Characterizing a Murine Model for Astrovirus Using Viral Isolates from Persistently Infected Immunocompromised Mice

ABSTRACT Human astroviruses are single-stranded RNA enteric viruses that cause a spectrum of disease ranging from asymptomatic infection to systemic extragastrointestinal spread; however, they are among the least-characterized enteric viruses, and there is a lack of a well-characterized small animal model. Finding that immunocompromised mice were resistant to human astrovirus infection via multiple routes of inoculation, our studies aimed to determine whether murine astrovirus (MuAstV) could be used to model human astrovirus disease. We experimentally infected wild-type mice with MuAstV isolated from immunocompromised mice and found that the virus was detected throughout the gastrointestinal tract, including the stomach, but was not associated with diarrhea. The virus was also detected in the lung. Although virus levels were higher in recently weaned mice, the levels were similar in male and female adult mice. Using two distinct viruses isolated from different immunocompromised mouse strains, we observed virus strain-specific differences in the duration of infection (3 versus 10 weeks) in wild-type mice, indicating that the within-host immune pressure from donor mice shaped the virus kinetics in immunocompetent recipient hosts. Both virus strains elicited minimal pathology and a lack of sustained immunity. In summary, MuAstV represents a useful model for studying asymptomatic human infection and gaining insight into the astrovirus pathogenesis and immunity. IMPORTANCE Astroviruses are widespread in both birds and mammals; however, little is known about the pathogenesis and the immune response to the virus due to the lack of a well-characterized small-animal model. Here we describe two distinct strains of murine astrovirus that cause infections in immunocompetent mice that mirror aspects of asymptomatic human infections, including minimal pathology and short-lived immunity. However, we noted that the duration of infection differed greatly between the strains, highlighting an important facet of these viruses that was not previously appreciated. The ubiquitous nature and diversity of murine astroviruses coupled with the continuous likelihood of reinfection raise the possibility of viral interference with other mouse models of disease.

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A Mouse Model for Human Norovirus

mBio ◽

10.1128/mbio.00450-13 ◽

2013 ◽

Vol 4 (4) ◽

Cited By ~ 122

Author(s):

Stefan Taube ◽

Abimbola O. Kolawole ◽

Marina Höhne ◽

John E. Wilkinson ◽

Scott A. Handley ◽

...

Keyword(s):

Animal Model ◽

Mouse Model ◽

Small Animal ◽

Morbidity And Mortality ◽

Significant Morbidity ◽

Wild Type ◽

Small Animal Model ◽

Human Norovirus ◽

Human Noroviruses ◽

Deficient Mice

ABSTRACT Human noroviruses (HuNoVs) cause significant morbidity and mortality worldwide. However, despite substantial efforts, a small-animal model for HuNoV has not been described to date. Since “humanized” mice have been successfully used to study human-tropic pathogens in the past, we challenged BALB/c mice deficient in recombination activation gene (Rag) 1 or 2 and common gamma chain (γc) (Rag-γc) engrafted with human CD34+ hematopoietic stem cells, nonengrafted siblings, and immunocompetent wild-type controls with pooled stool isolates from patients positive for HuNoV. Surprisingly, both humanized and nonhumanized BALB/c Rag-γc-deficient mice supported replication of a GII.4 strain of HuNoV, as indicated by increased viral loads over input. In contrast, immunocompetent wild-type BALB/c mice were not infected. An intraperitoneal route of infection and the BALB/c genetic background were important for facilitating a subclinical HuNoV infection of Rag-γc-deficient mice. Expression of structural and nonstructural proteins was detected in cells with macrophage-like morphology in the spleens and livers of BALB/c Rag-γc-deficient mice, confirming the ability of HuNoV to replicate in a mouse model. In summary, HuNoV replication in BALB/c Rag-γc-deficient mice is dependent on the immune-deficient status of the host but not on the presence of human immune cells and provides the first genetically manipulable small-animal model for studying HuNoV infection. IMPORTANCE Human noroviruses are a significant cause of viral gastroenteritis worldwide, resulting in significant morbidity and mortality. Antivirals and vaccines are currently not available, in part due to the inability to study these viruses in a genetically manipulable, small-animal model. Herein, we report the first mouse model for human noroviruses. This model will accelerate our understanding of human norovirus biology and provide a useful resource for evaluating antiviral therapies.

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STAT-1 Knockout Mice as a Model for Wild-Type Sudan Virus (SUDV)

Viruses ◽

10.3390/v13071388 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1388

Author(s):

Olivier Escaffre ◽

Terry L. Juelich ◽

Natasha Neef ◽

Shane Massey ◽

Jeanon Smith ◽

...

Keyword(s):

Animal Model ◽

Democratic Republic Of Congo ◽

White Blood Cells ◽

Small Animal ◽

Marburg Virus ◽

Wild Type ◽

Small Animal Model ◽

Knock Out ◽

Zaire Ebolavirus

Currently there is no FDA-licensed vaccine or therapeutic against Sudan ebolavirus (SUDV) infections. The largest ever reported 2014–2016 West Africa outbreak, as well as the 2021 outbreak in the Democratic Republic of Congo, highlight the critical need for countermeasures against filovirus infections. A well-characterized small animal model that is susceptible to wild-type filoviruses would greatly add to the screening of antivirals and vaccines. Here, we infected signal transducer and activator of transcription-1 knock out (STAT-1 KO) mice with five different wildtype filoviruses to determine susceptibility. SUDV and Marburg virus (MARV) were the most virulent, and caused 100% or 80% lethality, respectively. Zaire ebolavirus (EBOV), Bundibugyo ebolavirus (BDBV), and Taï Forest ebolavirus (TAFV) caused 40%, 20%, and no mortality, respectively. Further characterization of SUDV in STAT-1 KO mice demonstrated lethality down to 3.1 × 101 pfu. Viral genomic material was detectable in serum as early as 1 to 2 days post-challenge. The onset of viremia was closely followed by significant changes in total white blood cells and proportion of neutrophils and lymphocytes, as well as by an influx of neutrophils in the liver and spleen. Concomitant significant fluctuations in blood glucose, albumin, globulin, and alanine aminotransferase were also noted, altogether consistent with other models of filovirus infection. Finally, favipiravir treatment fully protected STAT-1 KO mice from lethal SUDV challenge, suggesting that this may be an appropriate small animal model to screen anti-SUDV countermeasures.

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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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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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