Date of Award:
Doctor of Philosophy (PhD)
Animal, Dairy, and Veterinary Sciences
Brian B. Gowen
E. Bart Tarbet
Several New World mammarenaviruses (NWM) are able to cause life-threatening hemorrhagic disease in humans. These agents use human transferrin receptor 1 (hTfR1), the main protein involved in cellular uptake of iron, to infect cells. Furthermore, use of hTfR1 correlates with the ability of these viruses to cause severe disease in humans.The most prevalent pathogenic NWM is Junín virus (JUNV), which is the etiological agent of Argentine hemorrhagic fever (AHF).The pathogenesis of AHF is poorly understood. A cardinal feature of severe cases of AHF is a prolonged increase of serum interferon-a (IFN-a) concentration. This increase is hypothesized to play a role in the development of severe AHF but definitive proof has yet to be reported. Untreated cases of AHF can have a mortality rate as high as 30%. Countermeasures for JUNV infection are limited to the Candid #1 vaccine and convalescent sera recovered from AHF survivors.
Small rodent species, such as mice, are commonly used to model viral diseases and for the evaluation of promising prophylactic and therapeutic countermeasures. Currently, there are few small animal models to study JUNV. This is because most common laboratory rodents, such as mice and hamsters, do not develop severe disease when challenged with JUNV. In contrast, guinea pigs do develop severe disease when infected with JUNV. While guinea pigs have been used extensively to study JUNV infection, use of this model is hindered by the lack of understanding of what factors drive the development of severe disease.
The research described here was undertaken to better understand the underlying factors driving the development of severe pathogenic NWM disease. To further understand why guinea pigs are susceptible to lethal JUNV disease, we determined if guinea pig TfR1 (gpTfR1) serves as a receptor for the pathogenic NWM. Our results show that expression of gpTfR1 enhances pathogenic NWM infection to levels comparable to hTfR1. We also investigated if expression of hTfR1 in mice would render them susceptible to severe JUNV disease. We found that hTfR1+/+ mice challenged with JUNV developed a lethal disease course marked by an increase in serum IFN-a concentration. Because this finding mirrored those of severe AHF cases, we investigate the role of the type I IFN response in the development of JUNV disease and found that eliminating this response prevented lethal disease in the JUNV-challenged hTfR1+/+ mice. Last, we determined if blockade of virus binding to hTfR1 prevents lethal JUNV disease in hTfR1+/+ mice. We found that administration of anti-hTfR1 monoclonal antibodies to JUNV-challenged hTfR1+/+ mice can prevent lethal disease, demonstrating the therapeutic potential of this type of intervention.
Hickerson, Brady T., "New World Mammarenaviral Hemorrhagic Fever Virus Determinants of Infection and Disease" (2020). All Graduate Theses and Dissertations. 7814.
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