BACKGROUND: The recent Zika virus (ZIKV) outbreak has linked ZIKV with microcephaly and other central nervous system pathologies in humans. Astrocytes are among the first cells to respond to ZIKV infection in the brain and are also targets for virus infection. In this study, we investigated the interaction between ZIKV and primary human brain cortical astrocytes (HBCA). RESULTS: HBCAs were highly sensitive to representatives of both Asian and African ZIKV lineages and produced high viral yields. The infection was associated with limited immune cytokine/chemokine response activation; the highest increase of expression, following infection, was seen in CXCL-10 (IP-10), interleukin-6, 8, 12, and CCL5 (RANTES). Ultrastructural changes in the ZIKV-infected HBCA were characterized by electron tomography (ET). ET reconstructions elucidated high-resolution 3D images of the proliferating and extensively rearranged endoplasmic reticulum (ER) containing viral particles and virus-induced vesicles, tightly juxtaposed to collapsed ER cisternae. CONCLUSIONS: The results confirm that human astrocytes are sensitive to ZIKV infection and could be a source of proinflammatory cytokines in the ZIKV-infected brain tissue.

Department of Virology Veterinary Research Institute Hudcova 70 62100 Brno Czech Republic

EHESP French School of Public Health IRD French Institute of Research for Development EPV UMR_D 190 Emergence des Pathologies Virales Aix Marseille Université Marseille France

Faculty of Science University of South Bohemia Branisovska 31 37005 Ceske Budejovice Czech Republic

Institute of Parasitology Biology Centre of the Czech Academy of Sciences Branisovska 31 37005 Ceske Budejovice Czech Republic

Laboratory of Molecular Evolution and Bioinformatics Department of Microbiology Institute of Microbiology Sciences University of São Paulo São Paulo 05508 000 Brazil

Zobrazit více v PubMed

Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg. 1952;46(5):509–520. doi: 10.1016/0035-9203(52)90042-4. PubMed DOI

Faye O, Freire CC, Iamarino A, Faye O, de Oliveira JV, Diallo M, Zanotto PM, Sall AA. Molecular evolution of Zika virus during its emergence in the 20(th) century. PLoS Negl Trop Dis. 2014;8(1):e2636. doi: 10.1371/journal.pntd.0002636. PubMed DOI PMC

Nugent EK, Nugent AK, Nugent R, Nugent K. Zika virus: epidemiology, pathogenesis and human disease. Am J Med Sci. 2017;353(5):466–473. doi: 10.1016/j.amjms.2016.12.018. PubMed DOI

Broutet N, Krauer F, Riesen M, Khalakdina A, Almiron M, Aldighieri S, Espinal M, Low N, Dye C. Zika virus as a cause of neurologic disorders. N Engl J Med. 2016;374(16):1506–1509. doi: 10.1056/NEJMp1602708. PubMed DOI

Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J, Kolenc M, Resman Rus K, Vesnaver Vipotnik T, Fabjan Vodušek V, Vizjak A, Pižem J, Petrovec M, Avšič Županc T. Zika virus associated with microcephaly. N Engl J Med. 2016;374(10):951–958. doi: 10.1056/NEJMoa1600651. PubMed DOI

Mécharles S, Herrmann C, Poullain P, Tran TH, Deschamps N, Mathon G, Landais A, Breurec S, Lannuzel A. Acute myelitis due to Zika virus infection. Lancet. 2016;387(10026):1481. doi: 10.1016/S0140-6736(16)00644-9. PubMed DOI

Carteaux G, Maquart M, Bedet A, Contou D, Brugières P, Fourati S, Cleret de Langavant L, de Broucker T, Brun-Buisson C, Leparc-Goffart I, Mekontso Dessap A. Zika virus associated with meningoencephalitis. N Engl J Med. 2016;374(16):1595–1596. doi: 10.1056/NEJMc1602964. PubMed DOI

Schwartzmann PV, Ramalho LN, Neder L, Vilar FC, Ayub-Ferreira SM, Romeiro MF, Takayanagui OM, Dos Santos AC, Schmidt A, Figueiredo LT, Arena R, Simões MV. Zika virus meningoencephalitis in an immunocompromised patient. Mayo Clin Proc. 2017;92(3):460–466. doi: 10.1016/j.mayocp.2016.12.019. PubMed DOI

Soares CN, Brasil P, Carrera RM, Sequeira P, de Filippis AB, Borges VA, Theophilo F, Ellul MA, Solomon T. Fatal encephalitis associated with Zika virus infection in an adult. J Clin Virol. 2016;83:63–65. doi: 10.1016/j.jcv.2016.08.297. PubMed DOI

Bell TM, Field EJ, Narang HK. Zika virus infection of the central nervous system of mice. Arch Gesamte Virusforsch. 1971;35(2):183–193. doi: 10.1007/BF01249709. PubMed DOI

van den Pol AN, Mao G, Yang Y, Ornaghi S, Davis JN. Zika virus targeting in the developing brain. J Neurosci. 2017;37(8):2161–2175. doi: 10.1523/JNEUROSCI.3124-16.2017. PubMed DOI PMC

Simonin Y, Loustalot F, Desmetz C, Foulongne V, Constant O, Fournier-Wirth C, Leon F, Molès JP, Goubaud A, Lemaitre JM, Maquart M, Leparc-Goffart I, Briant L, Nagot N, Van de Perre P, Salinas S. Zika virus strains potentially display different infectious profiles in human neural cells. EBioMedicine. 2016;12:161–169. doi: 10.1016/j.ebiom.2016.09.020. PubMed DOI PMC

Cugola FR, Fernandes IR, Russo FB, Freitas BC, Dias JL, Guimarães KP, Benazzato C, Almeida N, Pignatari GC, Romero S, Polonio CM, Cunha I, Freitas CL, Brandão WN, Rossato C, Andrade DG, Faria Dde P, Garcez AT, Buchpigel CA, Braconi CT, Mendes E, Sall AA, Zanotto PM, Peron JP, Muotri AR, Beltrão-Braga PC. The Brazilian Zika virus strain causes birth defects in experimental models. Nature. 2016;534(7606):267–271. doi: 10.1038/nature18296. PubMed DOI PMC

Eyer L, Nencka R, Huvarová I, Palus M, Joao Alves M, Gould EA, De Clercq E, Růžek D. Nucleoside inhibitors of Zika virus. J Infect Dis. 2016;214(5):707–711. doi: 10.1093/infdis/jiw226. PubMed DOI

Palus M, Bílý T, Elsterová J, Langhansová H, Salát J, Vancová M, Růžek D. Infection and injury of human astrocytes by tick-borne encephalitis virus. J Gen Virol. 2014;95(Pt 11):2411–2426. doi: 10.1099/vir.0.068411-0. PubMed DOI

Palus M, Formanová P, Salát J, Žampachová E, Elsterová J, Růžek D. Analysis of serum levels of cytokines, chemokines, growth factors, and monoamine neurotransmitters in patients with tick-borne encephalitis: identification of novel inflammatory markers with implications for pathogenesis. J Med Virol. 2015;87(5):885–892. doi: 10.1002/jmv.24140. PubMed DOI

Hamel R, Ferraris P, Wichit S, Diop F, Talignani L, Pompon J, Garcia D, Liégeois F, Sall AA, Yssel H, Missé D. African and Asian Zika virus strains differentially induce early antiviral responses in primary human astrocytes. Infect Genet Evol. 2017;49:134–137. doi: 10.1016/j.meegid.2017.01.015. PubMed DOI

Hanners NW, Eitson JL, Usui N, Richardson RB, Wexler EM, Konopka G, Schoggins JW. Western Zika virus in human fetal neural progenitors persists long term with partial cytopathic and limited immunogenic effects. Cell Rep. 2016;15(11):2315–2322. doi: 10.1016/j.celrep.2016.05.075. PubMed DOI PMC

Offerdahl DK, Dorward DW, Hansen BT, Bloom ME. A three-dimensional comparison of tick-borne flavivirus infection in mammalian and tick cell lines. PLoS ONE. 2012;7(10):e47912. doi: 10.1371/journal.pone.0047912. PubMed DOI PMC

Cortese M, Goellner S, Acosta EG, Chatel-Chaix L, Ruggieri A, Bartenschlager R. Ultrastructural characterization of Zika virus replication factories. Cell Rep. 2017;18:2113–2123. doi: 10.1016/j.celrep.2017.02.014. PubMed DOI PMC

Rossignol ED, Peters KN, Connor JH, Bullitt E. Zika virus induced cellular remodelling. Cell Microbiol. 2017 PubMed PMC

Welsch S, Miller S, Romero-Brey I, Merz A, Bleck CK, Walther P, Fuller SD, Antony C, Krijnse-Locker J, Bartenschlager R. Composition and three-dimensional architecture of the dengue virus replication and assembly sites. Cell Host Microbe. 2009;5(4):365–375. doi: 10.1016/j.chom.2009.03.007. PubMed DOI PMC

Bílý T, Palus M, Eyer L, Elsterová J, Vancová M, Růžek D. Electron tomography analysis of tick-borne encephalitis virus infection in human neurons. Sci Rep. 2015;5:10745. doi: 10.1038/srep10745. PubMed DOI PMC

Monel B, Compton AA, Bruel T, Amraoui S, Burlaud-Gaillard J, Roy N, Guivel-Benhassine F, Porrot F, Génin P, Meertens L, Sinigaglia L, Jouvenet N, Weil R, Casartelli N, Demangel C, Simon-Lorière E, Moris A, Roingeard P, Amara A, Schwartz O. Zika virus induces massive cytoplasmic vacuolization and paraptosis-like death in infected cells. EMBO J. 2017;36(12):1653–1668. doi: 10.15252/embj.201695597. PubMed DOI PMC

Nutt C, Adams P. Zika in Africa-the invisible epidemic? Lancet. 2017;389(10079):1595–1596. doi: 10.1016/S0140-6736(17)31051-6. PubMed DOI

Changes in cytokine and chemokine profiles in mouse serum and brain, and in human neural cells, upon tick-borne encephalitis virus infection