Primary High-Dose Murine Norovirus 1 Infection Fails To Protect from Secondary Challenge with Homologous Virus

ABSTRACT Human noroviruses in the Caliciviridae family are the major cause of nonbacterial epidemic gastroenteritis worldwide. Primary human norovirus infection does not elicit lasting protective immunity, a fact that could greatly affect the efficacy of vaccination strategies. Little is known regarding the pathogenesis of human noroviruses or the immune responses that control them because there has previously been no small-animal model or cell culture system of infection. Using the only available small-animal model of norovirus infection, we found that primary high-dose murine norovirus 1 (MNV-1) infection fails to afford protection against a rechallenge with a homologous virus. Thus, MNV-1 represents a valuable model with which to dissect the pathophysiological basis for the lack of lasting protection against human norovirus infection. Interestingly, the magnitude of protection afforded by a primary MNV-1 infection inversely correlates with the inoculum dose. Future studies will elucidate the mechanisms by which noroviruses avoid the induction of protective immunity and the role played by the inoculum dose in this process, ultimately translating this knowledge into successful vaccination approaches.

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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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Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model

Science ◽

10.1126/science.abc7520 ◽

2020 ◽

Vol 369 (6506) ◽

pp. 956-963 ◽

Cited By ~ 222

Author(s):

Thomas F. Rogers ◽

Fangzhu Zhao ◽

Deli Huang ◽

Nathan Beutler ◽

Alison Burns ◽

...

Keyword(s):

Animal Model ◽

Severe Acute Respiratory Syndrome ◽

Global Health ◽

Neutralizing Antibodies ◽

Small Animal ◽

Passive Transfer ◽

Antibody Responses ◽

High Dose ◽

Receptor Binding Domain ◽

Small Animal Model

Countermeasures to prevent and treat coronavirus disease 2019 (COVID-19) are a global health priority. We enrolled a cohort of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–recovered participants, developed neutralization assays to investigate antibody responses, adapted our high-throughput antibody generation pipeline to rapidly screen more than 1800 antibodies, and established an animal model to test protection. We isolated potent neutralizing antibodies (nAbs) to two epitopes on the receptor binding domain (RBD) and to distinct non-RBD epitopes on the spike (S) protein. As indicated by maintained weight and low lung viral titers in treated animals, the passive transfer of a nAb provides protection against disease in high-dose SARS-CoV-2 challenge in Syrian hamsters. The study suggests a role for nAbs in prophylaxis, and potentially therapy, of COVID-19. The nAbs also define protective epitopes to guide vaccine design.

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High Dose–Per-Fraction Irradiation of Limited Lung Volumes Using an Image-Guided, Highly Focused Irradiator: Simulating Stereotactic Body Radiotherapy Regimens in a Small-Animal Model

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2009.12.074 ◽

2010 ◽

Vol 77 (3) ◽

pp. 895-902 ◽

Cited By ~ 30

Author(s):

Jaeho Cho ◽

Reinhard Kodym ◽

Serguei Seliounine ◽

James A. Richardson ◽

Timothy D. Solberg ◽

...

Keyword(s):

Animal Model ◽

Stereotactic Body Radiotherapy ◽

Small Animal ◽

High Dose ◽

Small Animal Model ◽

Lung Volumes ◽

Image Guided ◽

Dose Per Fraction

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Establishing a small animal model for evaluating protective immunity against mumps virus

PLoS ONE ◽

10.1371/journal.pone.0174444 ◽

2017 ◽

Vol 12 (3) ◽

pp. e0174444 ◽

Cited By ~ 4

Author(s):

Adrian Pickar ◽

Pei Xu ◽

Andrew Elson ◽

James Zengel ◽

Christian Sauder ◽

...

Keyword(s):

Animal Model ◽

Protective Immunity ◽

Small Animal ◽

Mumps Virus ◽

Small Animal Model

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Rapid isolation of potent SARS-CoV-2 neutralizing antibodies and protection in a small animal model

10.1101/2020.05.11.088674 ◽

2020 ◽

Cited By ~ 24

Author(s):

Thomas F. Rogers ◽

Fangzhu Zhao ◽

Deli Huang ◽

Nathan Beutler ◽

Alison Burns ◽

...

Keyword(s):

Monoclonal Antibody ◽

Animal Model ◽

Global Health ◽

Neutralizing Antibodies ◽

Small Animal ◽

Passive Transfer ◽

Antibody Responses ◽

High Dose ◽

Small Animal Model ◽

Specific Antibodies

ABSTRACTThe development of countermeasures to prevent and treat COVID-19 is a global health priority. In under 7 weeks, we enrolled a cohort of SARS-CoV-2-recovered participants, developed neutralization assays to interrogate serum and monoclonal antibody responses, adapted our high throughput antibody isolation, production and characterization pipeline to rapidly screen over 1000 antigen-specific antibodies, and established an animal model to test protection. We report multiple highly potent neutralizing antibodies (nAbs) and show that passive transfer of a nAb provides protection against high-dose SARS-CoV-2 challenge in Syrian hamsters. The study suggests a role for nAbs in prophylaxis, and potentially therapy, of COVID-19. The nAbs define protective epitopes to guide vaccine design.

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Pathogenesis and replication of norovirus: following the mouse tail?

Microbiology Australia ◽

10.1071/ma12074 ◽

2012 ◽

Vol 33 (2) ◽

pp. 74

Author(s):

Jennifer Hyde ◽

Jason McKenzie

Keyword(s):

Tissue Culture ◽

Animal Model ◽

Dendritic Cell ◽

Cell Lines ◽

Culture System ◽

Small Animal ◽

Human Pathogens ◽

Small Animal Model ◽

Tissue Culture System ◽

Human Noroviruses

The emergence of human noroviruses (NoV) as significant human pathogens over the last decades has highlighted the need to research and understand the replication and pathogenesis of this group of viruses. One of the major hurdles faced by researchers in this field has been the lack of a viable tissue culture system or small animal model with which to study human NoV replication. The discovery of a murine NoV in 2003 and the identification of its tropism for macrophage and dendritic cell lines has provided the opportunity to study aspects of NoV replication and pathogenesis that were previously closed to researchers.

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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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