Animal Models in Human Adenovirus Research

Human adenovirus (HAdV) infections cause a wide variety of clinical symptoms, ranging from mild upper respiratory tract disease to lethal outcomes, particularly in immunocompromised individuals. To date, neither widely available vaccines nor approved antiadenoviral compounds are available to efficiently deal with HAdV infections. Thus, there is a need to thoroughly understand HAdV-induced disease, and for the development and preclinical evaluation of HAdV therapeutics and/or vaccines, and consequently for suitable standardizable in vitro systems and animal models. Current animal models to study HAdV pathogenesis, persistence, and tumorigenesis include rodents such as Syrian hamsters, mice, and cotton rats, as well as rabbits. In addition, a few recent studies on other species, such as pigs and tree shrews, reported promising data. These models mimic (aspects of) HAdV-induced pathological changes in humans and, although they are relevant, an ideal HAdV animal model has yet to be developed. This review summarizes the available animal models of HAdV infection with comprehensive descriptions of virus-induced pathogenesis in different animal species. We also elaborate on rodent HAdV animal models and how they contributed to insights into adenovirus-induced cell transformation and cancer.

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Human in vitro systems for examining synaptic function and plasticity in the brain

Journal of Neurophysiology ◽

10.1152/jn.00411.2019 ◽

2020 ◽

Vol 123 (3) ◽

pp. 945-965 ◽

Cited By ~ 1

Author(s):

Kevin Lee ◽

Thomas I.-H. Park ◽

Peter Heppner ◽

Patrick Schweder ◽

Edward W. Mee ◽

...

Keyword(s):

Animal Models ◽

Human Brain ◽

Brain Tissue ◽

Human Brain Tissue ◽

Adult Human Brain ◽

Adult Human ◽

Human Neurons ◽

In Vitro Systems ◽

Human Neuron

The human brain shows remarkable complexity in its cellular makeup and function, which are distinct from nonhuman species, signifying the need for human-based research platforms for the study of human cellular neurophysiology and neuropathology. However, the use of adult human brain tissue for research purposes is hampered by technical, methodological, and accessibility challenges. One of the major problems is the limited number of in vitro systems that, in contrast, are readily available from rodent brain tissue. With recent advances in the optimization of protocols for adult human brain preparations, there is a significant opportunity for neuroscientists to validate their findings in human-based systems. This review addresses the methodological aspects, advantages, and disadvantages of human neuron in vitro systems, focusing on the unique properties of human neurons and synapses in neocortical microcircuits. These in vitro models provide the incomparable advantage of being a direct representation of the neurons that have formed part of the human brain until the point of recording, which cannot be replicated by animal models nor human stem-cell systems. Important distinct cellular mechanisms are observed in human neurons that may underlie the higher order cognitive abilities of the human brain. The use of human brain tissue in neuroscience research also raises important ethical, diversity, and control tissue limitations that need to be considered. Undoubtedly however, these human neuron systems provide critical information to increase the potential of translation of treatments from the laboratory to the clinic in a way animal models are failing to provide.

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Feline Calicivirus Virulent Systemic Disease: Clinical Epidemiology, Analysis of Viral Isolates and In Vitro Efficacy of Novel Antivirals in Australian Outbreaks

Viruses ◽

10.3390/v13102040 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2040

Author(s):

Matteo Bordicchia ◽

Tulio Machado Fumian ◽

Kate Van Brussel ◽

Alice G. Russo ◽

Maura Carrai ◽

...

Keyword(s):

Clinical Epidemiology ◽

Systemic Disease ◽

Feline Calicivirus ◽

Metagenomic Sequencing ◽

Event Analysis ◽

Amino Acid Residues ◽

Upper Respiratory Tract ◽

E Region ◽

Tract Disease

Feline calicivirus (FCV) causes upper respiratory tract disease (URTD) and sporadic outbreaks of virulent systemic disease (FCV-VSD). The basis for the increased pathogenicity of FCV-VSD viruses is incompletely understood, and antivirals for FCV-VSD have yet to be developed. We investigated the clinicoepidemiology and viral features of three FCV-VSD outbreaks in Australia and evaluated the in vitro efficacy of nitazoxanide (NTZ), 2′-C-methylcytidine (2CMC) and NITD-008 against FCV-VSD viruses. Overall mortality among 23 cases of FCV-VSD was 39%. Metagenomic sequencing identified five genetically distinct FCV lineages within the three outbreaks, all seemingly evolving in situ in Australia. Notably, no mutations that clearly distinguished FCV-URTD from FCV-VSD phenotypes were identified. One FCV-URTD strain likely originated from a recombination event. Analysis of seven amino-acid residues from the hypervariable E region of the capsid in the cultured viruses did not support the contention that properties of these residues can reliably differentiate between the two pathotypes. On plaque reduction assays, dose–response inhibition of FCV-VSD was obtained with all antivirals at low micromolar concentrations; NTZ EC50, 0.4–0.6 µM, TI = 21; 2CMC EC50, 2.7–5.3 µM, TI > 18; NITD-008, 0.5 to 0.9 µM, TI > 111. Investigation of these antivirals for the treatment of FCV-VSD is warranted.

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XXII. Evaluation of drug efficacy by using animal models or in vitro systems

FEMS Immunology & Medical Microbiology ◽

10.1111/j.1574-695x.1998.tb01203.x ◽

1998 ◽

Vol 22 (1-2) ◽

pp. 173-179 ◽

Cited By ~ 3

Author(s):

Monique Brun Pascaud ◽

Esperanza Herreros ◽

El Moukhtar Aliouat ◽

Eduardo Dei-Cas

Keyword(s):

Animal Models ◽

Drug Efficacy ◽

In Vitro Systems

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CRISPR/Cas9 in Cancer Immunotherapy: Animal Models and Human Clinical Trials

Genes ◽

10.3390/genes11080921 ◽

2020 ◽

Vol 11 (8) ◽

pp. 921 ◽

Cited By ~ 1

Author(s):

Khalil Khalaf ◽

Krzysztof Janowicz ◽

Marta Dyszkiewicz-Konwińska ◽

Greg Hutchings ◽

Claudia Dompe ◽

...

Keyword(s):

Clinical Trials ◽

Animal Models ◽

Risk Evaluation ◽

Gene Editing ◽

Immunological Response ◽

Specific Gene ◽

Success Rates ◽

Treatment Resistant ◽

In Vitro Systems

Even though chemotherapy and immunotherapy emerged to limit continual and unregulated proliferation of cancer cells, currently available therapeutic agents are associated with high toxicity levels and low success rates. Additionally, ongoing multi-targeted therapies are limited only for few carcinogenesis pathways, due to continually emerging and evolving mutations of proto-oncogenes and tumor-suppressive genes. CRISPR/Cas9, as a specific gene-editing tool, is used to correct causative mutations with minimal toxicity, but is also employed as an adjuvant to immunotherapy to achieve a more robust immunological response. Some of the most critical limitations of the CRISPR/Cas9 technology include off-target mutations, resulting in nonspecific restrictions of DNA upstream of the Protospacer Adjacent Motifs (PAM), ethical agreements, and the lack of a scientific consensus aiming at risk evaluation. Currently, CRISPR/Cas9 is tested on animal models to enhance genome editing specificity and induce a stronger anti-tumor response. Moreover, ongoing clinical trials use the CRISPR/Cas9 system in immune cells to modify genomes in a target-specific manner. Recently, error-free in vitro systems have been engineered to overcome limitations of this gene-editing system. The aim of the article is to present the knowledge concerning the use of CRISPR Cas9 technique in targeting treatment-resistant cancers. Additionally, the use of CRISPR/Cas9 is aided as an emerging supplementation of immunotherapy, currently used in experimental oncology. Demonstrating further, applications and advances of the CRISPR/Cas9 technique are presented in animal models and human clinical trials. Concluding, an overview of the limitations of the gene-editing tool is proffered.

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Pathogenesis of Human Metapneumovirus Lung Infection in BALB/c Mice and Cotton Rats

Journal of Virology ◽

10.1128/jvi.79.14.8894-8903.2005 ◽

2005 ◽

Vol 79 (14) ◽

pp. 8894-8903 ◽

Cited By ~ 74

Author(s):

Marie-Ève Hamelin ◽

Kevin Yim ◽

Katie H. Kuhn ◽

Rose P. Cragin ◽

Marina Boukhvalova ◽

...

Keyword(s):

Animal Models ◽

Viral Replication ◽

Clinical Symptoms ◽

Small Animal ◽

Human Metapneumovirus ◽

Viral Loads ◽

Inflammatory Protein ◽

Cotton Rats ◽

Tract Infections ◽

Rats And Mice

ABSTRACT Human metapneumovirus (hMPV) is a newly described member of the Paramyxoviridae family causing acute respiratory tract infections, especially in young children. We studied the pathogenesis of this viral infection in two experimental small animal models (BALB/c mice and cotton rats). Significant viral replication in the lungs of both animals was found following an intranasal challenge of 108 50% tissue culture infectious doses (TCID50) and persisted for <2 and <3 weeks in the case of cotton rats and mice, respectively. Peak viral loads were found on day 5 postinfection in both mice (mean of 1.92 × 107 TCID50/g lung) and cotton rats (mean of 1.03 × 105 TCID50/g). Clinical symptoms consisting of breathing difficulties, ruffled fur, and weight loss were noted in mice only around the time of peak viral replication. Most significant pulmonary inflammatory changes and peak expression of macrophage inflammatory protein 1α, gamma interferon, and RANTES occurred at the time of maximal viral replication (day 5) in both models. Cellular infiltration occurred predominantly around and within alveoli and persisted for at least 21 days in mice, whereas it was more limited in time with more peribronchiolitis in cotton rats. Both animal models would be of great value in evaluating different therapeutic agents, as well as vaccine candidates against hMPV.

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Human organoid systems reveal in vitro correlates of fitness for SARS-CoV-2 B.1.1.7

10.1101/2021.05.03.441080 ◽

2021 ◽

Author(s):

Mart M Lamers ◽

Tim I Breugem ◽

Anna Z Mykytyn ◽

Yiquan Wang ◽

Nathalie Groen ◽

...

Keyword(s):

Animal Models ◽

Infectious Virus ◽

Replicative Fitness ◽

Human Airway ◽

Clade B ◽

B Virus ◽

In Vitro Systems ◽

Key Aspects ◽

New Phase

A new phase of the COVID-19 pandemic has started as several SARS-CoV-2 variants are rapidly emerging globally, raising concerns for increased transmissibility. As animal models and traditional in vitro systems may fail to model key aspects of the SARS-CoV-2 replication cycle, representative in vitro systems to assess variants phenotypically are urgently needed. We found that the British variant (clade B.1.1.7), compared to an ancestral SARS-CoV-2 clade B virus, produced higher levels of infectious virus late in infection and had a higher replicative fitness in human airway, alveolar and intestinal organoid models. Our findings unveil human organoids as powerful tools to phenotype viral variants and suggest extended shedding as a correlate of fitness for SARS-CoV-2.

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Feline Calicivirus Virulent Systemic Disease: Clinical Epidemiology, Analysis of Viral Isolates and in vitro Efficacy of Novel Antivirals in Australian Outbreaks

10.20944/preprints202108.0341.v1 ◽

2021 ◽

Author(s):

Matteo Bordicchia ◽

Tulio Machado Fumian ◽

Kate Van Brussel ◽

Alice G. Russo ◽

Maura Carrai ◽

...

Keyword(s):

Clinical Epidemiology ◽

Systemic Disease ◽

Feline Calicivirus ◽

Metagenomic Sequencing ◽

Event Analysis ◽

Amino Acid Residues ◽

Upper Respiratory Tract ◽

E Region ◽

Tract Disease

Feline calicivirus (FCV) causes upper respiratory tract disease (URTD) and sporadic outbreaks of virulent systemic disease (FCV-VSD). The basis for the increased pathogenicity of FCV-VSD viruses is incompletely understood, and antivirals for FCV have yet to be developed. We investigated the clinicoepidemiology and viral features of three FCV-VSD outbreaks in Australia and evaluated the in vitro efficacy of nitazoxanide (NTZ), 2’-C-methylcytidine (2CMC) and NITD-008 against FCV-VSD viruses. Overall mortality among 23 cases of FCV-VSD was 39%. Metagenomic sequencing identified five genetically distinct FCV lineages within the three outbreaks, all seemingly evolving in situ in Australia. Notably, no mutations that clearly distinguished FCV-URTD from FCV-VSD phenotypes were identified. One FCV-URTD strain likely originated from a recombination event. Analysis of seven amino acid residues from the hypervariable E region of the capsid in the cultured viruses provided no support for the contention that properties of these residues can reliably differentiate between the two pathotypes. On plaque reduction assays, dose-response inhibition of FCV-VSD was obtained with all antivirals at low micromolar concentrations; NTZ EC50, 0.4-0.6 µM, TI 21; 2CMC EC50, 2.7-5.3 µM, TI >18; NITD-008, 0.5 to 0.9 µM, TI >111. Investigation of these antivirals for treatment of FCV-VSD is warranted.

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Mastomys Species as Model Systems for Infectious Diseases

Viruses ◽

10.3390/v11020182 ◽

2019 ◽

Vol 11 (2) ◽

pp. 182 ◽

Cited By ~ 6

Author(s):

Daniel Hasche ◽

Frank Rösl

Keyword(s):

Animal Models ◽

Laboratory Mouse ◽

Model Systems ◽

Experimental Systems ◽

Non Melanoma Skin Cancer ◽

In Vitro Systems ◽

Mastomys Coucha ◽

First Time

Replacements of animal models by advanced in vitro systems in biomedical research, despite exceptions, are currently still not satisfactory in reproducing the whole complexity of pathophysiological mechanisms that finally lead to disease. Therefore, preclinical models are additionally required to reflect analogous in vivo situations as found in humans. Despite proven limitations of both approaches, only a combined experimental arrangement guarantees generalizability of results and their transfer to the clinics. Although the laboratory mouse still stands as a paradigm for many scientific discoveries and breakthroughs, it is mandatory to broaden our view by also using nontraditional animal models. The present review will first reflect the value of experimental systems in life science and subsequently describes the preclinical rodent model Mastomys coucha that—although still not well known in the scientific community—has a long history in research of parasites, bacteria, papillomaviruses and cancer. Using Mastomys, we could recently show for the first time that cutaneous papillomaviruses—in conjunction with UV as an environmental risk factor—induce squamous cell carcinomas of the skin via a “hit-and-run” mechanism. Moreover, Mastomys coucha was also used as a proof-of-principle model for the successful vaccination against non-melanoma skin cancer even under immunosuppressive conditions.

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Rhinitis, rhinosinusutus and phytotherapy

Medical Council ◽

10.21518/2079-701x-2021-6-12-19 ◽

2021 ◽

pp. 12-19

Author(s):

V. V. Shilenkova

Keyword(s):

Medicinal Product ◽

Clinical Symptoms ◽

Upper Respiratory Tract ◽

Herbal Medicinal Product ◽

Synthetic Drugs ◽

Herbal Medicinal ◽

Tract Infections ◽

Acute Rhinitis

Acute rhinitis and acute rhinosinusitis (ARS) have viral etiology in the most of cases, and their therapy is aimed at alleviating clinical symptoms and preventing new episodes. The indications for antibiotic therapy are severe bacterial ARS, ARS with complications, and recurrent bacterial ARS. Such a categorical approach is due to the increase of antibiotic resistance, which leads to the popularization of efficient phytotherapy. Modern herbal medical products comply with general recommendation and standards of efficacy, safety and quality, and their effectiveness has been proven in clinical trials along with synthetic drugs. In acute upper respiratory tract infections, herbal medical drugs stimulate the immune system, relieve clinical symptoms, and improve the patient’s quality of life. A significant emphasis in phytotherapy is given to complex drugs synthesized on the basis of phytoneering. One of such remedies is the herbal medicinal product containing the different parts of 5 medicinal herbs: Gentian root (Gentianae radix), Primrose flowers (with calyx) (Primulae flos (cum calycibus)), Common sorrel herb (Rumicis herba), Elder flowers (Sambuci flos) and Vervain herb (Verbenae herba). This herbal medicinal product shows secretolytic, secretomotor, antiinflammatory, antiviral and mild antibacterial farmacological effects. The article provides an analysis of studies in vitro and in vivo proving the anti-inflammatory effect of Sinupret®, its potentiating effect on nasal mucosa mucociliary transport as well as efficacy and safety in patients with rhinosinusitis.

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Dental optical coherence tomography: a comparison of two in vitro systems

Dentomaxillofacial Radiology ◽

10.1038/sj.dmfr.4600507 ◽

1999 ◽

Vol 29 (2) ◽

pp. 85-89 ◽

Cited By ~ 27

Author(s):

L L Otis ◽

B W Colston ◽

M J Everett ◽

H Nathel

Keyword(s):

Optical Coherence Tomography ◽

Optical Coherence ◽

In Vitro Systems

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