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      Epidemiology and Immune Pathogenesis of Viral Sepsis

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          Abstract

          Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis can be caused by a broad range of pathogens; however, bacterial infections represent the majority of sepsis cases. Up to 42% of sepsis presentations are culture negative, suggesting a non-bacterial cause. Despite this, diagnosis of viral sepsis remains very rare. Almost any virus can cause sepsis in vulnerable patients (e.g., neonates, infants, and other immunosuppressed groups). The prevalence of viral sepsis is not known, nor is there enough information to make an accurate estimate. The initial standard of care for all cases of sepsis, even those that are subsequently proven to be culture negative, is the immediate use of broad-spectrum antibiotics. In the absence of definite diagnostic criteria for viral sepsis, or at least to exclude bacterial sepsis, this inevitably leads to unnecessary antimicrobial use, with associated consequences for antimicrobial resistance, effects on the host microbiome and excess healthcare costs. It is important to understand non-bacterial causes of sepsis so that inappropriate treatment can be minimised, and appropriate treatments can be developed to improve outcomes. In this review, we summarise what is known about viral sepsis, its most common causes, and how the immune responses to severe viral infections can contribute to sepsis. We also discuss strategies to improve our understanding of viral sepsis, and ways we can integrate this new information into effective treatment.

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          Most cited references191

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          Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

          Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-alpha in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.
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            RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.

            Double-stranded RNA (dsRNA) produced during viral replication is believed to be the critical trigger for activation of antiviral immunity mediated by the RNA helicase enzymes retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We showed that influenza A virus infection does not generate dsRNA and that RIG-I is activated by viral genomic single-stranded RNA (ssRNA) bearing 5'-phosphates. This is blocked by the influenza protein nonstructured protein 1 (NS1), which is found in a complex with RIG-I in infected cells. These results identify RIG-I as a ssRNA sensor and potential target of viral immune evasion and suggest that its ability to sense 5'-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.
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              Avian flu: influenza virus receptors in the human airway.

              Although more than 100 people have been infected by H5N1 influenza A viruses, human-to-human transmission is rare. What are the molecular barriers limiting human-to-human transmission? Here we demonstrate an anatomical difference in the distribution in the human airway of the different binding molecules preferred by the avian and human influenza viruses. The respective molecules are sialic acid linked to galactose by an alpha-2,3 linkage (SAalpha2,3Gal) and by an alpha-2,6 linkage (SAalpha2,6Gal). Our findings may provide a rational explanation for why H5N1 viruses at present rarely infect and spread between humans although they can replicate efficiently in the lungs.
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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
                27 September 2018
                2018
                : 9
                : 2147
                Affiliations
                [1] 1Oxford Vaccine Group, Department of Paediatrics, University of Oxford , Oxford, United Kingdom
                [2] 2National Institute for Health Research, Oxford Biomedical Research Centre , Oxford, United Kingdom
                [3] 3Department of Paediatrics, St George's University Hospitals NHS Foundation Trust , London, United Kingdom
                Author notes

                Edited by: Luregn J. Schlapbach, The University of Queensland, Australia

                Reviewed by: John R. Teijaro, The Scripps Research Institute, United States; Paul Fisch, Universitätsklinikum Freiburg, Germany

                *Correspondence: Gu-Lung Lin gu-lung.lin@ 123456paediatrics.ox.ac.uk

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

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2018.02147
                6170629
                30319615
                c994065b-e90a-4d1b-b577-5cc1fd5369d7
                Copyright © 2018 Lin, McGinley, Drysdale and Pollard.

                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 May 2018
                : 30 August 2018
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 282, Pages: 21, Words: 20638
                Categories
                Immunology
                Review

                Immunology
                viral sepsis,epidemiology,immune pathogenesis,herpes simplex virus,human enterovirus,human parechovirus,influenza virus,dengue virus

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