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      Persistent Crimean-Congo hemorrhagic fever virus infection in the testes and within granulomas of non-human primates with latent tuberculosis

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          Abstract

          Crimean-Congo hemorrhagic fever (CCHF) is the most medically important tick-borne viral disease of humans and tuberculosis is the leading cause of death worldwide by a bacterial pathogen. These two diseases overlap geographically, however, concurrent infection of CCHF virus (CCHFV) with mycobacterial infection has not been assessed nor has the ability of virus to persist and cause long-term sequela in a primate model. In this study, we compared the disease progression of two diverse strains of CCHFV in the recently described cynomolgus macaque model. All animals demonstrated signs of clinical illness, viremia, significant changes in clinical chemistry and hematology values, and serum cytokine profiles consistent with CCHF in humans. The European and Asian CCHFV strains caused very similar disease profiles in monkeys, which demonstrates that medical countermeasures can be evaluated in this animal model against multiple CCHFV strains. We identified evidence of CCHFV persistence in the testes of three male monkeys that survived infection. Furthermore, the histopathology unexpectedly revealed that six additional animals had evidence of a latent mycobacterial infection with granulomatous lesions. Interestingly, CCHFV persisted within the granulomas of two animals. This study is the first to demonstrate the persistence of CCHFV in the testes and within the granulomas of non-human primates with concurrent latent tuberculosis. Our results have important public health implications in overlapping endemic regions for these emerging pathogens.

          Author summary

          CCHF is an emerging tick-borne viral disease that is endemic across much of Africa and Asia, and parts of Europe where its range and exposure risk to human populations is expanding. Tuberculosis threatens millions of lives world-wide and is the leading cause of death due to a bacterial pathogen. Concurrent mycobacterial infection with other infectious diseases has been described, but not for CCHFV despite the geographic overlap of these two pathogens. During our study we unexpectedly determined that some of the animals had latent tuberculosis and that CCHFV can persist within the granulomas. Furthermore, our study provides the first direct evidence that CCHFV can replicate and persist in the male genital tract, which has important implications for human sexual transmission. The ability of viral RNA to persist in immune-privileged sites or fluids has been described with increasing frequency for other emerging infectious diseases and can cause a burden on public health. This provides the impetus to utilize the model described here to better understand the mechanisms of CCHFV persistence and its effect on the development of long-term sequelae.

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          Crimean-Congo haemorrhagic fever

          Summary Crimean-Congo haemorrhagic fever (CCHF) is an often fatal viral infection described in about 30 countries, and it has the most extensive geographic distribution of the medically important tickborne viral diseases, closely approximating the known global distribution of Hyalomma spp ticks. Human beings become infected through tick bites, by crushing infected ticks, after contact with a patient with CCHF during the acute phase of infection, or by contact with blood or tissues from viraemic livestock. Clinical features commonly show a dramatic progression characterised by haemorrhage, myalgia, and fever. The levels of liver enzymes, creatinine phosphokinase, and lactate dehydrogenase are raised, and bleeding markers are prolonged. Infection of the endothelium has a major pathogenic role. Besides direct infection of the endothelium, indirect damage by viral factors or virus-mediated host-derived soluble factors that cause endothelial activations and dysfunction are thought to occur. In diagnosis, enzyme-linked immunoassay and real-time reverse transcriptase PCR are used. Early diagnosis is critical for patient therapy and prevention of potential nosocomial infections. Supportive therapy is the most essential part of case management. Recent studies suggest that ribavirin is effective against CCHF, although definitive studies are not available. Health-care workers have a serious risk of infection, particularly during care of patients with haemorrhages from the nose, mouth, gums, vagina, and injection sites. Simple barrier precautions have been reported to be effective.
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            Effects of Climate Change on Ticks and Tick-Borne Diseases in Europe

            Zoonotic tick-borne diseases are an increasing health burden in Europe and there is speculation that this is partly due to climate change affecting vector biology and disease transmission. Data on the vector tick Ixodes ricinus suggest that an extension of its northern and altitude range has been accompanied by an increased prevalence of tick-borne encephalitis. Climate change may also be partly responsible for the change in distribution of Dermacentor reticulatus. Increased winter activity of I. ricinus is probably due to warmer winters and a retrospective study suggests that hotter summers will change the dynamics and pattern of seasonal activity, resulting in the bulk of the tick population becoming active in the latter part of the year. Climate suitability models predict that eight important tick species are likely to establish more northern permanent populations in a climate-warming scenario. However, the complex ecology and epidemiology of such tick-borne diseases as Lyme borreliosis and tick-borne encephalitis make it difficult to implicate climate change as the main cause of their increasing prevalence. Climate change models are required that take account of the dynamic biological processes involved in vector abundance and pathogen transmission in order to predict future tick-borne disease scenarios.
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              Persistence and genetic stability of Ebola virus during the outbreak in Kikwit, Democratic Republic of the Congo, 1995.

              Ebola virus persistence was examined in body fluids from 12 convalescent patients by virus isolation and reverse transcription-polymerase chain reaction (RT-PCR) during the 1995 Ebola hemorrhagic fever outbreak in Kikwit, Democratic Republic of the Congo. Virus RNA could be detected for up to 33 days in vaginal, rectal, and conjunctival swabs of 1 patient and up to 101 days in the seminal fluid of 4 patients. Infectious virus was detected in 1 seminal fluid sample obtained 82 days after disease onset. Sequence analysis of an RT-PCR fragment of the most variable region of the glycoprotein gene amplified from 9 patients revealed no nucleotide changes. The patient samples were selected so that they would include some from a suspected line of transmission with at least three human-to-human passages, some from 5 survivors and 4 deceased patients, and 2 from patients who provided multiple samples through convalescence. There was no evidence of different virus variants cocirculating during the outbreak or of genetic variation accumulating during human-to-human passage or during prolonged persistence in individual patients.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: Methodology
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Methodology
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Methodology
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                26 September 2019
                September 2019
                : 15
                : 9
                : e1008050
                Affiliations
                [1 ] Virology Division, U.S. Army Medical Research Institute of Infectious Diseases, Ft. Detrick, Maryland, United States of America
                [2 ] Diagnostic Systems Division, U.S. Army Medical Research Institute of Infectious Diseases, Ft. Detrick, Maryland, United States of America
                [3 ] Pathology Division, U.S. Army Medical Research Institute of Infectious Diseases, Ft. Detrick, Maryland, United States of America
                [4 ] Headquarters Division, U.S. Army Medical Research Institute of Infectious Diseases, Ft. Detrick, Maryland, United States of America
                Karolinska Institute, SWEDEN
                Author notes

                The authors have declared that no competing interests exist.

                [¤]

                Current address: Immunodiagnostics Department, Biological Defense Research Directorate, Naval Medical Research Center, Ft. Detrick, MD, United States of America

                Author information
                http://orcid.org/0000-0002-0719-523X
                http://orcid.org/0000-0003-3034-6400
                http://orcid.org/0000-0002-9709-313X
                http://orcid.org/0000-0003-2977-1434
                http://orcid.org/0000-0002-6467-2012
                http://orcid.org/0000-0003-0126-9581
                http://orcid.org/0000-0003-3225-6599
                http://orcid.org/0000-0002-2854-9308
                http://orcid.org/0000-0002-7999-7397
                http://orcid.org/0000-0002-5026-0404
                Article
                PPATHOGENS-D-19-00458
                10.1371/journal.ppat.1008050
                6782109
                31557262
                964363bf-20ab-4bc6-8652-e3a49016eedc

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 11 March 2019
                : 27 August 2019
                Page count
                Figures: 6, Tables: 0, Pages: 22
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Biology and life sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Primates
                Monkeys
                Old World monkeys
                Macaque
                Medicine and health sciences
                Tropical diseases
                Neglected tropical diseases
                Viral hemorrhagic fevers
                Crimean-Congo hemorrhagic fever
                Medicine and health sciences
                Infectious diseases
                Viral diseases
                Viral hemorrhagic fevers
                Crimean-Congo hemorrhagic fever
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                Granulomas
                Biology and Life Sciences
                Immunology
                Immune Cells
                Granulomas
                Medicine and Health Sciences
                Immunology
                Immune Cells
                Granulomas
                Biology and Life Sciences
                Organisms
                Bacteria
                Actinobacteria
                Mycobacterium Tuberculosis
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Fevers
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Fevers
                Medicine and Health Sciences
                Infectious Diseases
                Viral Diseases
                Viremia
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Cytokines
                Medicine and Health Sciences
                Physiology
                Immune Physiology
                Cytokines
                Biology and Life Sciences
                Immunology
                Immune System
                Innate Immune System
                Cytokines
                Medicine and Health Sciences
                Immunology
                Immune System
                Innate Immune System
                Cytokines
                Biology and Life Sciences
                Developmental Biology
                Molecular Development
                Cytokines
                Medicine and Health Sciences
                Hematology
                Custom metadata
                vor-update-to-uncorrected-proof
                2019-10-08
                All relevant data are within the manuscript and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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