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TBFV infections cause thousands of human encephalitis cases worldwide annually. In the United States, human TBFV infections with Powassan virus (POWV) are increasing and have a fatality rate of 10 to 30%. Additionally, Langat virus (LGTV) is a TBFV of low neurovirulence and is used as a model TBFV. TBFV replication and dissemination within<jats:italic>I.\u00a0scapularis<\/jats:italic>organs are poorly characterized, and a deeper understanding of virus biology in this vector may inform effective countermeasures to reduce TBFV transmission. Here, we describe short-term,<jats:italic>I.\u00a0scapularis<\/jats:italic>organ culture models of TBFV infection.<jats:italic>Ex vivo<\/jats:italic>organs were metabolically active for 9 to 10\u00a0days and were permissive to LGTV and POWV replication. Imaging and videography demonstrated replication and spread of green fluorescent protein-expressing LGTV in the organs. Immunohistochemical staining confirmed LGTV envelope and POWV protein synthesis within the infected organs. LGTV- and POWV-infected organs produced infectious LGTV and POWV; thus, the<jats:italic>ex vivo<\/jats:italic>cultures were suitable for study of virus replication in individual organs. LGTV- and POWV-infected midgut and salivary glands were subjected to double-stranded RNA (dsRNA) transfection with dsRNA to the LGTV 3\u2032 untranslated region (UTR), which reduced infectious LGTV and POWV replication, providing a proof-of-concept use of RNA interference in<jats:italic>I.\u00a0scapularis<\/jats:italic>organ cultures to study the effects on TBFV replication. The results contribute important information on TBFV localization within<jats:italic>ex vivo I.\u00a0scapularis<\/jats:italic>organs and provide a significant translational tool for evaluating recombinant, live vaccine candidates and potential tick transcripts and proteins for possible therapeutic use and vaccine development to reduce TBFV transmission.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Tick-borne flavivirus (TBFV) infections cause neurological and\/or hemorrhagic disease in humans worldwide. There are currently no licensed therapeutics or vaccines against Powassan virus (POWV), the only TBFV known to circulate in North America. Evaluating tick vector targets for antitick vaccines directed at reducing TBFV infection within the arthropod vector is a critical step in identifying efficient approaches to controlling TBFV transmission. This study characterized infection of female<jats:italic>Ixodes scapularis<\/jats:italic>tick organ cultures of midgut, salivary glands, and synganglion with the low-neurovirulence Langat virus (LGTV) and the more pathogenic POWV. Cell types of specific organs were susceptible to TBFV infection, and a difference in LGTV and POWV replication was noted in TBFV-infected organs. This tick organ culture model of TBFV infection will be useful for various applications, such as screening of tick endogenous dsRNA corresponding to potential control targets within midgut and salivary glands to confirm restriction of TBFV infection.<\/jats:p>","DOI":"10.1128\/mbio.01255-17","type":"journal-article","created":{"date-parts":[[2017,8,23]],"date-time":"2017-08-23T00:10:50Z","timestamp":1503447050000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":36,"title":["Flavivirus Infection of<i>Ixodes scapularis<\/i>(Black-Legged Tick)<i>Ex Vivo<\/i>Organotypic Cultures and Applications for Disease Control"],"prefix":"10.1128","volume":"8","author":[{"given":"Jeffrey M.","family":"Grabowski","sequence":"first","affiliation":[{"name":"Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin A.","family":"Tsetsarkin","sequence":"additional","affiliation":[{"name":"Neurotropic Flaviviruses Section, Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Long","sequence":"additional","affiliation":[{"name":"Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana P.","family":"Scott","sequence":"additional","affiliation":[{"name":"Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Rosenke","sequence":"additional","affiliation":[{"name":"Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom G.","family":"Schwan","sequence":"additional","affiliation":[{"name":"Laboratory of Zoonotic Pathogens, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luwanika","family":"Mlera","sequence":"additional","affiliation":[{"name":"Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle K.","family":"Offerdahl","sequence":"additional","affiliation":[{"name":"Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"Pletnev","sequence":"additional","affiliation":[{"name":"Neurotropic Flaviviruses Section, Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marshall E.","family":"Bloom","sequence":"additional","affiliation":[{"name":"Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2012.07.003"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182004005967"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ento.53.103106.093429"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2672.2009.04598.x"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1705.101530"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1089\/vbz.2010.0091"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2009.08.024"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cll.2010.01.002"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-3527(03)61008-0"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.4.1746"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0044703"},{"key":"e_1_3_3_13_2","first-page":"89","article-title":"Vaccination of human volunteers against Russian spring-summer (RSS) virus complex with attenuated Langat E5 virus","volume":"42","author":"Price WH","year":"1970","unstructured":"Price WH Thind IS Teasdall RD O\u2019Leary W . 1970. 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