Review Animal models for viral haemorrhagic fever D. Falzaran 1 , 2 , D.A. Bente 1 , * 1) Special Pathogens Programme, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada 2) Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada article info Article history: Available online 22 June 2015 abstract Viral haemorrhagic fever can be caused by one of a diverse group of viruses that come from four different families of RNA viruses. Disease severity can vary from mild self-limiting febrile illness to severe disease characterized by high fever, high-level viraemia, increased vascular permeability that can progress to shock, multi-organ failure and death. Despite the urgent need, effective treatments and preventative vaccines are currently lacking for the majority of these viruses. A number of factors preclude the effective study of these diseases in humans including the high virulence of the agents involved, the sporadic nature of outbreaks of these viruses, which are typically in geographically isolated areas with under- serviced diagnostic capabilities, and the requirements for high level bio-containment. As a result, animal models that accurately mimic human disease are essential for advancing our understanding of the pathogenesis of viral haemorrhagic fevers. Moreover, animal models for viral haemorrhagic fevers are necessary to test vaccines and therapeutic intervention strategies. Here, we present an overview of the animal models that have been established for each of the haemorrhagic fever viruses and identify which aspects of human disease are modelled. Furthermore, we discuss how experimental design consider- ations, such as choice of species and virus strain as well as route and dose of inoculation, have an in- fluence on animal model development. We also bring attention to some of the pitfalls that need to be avoided when extrapolating results from animal models. D. Falzaran, Clin Microbiol Infect 2019;21:e17 © 2016 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. The term viral haemorrhagic fever (VHF) describes a group of similar diseases caused by single-stranded enveloped RNA viruses from the following four taxonomic families: Arenaviridae, Bunya- viridae, Filoviridae and Flaviviridae. Despite a divergence in clinical features, all VHFs are characterized by fever, malaise and hypo- volaemia that can lead to shock, as well as coagulopathy that can result in bleeding. In spite of the name, haemorrhage is generally a minor feature of VHFs. Instead, an increase in vascular permeability (‘capillary leak’) due to a release of pro-inflammatory mediators is the main pathophysiological change. VHFs lead to numerous changes in clinical laboratory tests, none of which are specific to the diseases. Leucopenia and thrombocytopenia are frequently observed, and coagulation factors are variously reduced. VHFs present difficult challenges to pathophysiology research because they occur mainly in regions lacking modern medical infrastructure, and most of the experimental work with haemorrhagic fever (HF) viruses must be performed in one of the few Biosafety Level 4 (BSL-4) containment laboratories worldwide. As a result of the sporadic nature of human outbreaks, typically in remote locations, detailed clinical data are lacking so animal models for VHF are crucial, because most information on VHF pathogenesis comes from such studies. With the exception of dengue virus, HF viruses persist in nature in infection cycles that involve reservoir animals and are thought to not cause disease in these animals. Humans are considered ‘accidental’ hosts. However, after accidental transmission from the host, humans can transmit some of these viruses to one another. The transmission from the reservoir animal to humans can occur through direct physical contact, exposure to virus-containing ex- cretions, or bites from an infected vector such as mosquitoes or ticks. The geographic range of each disease therefore reflects that of the reservoir species and, for some, the vector. Reservoir ani- mals are generally not suitable animal models because the virus has evolutionarily adapted to the reservoir host and typically does not cause serious disease comparable to what is observed in humans. * Corresponding author. E-mail address: [email protected] (D.A. Bente). Contents lists available at ScienceDirect Clinical Microbiology and Infection journal homepage: www.clinicalmicrobiologyandinfection.com http://dx.doi.org/10.1111/1469-0691.12630 1198-743X/© 2016 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. Clinical Microbiology and Infection 21 (2019) e17ee27
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