scholarly journals The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Sherry L. Kurtz ◽  
Amy P. Rossi ◽  
Gillian L. Beamer ◽  
Dan M. Gatti ◽  
Igor Kramnik ◽  
...  
Keyword(s):  
Animal Model ◽  
Full Range ◽  
Small Animal ◽  
Complex Case ◽  
Lung Pathology ◽  
Small Animal Model ◽  
Mouse Population ◽  
Content Type ◽  
Diversity Outbred ◽  
Wide Range

ABSTRACT Many studies of Mycobacterium tuberculosis infection and immunity have used mouse models. However, outcomes of vaccination and challenge with M. tuberculosis in inbred mouse strains do not reflect the full range of outcomes seen in people. Previous studies indicated that the novel Diversity Outbred (DO) mouse population exhibited a spectrum of outcomes after primary aerosol infection with M. tuberculosis. Here, we demonstrate the value of this novel mouse population for studies of vaccination against M. tuberculosis aerosol challenge. Using the only currently licensed tuberculosis vaccine, we found that the DO population readily controlled systemic Mycobacterium bovis BCG bacterial burdens and that BCG vaccination significantly improved survival across the DO population upon challenge with M. tuberculosis. Many individual DO mice that were vaccinated with BCG and then challenged with M. tuberculosis exhibited low bacterial burdens, low or even no systemic dissemination, little weight loss, and only minor lung pathology. In contrast, some BCG-vaccinated DO mice progressed quickly to fulminant disease upon M. tuberculosis challenge. Across the population, most of these disease parameters were at most modestly correlated with each other and were often discordant. This result suggests the need for a multiparameter metric to better characterize “disease” and “protection,” with closer similarity to the complex case definitions used in people. Taken together, these results demonstrate that DO mice provide a novel small-animal model of vaccination against tuberculosis that better reflects the wide spectrum of outcomes seen in people. IMPORTANCE We vaccinated the Diversity Outbred (DO) population of mice with BCG, the only vaccine currently used to protect against tuberculosis, and then challenged them with M. tuberculosis by aerosol. We found that the BCG-vaccinated DO mouse population exhibited a wide range of outcomes, in which outcomes in individual mice ranged from minimal respiratory or systemic disease to fulminant disease and death. The breadth of these outcomes appears similar to the range seen in people, indicating that DO mice may serve as an improved small-animal model to study tuberculosis infection and immunity. Moreover, sophisticated tools are available for the use of these mice to map genes contributing to control of vaccination. Thus, the present studies provided an important new tool in the fight against tuberculosis.

scholarly journals Development and Characterization of a Guinea Pig-Adapted Sudan Virus

2015 ◽  
Vol 90 (1) ◽  
pp. 392-399 ◽  
Author(s):  
Gary Wong ◽  
Shihua He ◽  
Haiyan Wei ◽  
Andrea Kroeker ◽  
Jonathan Audet ◽  
...  
Keyword(s):  
Animal Model ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Lethal Dose ◽  
Fatal Outcome ◽  
Small Animal ◽  
Disease Outbreak ◽  
Small Animal Model ◽  
Content Type

ABSTRACT Infections with Sudan virus (SUDV), a member of the genus Ebolavirus , result in a severe hemorrhagic fever with a fatal outcome in over 50% of human cases. The paucity of prophylactics and therapeutics against SUDV is attributed to the lack of a small-animal model to screen promising compounds. By repeatedly passaging SUDV within the livers and spleens of guinea pigs in vivo , a guinea pig-adapted SUDV variant (SUDV-GA) uniformly lethal to these animals, with a 50% lethal dose (LD 50 ) of 5.3 × 10 −2 50% tissue culture infective doses (TCID 50 ), was developed. Animals infected with SUDV-GA developed high viremia and died between 9 and 14 days postinfection. Several hallmarks of SUDV infection, including lymphadenopathy, increased liver enzyme activities, and coagulation abnormalities, were observed. Virological analyses and gross pathology, histopathology, and immunohistochemistry findings indicate that SUDV-GA replicates in the livers and spleens of infected animals similarly to SUDV infections in nonhuman primates. These developments will accelerate the development of specific medical countermeasures in preparation for a future disease outbreak due to SUDV. IMPORTANCE A disease outbreak due to Ebola virus (EBOV), suspected to have emerged during December 2013 in Guinea, with over 11,000 dead and 28,000 infected, is finally winding down. Experimental EBOV vaccines and treatments were administered to patients under compassionate circumstances with promising results, and availability of an approved countermeasure appears to be close. However, the same range of experimental candidates against a potential disease outbreak caused by other members of the genus Ebolavirus , such as Sudan virus (SUDV), is not readily available. One bottleneck contributing to this situation is the lack of a small-animal model to screen promising drugs in an efficient and economical manner. To address this, we have generated a SUDV variant (SUDV-GA) that is uniformly lethal to guinea pigs. Animals infected with SUDV-GA develop disease similar to that of SUDV-infected humans and monkeys. We believe that this model will significantly accelerate the development of life-saving measures against SUDV infections.

A model of brain abscess: septic homologous blood clot emboli in rats

1986 ◽  
Vol 64 (1) ◽  
pp. 125-127 ◽  
Author(s):  
Hiroshi Matsuura ◽  
Motoshige Kudo ◽  
Yukio Ikeda ◽  
Kazuo Isayama ◽  
Shozo Nakazawa
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Blood Clot ◽  
Small Animal ◽  
Small Animal Model ◽  
Homologous Blood ◽  
Content Type ◽  
Therapeutic Procedures ◽  
Brain Abscesses ◽  
Fine Print

✓ Brain abscesses in rats were produced by intra-arterial injection of septic homologous blood clot emboli. The production rate was 100% and the histopathological features closely resembled those seen in other animal models and in spontaneously occurring brain abscesses in humans. This small-animal model may be useful for systematic study of the development of brain abscesses as well as for evaluation of various therapeutic procedures.

scholarly journals Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease

2016 ◽  
Vol 90 (20) ◽  
pp. 9209-9223 ◽  
Author(s):  
Robert Kozak ◽  
Shihua He ◽  
Andrea Kroeker ◽  
Marc-Antoine de La Vega ◽  
Jonathan Audet ◽  
...  
Keyword(s):  
Animal Model ◽  
Ebola Virus ◽  
Virus Transmission ◽  
Case Fatality ◽  
Small Animal ◽  
Hemorrhagic Fever ◽  
Transmission Model ◽  
Global Public Health ◽  
Small Animal Model ◽  
Content Type

ABSTRACTBundibugyo virus (BDBV) is the etiological agent of a severe hemorrhagic fever in humans with a case-fatality rate ranging from 25 to 36%. Despite having been known to the scientific and medical communities for almost 1 decade, there is a dearth of studies on this pathogen due to the lack of a small animal model. Domestic ferrets are commonly used to study other RNA viruses, including members of the orderMononegavirales. To investigate whether ferrets were susceptible to filovirus infections, ferrets were challenged with a clinical isolate of BDBV. Animals became viremic within 4 days and succumbed to infection between 8 and 9 days, and a petechial rash was observed with moribund ferrets. Furthermore, several hallmarks of human filoviral disease were recapitulated in the ferret model, including substantial decreases in lymphocyte and platelet counts and dysregulation of key biochemical markers related to hepatic/renal function, as well as coagulation abnormalities. Virological, histopathological, and immunohistochemical analyses confirmed uncontrolled BDBV replication in the major organs. Ferrets were also infected with Ebola virus (EBOV) to confirm their susceptibility to another filovirus species and to potentially establish a virus transmission model. Similar to what was seen with BDBV, important hallmarks of human filoviral disease were observed in EBOV-infected ferrets. This study demonstrates the potential of this small animal model for studying BDBV and EBOV using wild-type isolates and will accelerate efforts to understand filovirus pathogenesis and transmission as well as the development of specific vaccines and antivirals.IMPORTANCEThe 2013-2016 outbreak of Ebola virus in West Africa has highlighted the threat posed by filoviruses to global public health. Bundibugyo virus (BDBV) is a member of the genusEbolavirusand has caused outbreaks in the past but is relatively understudied, likely due to the lack of a suitable small animal model. Such a model for BDBV is crucial to evaluating vaccines and therapies and potentially understanding transmission. To address this, we demonstrated that ferrets are susceptible models to BDBV infection as well as to Ebola virus infection and that no virus adaptation is required. Moreover, these animals develop a disease that is similar to that seen in humans and nonhuman primates. We believe that this will improve the ability to study BDBV and provide a platform to test vaccines and therapeutics.

scholarly journals Rat model of smoke inhalation-induced acute lung injury

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.

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

2015 ◽  
Vol 22 (6) ◽  
pp. 468-475 ◽  
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

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

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.

scholarly journals Serum Metabolomics Investigation of Humanized Mouse Model of Dengue Virus Infection

2017 ◽  
Vol 91 (14) ◽  
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.

Synchrotron-based intravenous cerebral angiography in a small animal model

2007 ◽  
Vol 52 (4) ◽  
pp. 1001-1012 ◽  
Author(s):  
Michael E Kelly ◽  
Elisabeth Schültke ◽  
Stephan Fiedler ◽  
Christian Nemoz ◽  
Raphael Guzman ◽  
...  
Keyword(s):  
Animal Model ◽  
Cerebral Angiography ◽  
Small Animal ◽  
Small Animal Model
Sign in / Sign up

Export Citation Format

Share Document