis. Most of these disturbed pathways are similar to our previous metabolomics findings in a longitudinal cohort of adult human dengue patients across different infection stages. Our analyses revealed the commonalities of host responses to DENV infection between humice and humans and suggested that humice could be a useful small-animal model for the study of dengue pathogenesis and the development of dengue therapeutics. IMPORTANCE Dengue virus is the most widespread arbovirus, causing an estimated 390 million dengue infections worldwide every year. There is currently no effective treatment for the disease, and the lack of an appropriate small-animal model of dengue infection has greatly increased the challenges in the study of dengue pathogenesis and the development of therapeutics. Metabolomics provides global views of small-molecule metabolites and is a useful tool for finding metabolic pathways related to disease processes. Here, we conducted a serum metabolomics study on a model using humanized mice with dengue infection that had significant levels of human platelets, monocytes/macrophages, and hepatocytes. Forty-eight differential metabolites were identified, and the underlying perturbed metabolic pathways are quite similar to the pathways found to be altered in dengue patients in previous metabolomics studies, indicating that humanized mice could be a highly relevant small-animal model for the study of dengue pathogenesis and the development of dengue therapeutics.

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BLT humanized mice as a small animal model of HIV infection

Current Opinion in Virology ◽

10.1016/j.coviro.2015.05.002 ◽

2015 ◽

Vol 13 ◽

pp. 75-80 ◽

Cited By ~ 48

Author(s):

Marshall E Karpel ◽

Christian L Boutwell ◽

Todd M Allen

Keyword(s):

Animal Model ◽

Hiv Infection ◽

Small Animal ◽

Humanized Mice ◽

Small Animal Model

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

Viruses ◽

10.3390/v13081641 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1641

Author(s):

Mohammad Enamul Hoque Kayesh ◽

Takahiro Sanada ◽

Michinori Kohara ◽

Kyoko Tsukiyama-Kohara

Keyword(s):

Animal Model ◽

Viral Infection ◽

Vaccine Development ◽

Natural Infection ◽

Tree Shrew ◽

Small Animal ◽

Influenza Viruses ◽

Infection Model ◽

Small Animal Model ◽

Tupaia Belangeri

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.

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Small Animal Model Mimics Poxvirus Infections

Microbe Magazine ◽

10.1128/microbe.2.608.1 ◽

2007 ◽

Vol 2 (12) ◽

pp. 608-608

Keyword(s):

Animal Model ◽

Small Animal ◽

Small Animal Model

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Rat model of smoke inhalation-induced acute lung injury

BMJ Open Respiratory Research ◽

10.1136/bmjresp-2021-000879 ◽

2021 ◽

Vol 8 (1) ◽

pp. e000879

Author(s):

Premila Devi Leiphrakpam ◽

Hannah R Weber ◽

Tobi Ogun ◽

Keely L Buesing

Keyword(s):

Animal Model ◽

Acute Lung Injury ◽

Lung Injury ◽

Caspase 3 ◽

Small Animal ◽

Therapeutic Options ◽

Smoke Inhalation ◽

Small Animal Model ◽

Injury Score ◽

Confounding Variables

BackgroundAcute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a lethal disease with limited therapeutic options and an unacceptably high mortality rate. Understanding the complex pathophysiological processes involved in the development of ALI/ARDS is critical for developing novel therapeutic strategies. Smoke inhalation (SI) injury is the leading cause of morbidity and mortality in patients with burn-associated ALI/ARDS; however, to our knowledge few reliable, reproducible models are available for pure SI animal model to investigate therapeutic options for ALI/ARDS without the confounding variables introduced by cutaneous burn or other pathology.ObjectiveTo develop a small animal model of pure SI-induced ALI and to use this model for eventual testing of novel therapeutics for ALI.MethodsRats were exposed to smoke using a custom-made smoke generator. Peripheral oxygen saturation (SpO2), heart rate, arterial blood gas, and chest X-ray (CXR) were measured before and after SI. Wet/dry weight (W/D) ratio, lung injury score and immunohistochemical staining of cleaved caspase 3 were performed on harvested lung tissues of healthy and SI animals.ResultsThe current study demonstrates the induction of ALI in rats after SI as reflected by a significant, sustained decrease in SpO2 and the development of diffuse bilateral pulmonary infiltrates on CXR. Lung tissue of animals exposed to SI showed increased inflammation, oedema and apoptosis as reflected by the increase in W/D ratio, injury score and cleaved caspase 3 level of the harvested tissues compared with healthy animals.ConclusionWe have successfully developed a small animal model of pure SI-induced ALI. This model is offered to the scientific community as a reliable model of isolated pulmonary SI-induced injury without the confounding variables of cutaneous injury or other systemic pathology to be used for study of novel therapeutics or other investigation.

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In vivo functional chronic imaging of a small animal model using optical-resolution photoacoustic microscopy

Medical Physics ◽

10.1118/1.3137572 ◽

2009 ◽

Vol 36 (6Part1) ◽

pp. 2320-2323 ◽

Cited By ~ 42

Author(s):

Song Hu ◽

Konstantin Maslov ◽

Lihong V. Wang

Keyword(s):

Animal Model ◽

Optical Resolution ◽

Small Animal ◽

Photoacoustic Microscopy ◽

Small Animal Model

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Rat-to-Chinese tree shrew heart transplantation is a novel small animal model to study non-Gal-mediated discordant xenograft humoral rejection

Xenotransplantation ◽

10.1111/xen.12211 ◽

2015 ◽

Vol 22 (6) ◽

pp. 468-475 ◽

Cited By ~ 2

Author(s):

WeiLi Chen ◽

Yuan Wu ◽

Akira Shimizu ◽

YinLong Lian ◽

Masayuki Tasaki ◽

...

Keyword(s):

Animal Model ◽

Heart Transplantation ◽

Tree Shrew ◽

Small Animal ◽

Humoral Rejection ◽

Small Animal Model

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Longitudinal Raman Spectroscopic Observation of Skin Biochemical Changes due to Chemotherapeutic Treatment for Breast Cancer in Small Animal Model

Journal of Spectroscopy ◽

10.1155/2017/3595078 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9

Author(s):

Myeongsu Seong ◽

NoSoung Myoung ◽

Songhyun Lee ◽

Hyeryun Jeong ◽

Sang-Youp Yim ◽

...

Keyword(s):

Breast Cancer ◽

Animal Model ◽

Raman Spectra ◽

Fiber Optic ◽

Animal Experiments ◽

Small Animal ◽

Fiber Optic Probe ◽

Small Animal Model ◽

Biochemical Compositions ◽

Optic Probe

The cancer field effect (CFE) has been highlighted as one of indirect indications for tissue variations that are insensitive to conventional diagnostic techniques. In this research, we had a hypothesis that chemotherapy for breast cancer would affect skin biochemical compositions that would be reflected by Raman spectral changes. We used a fiber-optic probe-based Raman spectroscopy to perform preliminary animal experiments to validate the hypothesis. Firstly, we verified the probing depth of the fiber-optic probe (~800 μm) using a simple intravenous fat emulsion-filled phantom having a silicon wafer at the bottom inside a cuvette. Then, we obtained Raman spectra during breast cancer treatment by chemotherapy from a small animal model in longitudinal manner. Our results showed that the treatment causes variations of biochemical compositions in the skin. For further validation, the Raman spectra will have to be collected from more populations and spectra will need to be compared with immunohistochemistry of the breast tissue.

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