Abstract
Human immune system (HIS) mice are a subset of humanized mice that are generated by xenoengraftment of human immune cells or tissues and/or their progenitors into immunodeficient mice. Viral hemorrhagic fevers (VHFs) cause severe disease in humans, typically with high case fatality rates. HIS mouse studies have been performed to investigate the pathogenesis and immune responses to VHFs that must be handled in high-containment laboratory facilities. Here, we summarize studies on filoviruses, nairoviruses, phenuiviruses, and hantaviruses, and discuss the knowledge gained from using various HIS mouse models. Furthermore, we discuss the complexities of designing and interpreting studies utilizing HIS mice while highlighting additional questions about VHFs that can still be addressed using HIS mouse models.
Highlights
Viral hemorrhagic fevers (VHFs) are a diverse group of animal and human illnesses that cause severe multisystem dysfunction syndromes, often accompanied by damage to the vascular system and associated signs of hemorrhagic disease
Both B and T cells develop within the murine environment, so reconstitution can be sustained for approximately a year with little or no incidence of graft versus host disease (GVHD)
Filoviruses like Marburg virus (MARV) and ebolaviruses have been identified as the cause of small human VHF outbreaks since the 1960s and more recently have been the etiologic agents of large-scale outbreaks with high case fatality rates [3,45]
Summary
Viral hemorrhagic fevers (VHFs) are a diverse group of animal and human illnesses that cause severe multisystem dysfunction syndromes, often accompanied by damage to the vascular system and associated signs of hemorrhagic disease. VHFs are a diverse group of RNA viruses including filoviruses, bunyaviruses, arenaviruses, flaviviruses, and rhabdoviruses [1] Research of these highly pathogenic viral families is often limited to high-containment biosafety level 3 (BSL-3) or BSL-4 laboratories due to the severity of the resulting disease and lack of efficacious therapeutics or vaccines. The overall global burden of VHFs has historically been considered low compared to other diseases, such as influenza, human immunodeficiency virus, and malaria. It is substantial; annual cases of Lassa fever, for example, are estimated at 100,000–300,000 [2], and the 2013–2016 outbreak of Ebola virus (EBOV; species Zaire ebolavirus; family Filoviridae) in western Africa [3] along with the ongoing outbreak that began in 2018 in the Democratic Republic of Congo [4,5] highlight the potential for VHFs to cause large-scale international epidemics.
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