{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T02:49:27Z","timestamp":1793328567729,"version":"4.5.0"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T00:00:00Z","timestamp":1568160000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T00:00:00Z","timestamp":1568160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011890","name":"Marie Bashir Institute, University of Sydney","doi-asserted-by":"crossref","award":["Seed Funding"],"award-info":[{"award-number":["Seed Funding"]}],"id":[{"id":"10.13039\/501100011890","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neuroinflammation"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Until the end of the twentieth century, Zika virus (ZIKV) was thought to cause a mostly mild, self-limiting disease in humans. However, as the geographic distribution of ZIKV has shifted, so too has its pathogenicity. Modern-day ZIKV infection is now known to cause encephalitis, acute disseminated encephalomyelitis, and Guillain-Barr\u00e9 syndrome in otherwise healthy adults. Nevertheless, the underlying pathogenetic mechanisms responsible for this shift in virulence remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we investigated the contribution of the innate versus the adaptive immune response using a new mouse model involving intracranial infection of adult immunocompetent mice with a moderately low dose of ZIKV MR766. To determine the contribution of type I interferons (IFN-Is) and adaptive immune cells, we also studied mice deficient for the IFN-I receptor 1 (<jats:italic>Ifnar1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) and recombination-activating gene 1 (<jats:italic>Rag1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that intracranial infection with ZIKV resulted in lethal encephalitis. In wild-type mice, ZIKV remained restricted predominantly to the central nervous system (CNS) and infected neurons, whereas astrocytes and microglia were spared. Histological and molecular analysis revealed prominent activation of resident microglia and infiltrating monocytes that were accompanied by an expression of pro-inflammatory cytokines. The disease was independent of T and B cells. Importantly, unlike peripheral infection, IFN-Is modulated but did not protect from infection and lethal disease. Lack of IFN-I signaling resulted in spread of the virus, generalized inflammatory changes, and accelerated disease onset.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Using intracranial infection of immunocompetent wild-type mice with ZIKV, we demonstrate that in contrast to the peripheral immune system, the CNS is susceptible to infection and responds to ZIKV by initiating an antiviral immune response. This response is dominated by resident microglia and infiltrating monocytes and macrophages but does not require T or B cells. Unlike in the periphery, IFN-Is in the CNS cannot prevent the establishment of infection. Our findings show that ZIKV encephalitis in mice is dependent on the innate immune response, and adaptive immune cells play at most a minor role in disease pathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12974-019-1566-5","type":"journal-article","created":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T15:02:57Z","timestamp":1568214177000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Zika virus encephalitis in immunocompetent mice is dominated by innate immune cells and does not require T or B cells"],"prefix":"10.1186","volume":"16","author":[{"given":"Emina","family":"Hayashida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng Lung","family":"Ling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Ashhurst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barney","family":"Viengkhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So Ri","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pattama","family":"Songkhunawej","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip K.","family":"West","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J. C.","family":"King","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5111-3978","authenticated-orcid":false,"given":"Markus J.","family":"Hofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,11]]},"reference":[{"issue":"5","key":"1566_CR1","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/0035-9203(52)90042-4","volume":"46","author":"GW Dick","year":"1952","unstructured":"Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg. 1952;46(5):509\u201320.","journal-title":"Trans R Soc Trop Med Hyg"},{"issue":"7","key":"1566_CR2","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1038\/nrmicro.2016.80","volume":"14","author":"U Hofer","year":"2016","unstructured":"Hofer U. Viral pathogenesis: tracing the steps of Zika virus. Nat Rev Microbiol. 2016;14(7):401.","journal-title":"Nat Rev Microbiol"},{"issue":"2","key":"1566_CR3","doi-asserted-by":"crossref","first-page":"223","DOI":"10.4049\/jimmunol.69.2.223","volume":"69","author":"KC Smithburn","year":"1952","unstructured":"Smithburn KC. Neutralizing antibodies against certain recently isolated viruses in the sera of human beings residing in East Africa. J Immunol (Baltimore, Md : 1950). 1952;69(2):223\u201334.","journal-title":"J Immunol (Baltimore, Md : 1950)."},{"issue":"24","key":"1566_CR4","doi-asserted-by":"publisher","first-page":"2536","DOI":"10.1056\/NEJMoa0805715","volume":"360","author":"MR Duffy","year":"2009","unstructured":"Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL, Lanciotti RS, et al. Zika virus outbreak on Yap Island, federated states of Micronesia. N Engl J Med. 2009;360(24):2536\u201343.","journal-title":"N Engl J Med"},{"key":"1566_CR5","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.ijid.2016.05.014","volume":"48","author":"R Vorou","year":"2016","unstructured":"Vorou R. Zika virus, vectors, reservoirs, amplifying hosts, and their potential to spread worldwide: what we know and what we should investigate urgently. Int J Infect Dis. 2016;48:85\u201390.","journal-title":"Int J Infect Dis"},{"key":"1566_CR6","doi-asserted-by":"crossref","unstructured":"Pettersson JH, Eldholm V, Seligman SJ, Lundkvist A, Falconar AK, Gaunt MW, et al. How did Zika virus emerge in the Pacific Islands and Latin America? MBio. 2016;7(5):e01239\u201316.","DOI":"10.1128\/mBio.01239-16"},{"issue":"9","key":"1566_CR7","doi-asserted-by":"publisher","first-page":"242","DOI":"10.15585\/mmwr.mm6509e2","volume":"65","author":"W Kleber de Oliveira","year":"2016","unstructured":"Kleber de Oliveira W, Cortez-Escalante J, De Oliveira WT, do Carmo GM, Henriques CM, Coelho GE, et al. Increase in reported prevalence of microcephaly in infants born to women living in areas with confirmed Zika virus transmission during the first trimester of pregnancy - Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(9):242\u20137.","journal-title":"MMWR Morb Mortal Wkly Rep"},{"issue":"24","key":"1566_CR8","doi-asserted-by":"publisher","first-page":"2321","DOI":"10.1056\/NEJMoa1602412","volume":"375","author":"P Brasil","year":"2016","unstructured":"Brasil P, Pereira JP Jr, Moreira ME, Ribeiro Nogueira RM, Damasceno L, Wakimoto M, et al. Zika virus infection in pregnant women in Rio de Janeiro. N Engl J Med. 2016;375(24):2321\u201334.","journal-title":"N Engl J Med"},{"issue":"10020","key":"1566_CR9","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/S0140-6736(16)00320-2","volume":"387","author":"DL Heymann","year":"2016","unstructured":"Heymann DL, Hodgson A, Sall AA, Freedman DO, Staples JE, Althabe F, et al. Zika virus and microcephaly: why is this situation a PHEIC? Lancet. 2016;387(10020):719\u201321.","journal-title":"Lancet"},{"issue":"10027","key":"1566_CR10","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1016\/S0140-6736(16)00562-6","volume":"387","author":"VM Cao-Lormeau","year":"2016","unstructured":"Cao-Lormeau VM, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J, et al. Guillain-Barre syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet. 2016;387(10027):1531\u20139.","journal-title":"Lancet"},{"issue":"10038","key":"1566_CR11","doi-asserted-by":"publisher","first-page":"2599","DOI":"10.1016\/S0140-6736(16)30844-3","volume":"387","author":"LE Bautista","year":"2016","unstructured":"Bautista LE, Sethi AK. Association between Guillain-Barre syndrome and Zika virus infection. Lancet. 2016;387(10038):2599\u2013600.","journal-title":"Lancet"},{"issue":"16","key":"1566_CR12","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1056\/NEJMc1609015","volume":"375","author":"T Dos Santos","year":"2016","unstructured":"Dos Santos T, Rodriguez A, Almiron M, Sanhueza A, Ramon P, de Oliveira WK, et al. Zika virus and the Guillain-Barre syndrome - case series from seven countries. N Engl J Med. 2016;375(16):1598\u2013601.","journal-title":"N Engl J Med"},{"issue":"16","key":"1566_CR13","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1056\/NEJMoa1605564","volume":"375","author":"B Parra","year":"2016","unstructured":"Parra B, Lizarazo J, Jimenez-Arango JA, Zea-Vera AF, Gonzalez-Manrique G, Vargas J, et al. Guillain-Barre syndrome associated with Zika virus infection in Colombia. N Engl J Med. 2016;375(16):1513\u201323.","journal-title":"N Engl J Med"},{"issue":"1\u20132","key":"1566_CR14","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1159\/000453396","volume":"77","author":"B Niemeyer","year":"2017","unstructured":"Niemeyer B, Niemeyer R, Borges R, Marchiori E. Acute disseminated encephalomyelitis following Zika virus infection. Eur Neurol. 2017;77(1\u20132):45\u20136.","journal-title":"Eur Neurol"},{"key":"1566_CR15","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jcv.2016.08.297","volume":"83","author":"CN Soares","year":"2016","unstructured":"Soares CN, Brasil P, Carrera RM, Sequeira P, de Filippis AB, Borges VA, et al. Fatal encephalitis associated with Zika virus infection in an adult. J Clin Virol. 2016;83:63\u20135.","journal-title":"J Clin Virol"},{"issue":"16","key":"1566_CR16","doi-asserted-by":"publisher","first-page":"1595","DOI":"10.1056\/NEJMc1602964","volume":"374","author":"G Carteaux","year":"2016","unstructured":"Carteaux G, Maquart M, Bedet A, Contou D, Brugieres P, Fourati S, et al. Zika virus associated with meningoencephalitis. N Engl J Med. 2016;374(16):1595\u20136.","journal-title":"N Engl J Med"},{"key":"1566_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/srep41389","volume":"7","author":"KM Aagaard","year":"2017","unstructured":"Aagaard KM, Lahon A, Suter MA, Arya RP, Seferovic MD, Vogt MB, et al. Primary human placental trophoblasts are permissive for Zika virus (ZIKV) replication. Sci Rep. 2017;7:41389.","journal-title":"Sci Rep"},{"issue":"5","key":"1566_CR18","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1016\/j.cell.2016.05.008","volume":"165","author":"JJ Miner","year":"2016","unstructured":"Miner JJ, Cao B, Govero J, Smith AM, Fernandez E, Cabrera OH, et al. Zika virus infection during pregnancy in mice causes placental damage and fetal demise. Cell. 2016;165(5):1081\u201391.","journal-title":"Cell"},{"issue":"5","key":"1566_CR19","doi-asserted-by":"publisher","first-page":"e1006378","DOI":"10.1371\/journal.ppat.1006378","volume":"13","author":"SM Nguyen","year":"2017","unstructured":"Nguyen SM, Antony KM, Dudley DM, Kohn S, Simmons HA, Wolfe B, et al. Highly efficient maternal-fetal Zika virus transmission in pregnant rhesus macaques. PLoS Pathog. 2017;13(5):e1006378.","journal-title":"PLoS Pathog"},{"issue":"5","key":"1566_CR20","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1016\/j.cell.2016.08.004","volume":"166","author":"LJ Yockey","year":"2016","unstructured":"Yockey LJ, Varela L, Rakib T, Khoury-Hanold W, Fink SL, Stutz B, et al. Vaginal exposure to Zika virus during pregnancy leads to fetal brain infection. Cell. 2016;166(5):1247\u201356 e4.","journal-title":"Cell"},{"issue":"8","key":"1566_CR21","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1089\/dna.2016.3404","volume":"35","author":"D Olagnier","year":"2016","unstructured":"Olagnier D, Muscolini M, Coyne CB, Diamond MS, Hiscott J. Mechanisms of Zika virus infection and neuropathogenesis. DNA Cell Biol. 2016;35(8):367\u201372.","journal-title":"DNA Cell Biol"},{"issue":"9","key":"1566_CR22","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/j.tim.2017.05.005","volume":"25","author":"NJC King","year":"2017","unstructured":"King NJC, Teixeira MM, Mahalingam S. Zika virus: mechanisms of infection during pregnancy. Trends Microbiol. 2017;25(9):701\u20132.","journal-title":"Trends Microbiol"},{"issue":"10045","key":"1566_CR23","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/S0140-6736(16)00339-1","volume":"388","author":"HJ Willison","year":"2016","unstructured":"Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barre syndrome. Lancet. 2016;388(10045):717\u201327.","journal-title":"Lancet"},{"issue":"1","key":"1566_CR24","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/nri3581","volume":"14","author":"LB Ivashkiv","year":"2014","unstructured":"Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14(1):36\u201349.","journal-title":"Nat Rev Immunol"},{"issue":"2","key":"1566_CR25","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/nri3787","volume":"15","author":"F McNab","year":"2015","unstructured":"McNab F, Mayer-Barber K, Sher A, Wack A, O\u2019Garra A. Type I interferons in infectious disease. Nat Rev Immunol. 2015;15(2):87\u2013103.","journal-title":"Nat Rev Immunol"},{"issue":"2","key":"1566_CR26","doi-asserted-by":"publisher","first-page":"e1006164","DOI":"10.1371\/journal.ppat.1006164","volume":"13","author":"JR Bowen","year":"2017","unstructured":"Bowen JR, Quicke KM, Maddur MS, O'Neal JT, McDonald CE, Fedorova NB, et al. Zika virus antagonizes type I interferon responses during infection of human dendritic cells. PLoS Pathog. 2017;13(2):e1006164.","journal-title":"PLoS Pathog"},{"issue":"6","key":"1566_CR27","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1016\/j.chom.2016.05.009","volume":"19","author":"A Grant","year":"2016","unstructured":"Grant A, Ponia SS, Tripathi S, Balasubramaniam V, Miorin L, Sourisseau M, et al. Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe. 2016;19(6):882\u201390.","journal-title":"Cell Host Microbe"},{"issue":"12","key":"1566_CR28","doi-asserted-by":"publisher","first-page":"1766","DOI":"10.15252\/embr.201642627","volume":"17","author":"A Kumar","year":"2016","unstructured":"Kumar A, Hou S, Airo AM, Limonta D, Mancinelli V, Branton W, et al. Zika virus inhibits type-I interferon production and downstream signaling. EMBO Rep. 2016;17(12):1766\u201375.","journal-title":"EMBO Rep"},{"issue":"6","key":"1566_CR29","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.4269\/ajtmh.16-0111","volume":"94","author":"SL Rossi","year":"2016","unstructured":"Rossi SL, Tesh RB, Azar SR, Muruato AE, Hanley KA, Auguste AJ, et al. Characterization of a novel murine model to study Zika virus. Am J Trop Med Hyg. 2016;94(6):1362\u20139.","journal-title":"Am J Trop Med Hyg"},{"key":"1566_CR30","first-page":"8","volume":"91","author":"TE Morrison","year":"2017","unstructured":"Morrison TE, Diamond MS. Animal models of Zika virus infection, pathogenesis, and immunity. J Virol. 2017;91:8.","journal-title":"J Virol"},{"issue":"5","key":"1566_CR31","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/j.chom.2016.03.010","volume":"19","author":"HM Lazear","year":"2016","unstructured":"Lazear HM, Govero J, Smith AM, Platt DJ, Fernandez E, Miner JJ, et al. A mouse model of Zika virus pathogenesis. Cell Host Microbe. 2016;19(5):720\u201330.","journal-title":"Cell Host Microbe"},{"issue":"2","key":"1566_CR32","doi-asserted-by":"publisher","first-page":"e1006184","DOI":"10.1371\/journal.ppat.1006184","volume":"13","author":"RD Pardy","year":"2017","unstructured":"Pardy RD, Rajah MM, Condotta SA, Taylor NG, Sagan SM, Richer MJ. Analysis of the T cell response to Zika virus and identification of a novel CD8+ T cell epitope in immunocompetent mice. PLoS Pathog. 2017;13(2):e1006184.","journal-title":"PLoS Pathog"},{"issue":"6","key":"1566_CR33","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1016\/j.cell.2016.11.016","volume":"167","author":"W Ma","year":"2016","unstructured":"Ma W, Li S, Ma S, Jia L, Zhang F, Zhang Y, et al. Zika virus causes testis damage and leads to male infertility in mice. Cell. 2016;167(6):1511\u201324 e10.","journal-title":"Cell"},{"key":"1566_CR34","doi-asserted-by":"crossref","unstructured":"Huang H, Li S, Zhang Y, Han X, Jia B, Liu H, et al. CD8(+) T cell immune response in immunocompetent mice during Zika virus infection. J Virol. 2017;91(22):e00900\u201317.","DOI":"10.1128\/JVI.00900-17"},{"issue":"5","key":"1566_CR35","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1016\/j.chom.2018.04.003","volume":"23","author":"MJ Gorman","year":"2018","unstructured":"Gorman MJ, Caine EA, Zaitsev K, Begley MC, Weger-Lucarelli J, Uccellini MB, et al. An immunocompetent mouse model of Zika virus infection. Cell Host Microbe. 2018;23(5):672\u201385 e6.","journal-title":"Cell Host Microbe"},{"issue":"5","key":"1566_CR36","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/0035-9203(52)90043-6","volume":"46","author":"GW Dick","year":"1952","unstructured":"Dick GW. Zika virus. II. Pathogenicity and physical properties. Trans R Soc Trop Med Hyg. 1952;46(5):521\u201334.","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"1566_CR37","doi-asserted-by":"publisher","first-page":"593","DOI":"10.3389\/fimmu.2018.00593","volume":"9","author":"L Nazerai","year":"2018","unstructured":"Nazerai L, Scholler AS, Rasmussen POS, Buus S, Stryhn A, Christensen JP, et al. A new in vivo model to study protective immunity to Zika virus infection in mice with intact type I interferon signaling. Front Immunol. 2018;9:593.","journal-title":"Front Immunol"},{"issue":"5167","key":"1566_CR38","doi-asserted-by":"publisher","first-page":"1918","DOI":"10.1126\/science.8009221","volume":"264","author":"U Muller","year":"1994","unstructured":"Muller U, Steinhoff U, Reis LF, Hemmi S, Pavlovic J, Zinkernagel RM, et al. Functional role of type I and type II interferons in antiviral defense. Science. 1994;264(5167):1918\u201321.","journal-title":"Science"},{"issue":"5","key":"1566_CR39","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1016\/0092-8674(92)90030-G","volume":"68","author":"P Mombaerts","year":"1992","unstructured":"Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992;68(5):869\u201377.","journal-title":"Cell"},{"issue":"3","key":"1566_CR40","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1111\/j.1471-4159.2007.04798.x","volume":"103","author":"DR Getts","year":"2007","unstructured":"Getts DR, Matsumoto I, Muller M, Getts MT, Radford J, Shrestha B, et al. Role of IFN-gamma in an experimental murine model of West Nile virus-induced seizures. J Neurochem. 2007;103(3):1019\u201330.","journal-title":"J Neurochem"},{"issue":"3","key":"1566_CR41","doi-asserted-by":"publisher","first-page":"630","DOI":"10.3171\/2011.10.JNS11852","volume":"116","author":"K Iwami","year":"2012","unstructured":"Iwami K, Momota H, Natsume A, Kinjo S, Nagatani T, Wakabayashi T. A novel method of intracranial injection via the postglenoid foramen for brain tumor mouse models. J Neurosurg. 2012;116(3):630\u20135.","journal-title":"J Neurosurg"},{"issue":"12","key":"1566_CR42","doi-asserted-by":"publisher","first-page":"6932","DOI":"10.1128\/JVI.07147-11","volume":"86","author":"MJ Hofer","year":"2012","unstructured":"Hofer MJ, Li W, Manders P, Terry R, Lim SL, King NJ, et al. Mice deficient in STAT1 but not STAT2 or IRF9 develop a lethal CD4+ T-cell-mediated disease following infection with lymphocytic choriomeningitis virus. J Virol. 2012;86(12):6932\u201346.","journal-title":"J Virol"},{"key":"1566_CR43","first-page":"115","volume":"116","author":"SS Ousman","year":"2005","unstructured":"Ousman SS, Campbell IL. Regulation of murine interferon regulatory factor gene expression in the central nervous system determined by multiprobe RNase protection assay. Methods Mol Med. 2005;116:115\u201334.","journal-title":"Methods Mol Med"},{"issue":"10","key":"1566_CR44","doi-asserted-by":"crossref","first-page":"7832","DOI":"10.1128\/JVI.71.10.7832-7840.1997","volume":"71","author":"VC Asensio","year":"1997","unstructured":"Asensio VC, Campbell IL. Chemokine gene expression in the brains of mice with lymphocytic choriomeningitis. J Virol. 1997;71(10):7832\u201340.","journal-title":"J Virol"},{"issue":"4","key":"1566_CR45","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1089\/vim.2008.0057","volume":"21","author":"MJ Hofer","year":"2008","unstructured":"Hofer MJ, Carter SL, Muller M, Campbell IL. Unaltered neurological disease and mortality in CXCR3-deficient mice infected intracranially with lymphocytic choriomeningitis virus-Armstrong. Viral Immunol. 2008;21(4):425\u201333.","journal-title":"Viral Immunol"},{"issue":"10","key":"1566_CR46","doi-asserted-by":"publisher","first-page":"2319","DOI":"10.1084\/jem.20080421","volume":"205","author":"DR Getts","year":"2008","unstructured":"Getts DR, Terry RL, Getts MT, Muller M, Rana S, Shrestha B, et al. Ly6c+ \u201cinflammatory monocytes\u201d are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis. J Exp Med. 2008;205(10):2319\u201337.","journal-title":"J Exp Med"},{"key":"1566_CR47","unstructured":"Sydney SCFTUo. www.sydneycytometry.org.au\/capx . Accessed 7 Jan 2019."},{"issue":"7","key":"1566_CR48","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1002\/cyto.a.22625","volume":"87","author":"S Van Gassen","year":"2015","unstructured":"Van Gassen S, Callebaut B, Van Helden MJ, Lambrecht BN, Demeester P, Dhaene T, et al. FlowSOM: using self-organizing maps for visualization and interpretation of cytometry data. Cytometry A. 2015;87(7):636\u201345.","journal-title":"Cytometry A"},{"key":"1566_CR49","unstructured":"van der Maaten L, Hinton G. Visualizing data using t-SNE. J Mach Learn Res. 2008. p. 2579\u2013605."},{"key":"1566_CR50","first-page":"3221","volume":"15","author":"L van der Maaten","year":"2014","unstructured":"van der Maaten L. Accelerating t-SNE using tree-based algorithms. J Mach Learn Res. 2014;15:3221\u201345.","journal-title":"J Mach Learn Res"},{"issue":"6","key":"1566_CR51","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1038\/nbt.2594","volume":"31","author":"AD Amir el","year":"2013","unstructured":"Amir el AD, Davis KL, Tadmor MD, Simonds EF, Levine JH, Bendall SC, et al. viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat Biotechnol. 2013;31(6):545\u201352.","journal-title":"Nat Biotechnol"},{"issue":"9","key":"1566_CR52","doi-asserted-by":"publisher","first-page":"3526","DOI":"10.4049\/jimmunol.1601949","volume":"198","author":"CW Winkler","year":"2017","unstructured":"Winkler CW, Myers LM, Woods TA, Messer RJ, Carmody AB, McNally KL, et al. Adaptive immune responses to Zika virus are important for controlling virus infection and preventing infection in brain and testes. J Immunol (Baltimore, Md : 1950). 2017;198(9):3526\u201335.","journal-title":"J Immunol (Baltimore, Md : 1950)"},{"issue":"4","key":"1566_CR53","doi-asserted-by":"publisher","first-page":"e0004682","DOI":"10.1371\/journal.pntd.0004682","volume":"10","author":"MT Aliota","year":"2016","unstructured":"Aliota MT, Caine EA, Walker EC, Larkin KE, Camacho E, Osorio JE. Characterization of lethal Zika virus infection in AG129 mice. PLoS Negl Trop Dis. 2016;10(4):e0004682.","journal-title":"PLoS Negl Trop Dis"},{"issue":"7","key":"1566_CR54","doi-asserted-by":"publisher","first-page":"e0005704","DOI":"10.1371\/journal.pntd.0005704","volume":"11","author":"SD Dowall","year":"2017","unstructured":"Dowall SD, Graham VA, Rayner E, Hunter L, Atkinson B, Pearson G, et al. Lineage-dependent differences in the disease progression of Zika virus infection in type-I interferon receptor knockout (A129) mice. PLoS Negl Trop Dis. 2017;11(7):e0005704.","journal-title":"PLoS Negl Trop Dis"},{"issue":"7633","key":"1566_CR55","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1038\/nature20556","volume":"540","author":"J Govero","year":"2016","unstructured":"Govero J, Esakky P, Scheaffer SM, Fernandez E, Drury A, Platt DJ, et al. Zika virus infection damages the testes in mice. Nature. 2016;540(7633):438\u201342.","journal-title":"Nature"},{"issue":"3","key":"1566_CR56","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/j.celrep.2017.03.058","volume":"19","author":"AK Hastings","year":"2017","unstructured":"Hastings AK, Yockey LJ, Jagger BW, Hwang J, Uraki R, Gaitsch HF, et al. TAM receptors are not required for Zika virus infection in mice. Cell Rep. 2017;19(3):558\u201368.","journal-title":"Cell Rep"},{"issue":"8","key":"1566_CR57","doi-asserted-by":"publisher","first-page":"2161","DOI":"10.1523\/JNEUROSCI.3124-16.2017","volume":"37","author":"AN van den Pol","year":"2017","unstructured":"van den Pol AN, Mao G, Yang Y, Ornaghi S, Davis JN. Zika virus targeting in the developing brain. J Neurosci. 2017;37(8):2161\u201375.","journal-title":"J Neurosci"},{"issue":"11","key":"1566_CR58","doi-asserted-by":"publisher","first-page":"e1006004","DOI":"10.1371\/journal.ppat.1006004","volume":"12","author":"M Manangeeswaran","year":"2016","unstructured":"Manangeeswaran M, Ireland DD, Verthelyi D. Zika (PRVABC59) infection is associated with T cell infiltration and neurodegeneration in CNS of immunocompetent neonatal C57Bl\/6 mice. PLoS Pathog. 2016;12(11):e1006004.","journal-title":"PLoS Pathog"},{"key":"1566_CR59","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1186\/1742-2094-9-246","volume":"9","author":"DR Getts","year":"2012","unstructured":"Getts DR, Terry RL, Getts MT, Muller M, Rana S, Deffrasnes C, et al. Targeted blockade in lethal West Nile virus encephalitis indicates a crucial role for very late antigen (VLA)-4-dependent recruitment of nitric oxide-producing macrophages. J Neuroinflammation. 2012;9:246.","journal-title":"J Neuroinflammation"},{"key":"1566_CR60","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1742-2094-8-23","volume":"8","author":"DC Amaral","year":"2011","unstructured":"Amaral DC, Rachid MA, Vilela MC, Campos RD, Ferreira GP, Rodrigues DH, et al. Intracerebral infection with dengue-3 virus induces meningoencephalitis and behavioral changes that precede lethality in mice. J Neuroinflammation. 2011;8:23.","journal-title":"J Neuroinflammation"},{"issue":"5","key":"1566_CR61","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.stem.2016.03.012","volume":"18","author":"TJ Nowakowski","year":"2016","unstructured":"Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein AR. Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell. 2016;18(5):591\u20136.","journal-title":"Cell Stem Cell"},{"issue":"4","key":"1566_CR62","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1016\/j.chom.2012.08.009","volume":"12","author":"L Meertens","year":"2012","unstructured":"Meertens L, Carnec X, Lecoin MP, Ramdasi R, Guivel-Benhassine F, Lew E, et al. The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. Cell Host Microbe. 2012;12(4):544\u201357.","journal-title":"Cell Host Microbe"},{"issue":"1","key":"1566_CR63","doi-asserted-by":"publisher","first-page":"3136","DOI":"10.1038\/s41467-018-05519-4","volume":"9","author":"CGO Lucas","year":"2018","unstructured":"Lucas CGO, Kitoko JZ, Ferreira FM, Suzart VG, Papa MP, Coelho SVA, et al. Critical role of CD4(+) T cells and IFNgamma signaling in antibody-mediated resistance to Zika virus infection. Nat Commun. 2018;9(1):3136.","journal-title":"Nat Commun"},{"issue":"2","key":"1566_CR64","doi-asserted-by":"publisher","first-page":"e1001304","DOI":"10.1371\/journal.ppat.1001304","volume":"7","author":"SU Seo","year":"2011","unstructured":"Seo SU, Kwon HJ, Ko HJ, Byun YH, Seong BL, Uematsu S, et al. Type I interferon signaling regulates Ly6C(hi) monocytes and neutrophils during acute viral pneumonia in mice. PLoS Pathog. 2011;7(2):e1001304.","journal-title":"PLoS Pathog"},{"key":"1566_CR65","doi-asserted-by":"publisher","first-page":"27670","DOI":"10.1038\/srep27670","volume":"6","author":"TT Tsai","year":"2016","unstructured":"Tsai TT, Chen CL, Lin YS, Chang CP, Tsai CC, Cheng YL, et al. Microglia retard dengue virus-induced acute viral encephalitis. Sci Rep. 2016;6:27670.","journal-title":"Sci Rep"},{"issue":"1","key":"1566_CR66","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/s41467-017-02645-3","volume":"9","author":"W Wang","year":"2018","unstructured":"Wang W, Li G, De W, Luo Z, Pan P, Tian M, et al. Zika virus infection induces host inflammatory responses by facilitating NLRP3 inflammasome assembly and interleukin-1beta secretion. Nat Commun. 2018;9(1):106.","journal-title":"Nat Commun"},{"issue":"1","key":"1566_CR67","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1038\/nrrheum.2016.166","volume":"12","author":"G Schett","year":"2016","unstructured":"Schett G, Dayer JM, Manger B. Interleukin-1 function and role in rheumatic disease. Nat Rev Rheumatol. 2016;12(1):14\u201324.","journal-title":"Nat Rev Rheumatol"}],"container-title":["Journal of Neuroinflammation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-019-1566-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12974-019-1566-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-019-1566-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T04:10:43Z","timestamp":1695183043000},"score":1,"resource":{"primary":{"URL":"https:\/\/jneuroinflammation.biomedcentral.com\/articles\/10.1186\/s12974-019-1566-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,11]]},"references-count":67,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["1566"],"URL":"https:\/\/doi.org\/10.1186\/s12974-019-1566-5","relation":{},"ISSN":["1742-2094"],"issn-type":[{"value":"1742-2094","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,11]]},"assertion":[{"value":"8 February 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 September 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Ethics approval for all animal experiments was obtained from the animal ethics committee of The University of Sydney (987\/2016 and 988\/2016). Animal experiments were performed in compliance with the NSW Animal Research Act and its associated Regulations and the 2004 NHMRC \u201cAustralian code of practice for the care and use of animals for scientific purposes.\u201d","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"177"}}