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      Transcriptional Immunoprofiling at the Tick-Virus-Host Interface during Early Stages of Tick-Borne Encephalitis Virus Transmission

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          Emerging and re-emerging diseases transmitted by blood feeding arthropods are significant global public health problems. Ticks transmit the greatest variety of pathogenic microorganisms of any blood feeding arthropod. Infectious agents transmitted by ticks are delivered to the vertebrate host together with saliva at the bite site. Tick salivary glands produce complex cocktails of bioactive molecules that facilitate blood feeding and pathogen transmission by modulating host hemostasis, pain/itch responses, wound healing, and both innate and adaptive immunity. In this study, we utilized Illumina Next Generation Sequencing to characterize the transcriptional immunoprofile of cutaneous immune responses to Ixodes ricinus transmitted tick-borne encephalitis virus (TBEV). A comparative immune gene expression analysis of TBEV-infected and uninfected tick feeding sites was performed. Our analysis reveals that ticks create an inflammatory environment at the bite site during the first 3 h of feeding, and significant differences in host responses were observed between TBEV-infected and uninfected tick feeding. Gene-expression analysis reveals modulation of inflammatory genes after 1 and 3 h of TBEV-infected tick feeding. Transcriptional levels of genes specific to chemokines and cytokines indicated a neutrophil-dominated immune response. Immunohistochemistry of the tick feeding site revealed that mononuclear phagocytes and fibroblasts are the primary target cells for TBEV infection and did not detect TBEV antigens in neutrophils. Together, the transcriptional and immunohistochemistry results suggest that early cutaneous host responses to TBEV-infected tick feeding are more inflammatory than expected and highlight the importance of inflammatory chemokine and cytokine pathways in tick-borne flavivirus transmission.

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          Most cited references 37

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          Tick-borne encephalitis.

          We review the epidemiological and clinical characteristics of tick-borne encephalitis, and summarise biological and virological aspects that are important for understanding the life-cycle and transmission of the virus. Tick-borne encephalitis virus is a flavivirus that is transmitted by Ixodes spp ticks in a vast area from western Europe to the eastern coast of Japan. Tick-borne encephalitis causes acute meningoencephalitis with or without myelitis. Morbidity is age dependent, and is highest in adults of whom half develop encephalitis. A third of patients have longlasting sequelae, frequently with cognitive dysfunction and substantial impairment in quality of life. The disease arises in patchy endemic foci in Europe, with climatic and ecological conditions suitable for circulation of the virus. Climate change and leisure habits expose more people to tick-bites and have contributed to the increase in number of cases despite availability of effective vaccines. The serological diagnosis is usually straightforward. No specific treatment for the disease exists, and immunisation is the main preventive measure.
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            An annotated catalog of salivary gland transcripts from Ixodes scapularis ticks.

            Over 8000 expressed sequence tags from six different salivary gland cDNA libraries from the tick Ixodes scapularis were analyzed. These libraries derive from feeding nymphs infected or not with the Lyme disease agent, Borrelia burgdorferi, from unfed adults, and from adults feeding on a rabbit for 6-12 h, 18-24 h, and 3-4 days. Comparisons of the several libraries led to identification of several significantly differentially expressed transcripts. Additionally, over 500 new predicted protein sequences are described, including several novel gene families unique to ticks; no function can be presently ascribed to most of these novel families. Among the housekeeping-associated transcripts, we highlight those enzymes associated with post translation modification of amino acids, particularly those forming sulfotyrosine, hydroxyproline, and carboxyl-glutamic acid. Results support the hypothesis that gene duplication, most possibly including genome duplications, is a major player in tick evolution.
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              Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection

              The molecular immunopathogenesis of West Nile virus (WNV) infection is poorly understood. Here, we characterize a mouse model for WNV using a subcutaneous route of infection and delineate leukocyte subsets and immunoregulatory factors present in the brains of infected mice. Central nervous system (CNS) expression of the chemokine receptor CCR5 and its ligand CCL5 was prominently up-regulated by WNV, and this was associated with CNS infiltration of CD4 + and CD8 + T cells, NK1.1 + cells and macrophages expressing the receptor. The significance of CCR5 in pathogenesis was established by mortality studies in which infection of CCR5 −/− mice was rapidly and uniformly fatal. In the brain, WNV-infected CCR5 −/− mice had increased viral burden but markedly reduced NK1.1 + cells, macrophages, and CD4 + and CD8 + T cells compared with WNV-infected CCR5+/+ mice. Adoptive transfer of splenocytes from WNV-infected CCR5 +/+ mice into infected CCR5 −/− mice increased leukocyte accumulation in the CNS compared with transfer of splenocytes from infected CCR5 −/− mice into infected CCR5 −/− mice, and increased survival to 60%, the same as in infected CCR5 +/+ control mice. We conclude that CCR5 is a critical antiviral and survival determinant in WNV infection of mice that acts by regulating trafficking of leukocytes to the infected brain.

                Author and article information

                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                01 December 2017
                : 7
                1Department of Pathology, The University of Texas Medical Branch , Galveston, TX, United States
                2Institute for Human Infections and Immunity, The University of Texas Medical Branch , Galveston, TX, United States
                3Center for Tropical Diseases, The University of Texas Medical Branch , Galveston, TX, United States
                4Institute of Zoology, Slovak Academy of Sciences , Bratislava, Slovakia
                5Department of Surgery, Center for Regenerative Medicine, Boston University and Boston Medical Center , Boston, MA, United States
                6Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch , Galveston, TX, United States
                Author notes

                Edited by: Jose De La Fuente, Instituto de Investigación en Recursos Cinegéticos (CSIC-UCLM-JCCM), Spain

                Reviewed by: Jianfeng Dai, Soochow University, China; Janakiram Seshu, University of Texas at San Antonio, United States; Nicholas Johnson, Animal Health and Veterinary Laboratories Agency, United Kingdom

                *Correspondence: Saravanan Thangamani sathanga@ 123456utmb.edu
                Copyright © 2017 Thangamani, Hermance, Santos, Slovak, Heinze, Widen and Kazimirova.

                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) or licensor 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.

                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 47, Pages: 12, Words: 7878
                Original Research

                Infectious disease & Microbiology

                tbev, flavivirus, tick, ixodes ricinus, cutaneous, immune response


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