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      Hemorrhagic Fever-Causing Arenaviruses: Lethal Pathogens and Potent Immune Suppressors

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          Abstract

          Hemorrhagic fevers (HF) resulting from pathogenic arenaviral infections have traditionally been neglected as tropical diseases primarily affecting African and South American regions. There are currently no FDA-approved vaccines for arenaviruses, and treatments have been limited to supportive therapy and use of non-specific nucleoside analogs, such as Ribavirin. Outbreaks of arenaviral infections have been limited to certain geographic areas that are endemic but known cases of exportation of arenaviruses from endemic regions and socioeconomic challenges for local control of rodent reservoirs raise serious concerns about the potential for larger outbreaks in the future. This review synthesizes current knowledge about arenaviral evolution, ecology, transmission patterns, life cycle, modulation of host immunity, disease pathogenesis, as well as discusses recent development of preventative and therapeutic pursuits against this group of deadly viral pathogens.

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          Most cited references348

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          Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures.

          The interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. We reviewed this topic in 2000 [Goodbourn, S., Didcock, L. & Randall, R. E. (2000). J Gen Virol 81, 2341-2364] but, since then, a great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs. In the first part of this review, we describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. In the second part, we describe how viruses circumvent the IFN response. Here, we reflect upon possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, we briefly describe applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer.
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            The interferon response circuit: Induction and suppression by pathogenic viruses

            Type I interferons (IFN-α/β) are potent antiviral cytokines and modulators of the adaptive immune system. They are induced by viral infection or by double-stranded RNA (dsRNA), a by-product of viral replication, and lead to the production of a broad range of antiviral proteins and immunoactive cytokines. Viruses, in turn, have evolved multiple strategies to counter the IFN system which would otherwise stop virus growth early in infection. Here we discuss the current view on the balancing act between virus-induced IFN responses and the viral counterplayers.
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              Human dendritic cell subsets

              Dendritic cells are highly adapted to their role of presenting antigen and directing immune responses. Developmental studies indicate that DCs originate independently from monocytes and tissue macrophages. Emerging evidence also suggests that distinct subsets of DCs have intrinsic differences that lead to functional specialisation in the generation of immunity. Comparative studies are now allowing many of these properties to be more fully understood in the context of human immunology.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                13 March 2019
                2019
                : 10
                : 372
                Affiliations
                [1] 1Biochemistry, Molecular Biology, and Biophysics Graduate Program, University of Minnesota , St. Paul, MN, United States
                [2] 2Department of Veterinary and Biomedical Sciences, University of Minnesota , St. Paul, MN, United States
                Author notes

                Edited by: Constantinos Petrovas, Vaccine Research Center (NIAID), United States

                Reviewed by: Kartika Padhan, National Institutes of Health (NIH), United States; Takaaki Koma, Tokushima University, Japan

                *Correspondence: Hinh Ly hly@ 123456umn.edu

                This article was submitted to Viral Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2019.00372
                6424867
                30918506
                ea3ffa24-0dce-479a-adc5-9e04496c1315
                Copyright © 2019 Brisse and Ly.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 January 2019
                : 14 February 2019
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 420, Pages: 25, Words: 22822
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Categories
                Immunology
                Review

                Immunology
                arenaviruses,lassa fever,host-virus interactions,innate and adaptive immunity,viral immunology,viral pathogenesis,host defense

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