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      Seoul Virus Tropism and Pathology in Naturally Infected Feeder Rats

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          Abstract

          Seoul virus (SEOV) is a zoonotic orthohantavirus carried by black and brown rats, and can cause hemorrhagic fever with renal syndrome in humans. Human cases of SEOV virus infection have most recently been reported in the USA, United Kingdom, France and the Netherlands and were primarily associated with contact with pet rats and feeder rats. Infection of rats results in an asymptomatic but persistent infection. Little is known about the cell tropism of SEOV in its reservoir and most available data is based on experimental infection studies in which rats were inoculated via a route which does not recapitulate virus transmission in nature. Here we report the histopathological analysis of SEOV cell tropism in key target organs following natural infection of a cohort of feeder rats, comprising 19 adults and 11 juveniles. All adult rats in this study were positive for SEOV specific antibodies and viral RNA in their tissues. One juvenile rat was seropositive, but negative in the rRT-PCR. Of the 19 adult rats of which subsequently additional organs were tested, SEOV RNA was detected in all lungs, followed by kidney (79%) and liver (74%). Histopathologic changes associated with SEOV infection were primarily found in the liver, consistent with a pathological diagnosis of a mild hepatitis. In conclusion, natural SEOV infection results in mild inflammation of the liver in the absence of clinical disease.

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          Most cited references34

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          Hantaviruses--globally emerging pathogens.

          Hantaviruses are emerging zoonotic viruses which cause human disease in Africa, America, Asia, and Europe. This review summarizes the progress in hantavirus epidemiology and diagnostics during the previous decade. Moreover, we discuss the influence of ecological factors on the worldwide virus distribution and give an outlook on research perspectives for the next years.
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            Validation of an internally controlled one-step real-time multiplex RT-PCR assay for the detection and quantitation of dengue virus RNA in plasma.

            Dengue is mosquito-borne virus infection that annually causes ~50 million clinically apparent cases worldwide. An internally controlled one-step real-time multiplex RT-PCR assay was developed for detection and quantitation of DENV RNA in plasma sample by using specific primers and fluorogenic TaqMan probes. All primers and probes targeted sequences near the 3' end of the NS5 gene. The method comprised two multiplex assays and was validated for sensitivity, specificity, linearity, reproducibility and precision. An internal control template was spiked into each clinical specimen to provide quality assurance for each experimental step. The assay allowed for detection of between 0.5 and 3 infectious particles per mL, is rapid and has been operationally characterized in 287 Vietnamese dengue patients from two therapeutic intervention trials at the Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam. Copyright © 2011 Elsevier B.V. All rights reserved.
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              Hantaviruses direct endothelial cell permeability by sensitizing cells to the vascular permeability factor VEGF, while angiopoietin 1 and sphingosine 1-phosphate inhibit hantavirus-directed permeability.

              Hantaviruses infect human endothelial cells and cause two vascular permeability-based diseases: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Hantavirus infection alone does not permeabilize endothelial cell monolayers. However, pathogenic hantaviruses inhibit the function of alphav beta3 integrins on endothelial cells, and hemorrhagic disease and vascular permeability deficits are consequences of dysfunctional beta3 integrins that normally regulate permeabilizing vascular endothelial growth factor (VEGF) responses. Here we show that pathogenic Hantaan, Andes, and New York-1 hantaviruses dramatically enhance the permeability of endothelial cells in response to VEGF, while the nonpathogenic hantaviruses Prospect Hill and Tula have no effect on endothelial cell permeability. Pathogenic hantaviruses directed endothelial cell permeability 2 to 3 days postinfection, coincident with pathogenic hantavirus inhibition of alphav beta3 integrin functions, and hantavirus-directed permeability was inhibited by antibodies to VEGF receptor 2 (VEGFR2). These studies demonstrate that pathogenic hantaviruses, similar to alphav beta3 integrin-deficient cells, specifically enhance VEGF-directed permeabilizing responses. Using the hantavirus permeability assay we further demonstrate that the endothelial-cell-specific growth factor angiopoietin 1 (Ang-1) and the platelet-derived lipid mediator sphingosine 1-phosphate (S1P) inhibit hantavirus directed endothelial cell permeability at physiologic concentrations. These results demonstrate the utility of a hantavirus permeability assay and rationalize the testing of Ang-1, S1P, and antibodies to VEGFR2 as potential hantavirus therapeutics. The central importance of beta3 integrins and VEGF responses in vascular leak and hemorrhagic disease further suggest that altering beta3 or VEGF responses may be a common feature of additional viral hemorrhagic diseases. As a result, our findings provide a potential mechanism for vascular leakage after infection by pathogenic hantaviruses and the means to inhibit hantavirus-directed endothelial cell permeability that may be applicable to additional vascular leak syndromes.

                Author and article information

                Journal
                Viruses
                Viruses
                viruses
                Viruses
                MDPI
                1999-4915
                07 June 2019
                June 2019
                : 11
                : 6
                : 531
                Affiliations
                [1 ]Center for Infectious Disease Control, National Institute for Public Health and the Environment, 3720 BA Bilthoven, The Netherlands; Ankje.de.Vries@ 123456rivm.nl (A.d.V.); tabitha.hoornweg@ 123456rivm.nl (T.H.)
                [2 ]Department of Viroscience, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands; m.vanheteren-hemelop@ 123456erasmusmc.nl (M.v.H.); t.kuiken@ 123456erasmusmc.nl (T.K.); e.veldhuiskroeze@ 123456erasmusmc.nl (E.V.K.)
                Author notes
                [* ]Correspondence: miriam.maas@ 123456rivm.nl (M.M.); b.rockx@ 123456erasmusmc.nl (B.R.); Tel.: +31-302-744-712 (M.M.); +31-107-044-068 (B.R.)
                Author information
                https://orcid.org/0000-0003-0122-106X
                https://orcid.org/0000-0003-2463-027X
                Article
                viruses-11-00531
                10.3390/v11060531
                6630879
                31181690
                e0b15b42-e750-4775-85aa-9a2a0e1a6541
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 April 2019
                : 05 June 2019
                Categories
                Article

                Microbiology & Virology
                seoul virus,reservoir,tropism,inflammation
                Microbiology & Virology
                seoul virus, reservoir, tropism, inflammation

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