Combatting the world's deadliest infections using groundbreaking human-mimetic tools

(June 24th 2019) - A new article published today in the journal Frontiers in Cellular and Infection Microbiology shows that research built around human-mimetic [1] tools are more likely to succeed in the search for effective treatments for and prevention of flavivirus infection as compared to research using monkeys or other animals as laboratory models. The study, led by Dr. David Pamies at the University of Lausanne, with researchers at Johns Hopkins University and the National Institute of Allergy and Infectious Diseases' Vaccines Research Center in the United States, includes a comprehensive review of the models used to study deadly mosquito-borne flaviviruses (MBF) such as dengue fever and the Zika virus, known to cause neurological disease in humans [2].

The authors report that the host specificity of viral diseases presents a challenge for studying these human viruses in animals. Vaccines that had proved successful in primate tests have failed in human trials [3], leading to intense research using knockout and humanised transgenic mice. Thus, human genes relevant to the capacity of the virus to infect humans have been inserted into mice, but these modified animals are still mice, and the authors appreciate the drawbacks to this approach: "... several factors are recognized to influence the susceptibility of mice to MBF infection that limit applicability to humans." For example, mice fail to display human disease symptoms if bitten by an infected mosquito (the human route of infection), and the mouse immune response varies depending on the animal's age. Furthermore, the experiments are not reproducible in different laboratories - often an issue in animal experiments [4].

Dr. Pamies and colleagues recommend "a future of MBF research with less reliance on primate and rodent models and an increase in in vitro and in silico studies [5]. The emergence of new technologies (e.g. induced pluripotent stem cell models, organotypic cultures, and high throughput in silico screening) will help to better predict human pathogenesis and drug efficacy. We believe that harmonization of methods and centralization of data, together with combining different approaches to reach a common objective, are crucial to better understand MBF infection and neuropathogenesis and obtain clinical solutions."

The authors further propose that MBF research adopt best non-animal methodology practices from other research fields, applying advances such as novel brain-specific organoids, multi-cell brain spheroid cultures [6], blood-brain barrier models and in silico mathematical modelling for viral replication, disease transmission and vaccine development.

The review, entitled 'A roadmap for 21st century models to study mosquito-borne flavivirus neuropathogenesis, prevention, and treatment', is available HERE. Funding for this review was provided by Humane Society International as part of the Biomedical Research for the 21st Century Collaboration.

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Media Contact: Lindsay Marshall, +44 (0)7719531675, lmarshall@hsi.org

Notes to Editor:

1. Human-mimetic tools are methods used for research that do not rely on animals or animal testing. They range from straightforward techniques, such as culture of human cells, to more sophisticated methods - like those employing human stem cells to create organ models. The human-mimetic toolbox would also include in silico methodologies, use of human volunteers, gene analysis studies, computer-based modelling, pathways-based approaches and microphysiological systems.

2. The Aedes aegypti mosquito can transmit some of the deadliest diseases in the world, including the flaviviruses dengue and Zika. Over half the global population inhabit areas where this mosquito species is present and more than 3.6 billion people are at risk of infection with dengue virus, where complications can be fatal. Infection with the Zika virus causes a mild disease but has devastating effects on pregnant women that may result in babies born with microcephaly - small heads and underdeveloped brains. These viruses are a huge health burden on the countries in which they are endemic and also pose a threat for visiting travellers.

3. Non-human primates have traditionally been used to study human viruses, especially in preclinical animal vaccine research and antiviral drug development. Protective efficacy of novel vaccines for the flaviviruses has been demonstrated in primates for dengue and Zika viruses but these preclinical successes have not translated into human clinical efficacy.

4. It is notoriously difficult to replicate the results of animal experiments in different labs, leading to the so-called reproducibility crisis. This has been attributed to various different factors and led to the creation of publication guidelines for animal studies. Those guidelines, however, have not improved the issue and still fail to address the species differences that exist between animals used in research and the species of interest - the human.

5. Analysis carroed out for this review revealed that in vivo (animal) models of MBF infection are still the most commonly used approach, with over 75% of articles retrieved from PubMed in the review's time frame (2001 to 2017) employing animal models. However, in 2017, the search retrieved more in vitro studies than in vivo, indicating an upswing in the use of non-animal methods for flavivirus research.

6. Neurospheres and organoids are the most popular 3D cultures used to study viral infection. Neurospheres consist of one cell type, such as neural precursors, neurons or other CNS cells whereas organoid cultures are composed of multiple cell types and represent some aspect of organ structure and function.

The Biomedical Research for the 21st Century (BioMed21) Collaboration brings together scientists and institutions from across Europe, Asia and the Americas who share a vision of a new, human-focused paradigm in health research. Online at biomed21.org.

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