Abstract
Junín virus (JUNV), an arenavirus, is the causative agent of Argentine hemorrhagic fever, an infectious human disease with 15–30% case fatality. The pathogenesis of AHF is still not well understood. Elevated levels of interferon and cytokines are reported in AHF patients, which might be correlated to the severity of the disease. However the innate immune response to JUNV infection has not been well evaluated. Previous studies have suggested that the virulent strain of JUNV does not induce IFN in human macrophages and monocytes, whereas the attenuated strain of JUNV was found to induce IFN response in murine macrophages via the TLR-2 signaling pathway. In this study, we investigated the interaction between JUNV and IFN pathway in human epithelial cells highly permissive to JUNV infection. We have determined the expression pattern of interferon-stimulated genes (ISGs) and IFN-β at both mRNA and protein levels during JUNV infection. Our results clearly indicate that JUNV infection activates the type I IFN response. STAT1 phosphorylation, a downstream marker of activation of IFN signaling pathway, was readily detected in JUNV infected IFN-competent cells. Our studies also demonstrated for the first time that RIG-I was required for IFN production during JUNV infection. IFN activation was detected during infection by either the virulent or attenuated vaccine strain of JUNV. Curiously, both virus strains were relatively insensitive to human IFN treatment. Our studies collectively indicated that JUNV infection could induce host type I IFN response and provided new insights into the interaction between JUNV and host innate immune system, which might be important in future studies on vaccine development and antiviral treatment.
Highlights
Arenaviruses are enveloped viruses with a bi-segmented negative strand RNA genome [1]
Junın virus (JUNV), which is endemic to the Argentinean Pampas region, is the causative agent of Argentine hemorrhagic fever (AHF), a severe illness with hemorrhagic and neurological manifestations and with a case fatality of 15–30%
Clinical studies demonstrate that elevated levels of interferon and cytokines are produced in AHF patients, which might be correlated to the severity of disease
Summary
Arenaviruses are enveloped viruses with a bi-segmented negative strand RNA genome [1]. The viral S segment RNA encodes the viral glycoprotein precursor (GPC) and the nucleoprotein (NP). 11 kDa) RING finger protein Z, the latter representing arenavirus counterpart of the matrix protein found in many other negative strand RNA viruses [8,9,10]. Infection in humans occurs usually through mucosal exposure to aerosols or by direct contact of abraded skin with infectious materials and may result in severe diseases such as hemorrhagic fever (HF). JUNV, an agent handled mandatorily in a high-containment biosafety level 4 facility, causes Argentine hemorrhagic fever (AHF), a highly infectious human disease with 15–30% case fatality [13,14,15,16]. Despite extensive studies in the past, the pathogenesis of HF arenaviruses remains largely uncharacterized
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