Type I interferon underlies severe disease associated with Junín virus infection in mice.

Eric J Sefing,Brian B Gowen,Arnaud J Van Wettere,Kevin W Bailey,Brady T Hickerson,Manuel L Penichet

doi:10.7554/elife.55352

Eric J Sefing, Brian B Gowen + Show 4 more

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https://doi.org/10.7554/elife.55352

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Abstract

Junín virus (JUNV) is one of five New World mammarenaviruses (NWMs) that causes fatal hemorrhagic disease in humans and is the etiological agent of Argentine hemorrhagic fever (AHF). The pathogenesis underlying AHF is poorly understood; however, a prolonged, elevated interferon-α (IFN-α) response is associated with a negative disease outcome. A feature of all NWMs that cause viral hemorrhagic fever is the use of human transferrin receptor 1 (hTfR1) for cellular entry. Here, we show that mice expressing hTfR1 develop a lethal disease course marked by an increase in serum IFN-α concentration when challenged with JUNV. Further, we provide evidence that the type I IFN response is central to the development of severe JUNV disease in hTfR1 mice. Our findings identify hTfR1-mediated entry and the type I IFN response as key factors in the pathogenesis of JUNV infection in mice.

Highlights

The etiological agents of the complex of South American arenaviral hemorrhagic fevers are a group of closely related New World mammarenaviruses (NWMs) including Junın, Machupo, Guanarito, Sabiaand Chapare
Junın virus (JUNV) disease was observed in the human transferrin receptor 1 (hTfR1) HET mice but to a lesser degree with the mice exhibiting stagnated weight gain beginning on day 9 p.i with a single animal requiring euthanasia due to severe neurologic signs on day 14 p.i
Species known to be susceptible to disease when challenged with pathogenic NWMs express TfR1 orthologs capable of mediating attachment and cellular entry (Helguera et al, 2012; Hickerson et al, 2020)

Summary

Introduction

The etiological agents of the complex of South American arenaviral hemorrhagic fevers are a group of closely related New World mammarenaviruses (NWMs) including Junın, Machupo, Guanarito, Sabiaand Chapare. These viruses are maintained in nature through persistent infections of their respective host rodent species (Salazar-Bravo et al, 2002). The case-fatality rate of AHF can be as high as 30% in untreated individuals and the only countermeasures available for the prevention and treatment of severe JUNV infections are the Candid #1 vaccine and convalescent plasma (Enria et al, 2008). Neither has been approved for use outside of the area of endemicity and recent studies suggest that reversion to virulence by the vaccine virus can occur through a single nucleotide

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