The interactions of viruses with the nervous system were thought to be well understood until the recent outbreaks of Zika and SARS-CoV-2. In this review, we consider these emerging pathogens, the range and mechanisms of the neurological disease in humans, and how the biomedical research enterprise has pivoted to answer questions about viral pathogenesis, immune response, and the special vulnerability of the nervous system. ZIKV stands out as the only new virus in a generation, associating with congenital brain defects, neurological manifestations of microcephaly in newborns, and radiculopathy in adults. COVID-19, the disease caused by SARS-CoV-2, has swept the planet in an unprecedented manner and is feared worldwide for its effect on the respiratory system, but recent evidence points to important neurological sequelae. These can include anosmia, vasculopathy, paresthesias, and stroke. Evidence of ZIKV and SARS-CoV-2 genetic material from neural tissue, and evidence of infection of neural cells, raises questions about how these emerging viruses produce disease, and where new therapies might emerge.
Adams WaldorfKMNelsonBRStencel-BaerenwaldJEStudholmeCKapurRPArmisteadB, and others. 2018. Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. Nat Med24:368–74.
2.
AkerstromSTanYJMirazimiA.2006. Amino acids 15-28 in the ectodomain of SARS coronavirus 3a protein induces neutralizing antibodies. FEBS Lett580:3799–803.
3.
Al-HameedFM. 2017. Spontaneous intracranial hemorrhage in a patient with Middle East respiratory syndrome corona virus. Saudi Med J38:196–200.
4.
AndersenKGRambautALipkinWIHolmesECGarryRF. 2020. The proximal origin of SARS-CoV-2. Nat Med26:450–2.
5.
BardinaSVBunducPTripathiSDuehrJFrereJJBrownJA, and others. 2017. Enhancement of Zika virus pathogenesis by preexisting antiflavivirus immunity. Science356:175–80.
6.
BeigelJHTomashekKMDoddLEMehtaAKZingmanBSKalilAC, and others. 2020. Remdesivir for the treatment of Covid-19—final report. N Engl J Med383:1813–26.
7.
BradyOJOsgood-ZimmermanAKassebaumNJRaySEde AraujoVEMda NobregaAA, and others. 2019. The association between Zika virus infection and microcephaly in Brazil 2015-2017: an observational analysis of over 4 million births. PLoS Med16:e1002755.
8.
CaressJBCastoroRJSimmonsZScelsaSNLewisRAAhlawatA, and others. 2020. COVID-19-associated Guillain-Barre syndrome: the early pandemic experience. Muscle Nerve62:485–91.
9.
CarteauxGMaquartMBedetAContouDBrugieresPFouratiS, and others. 2016. Zika virus associated with meningoencephalitis. N Engl J Med374:1595–6.
10.
Cassuto-ViguierESandersonFKullmanBQuarantaJFMontagneNGueyraudA, and others. 1988. Functional recovery in Guillain-Barre syndrome: benefits of plasma exchange. Ann Med Interne (Paris)139(Suppl 1):43–5.
11.
ChangCKHouMHChangCFHsiaoCDHuangTH.2014. The SARS coronavirus nucleocapsid protein—forms and functions. Antiviral Res103:39–50.
12.
ChenLLiXChenMFengYXiongC.2020a. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res116:1097–100.
13.
ChenTWuDChenHYanWYangDChenG, and others. 2020b. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ368:m1091.
14.
ChengDSHanWChenSMSherrillTPChontMParkGY, and others. 2007. Airway epithelium controls lung inflammation and injury through the NF-κB pathway. J Immunol178:6504–13.
15.
CugolaFRFernandesIRRussoFBFreitasBCDiasJLGuimarãesKP, and others. . 2016. The Brazilian Zika virus strain causes birth defects in experimental models. Nature534:267–71.
16.
da SilvaIRFFronteraJABispo de FilippisAMNascimentoOJM, RIO-GBS-ZIKV Research Group. 2017. Neurologic complications associated with the Zika virus in Brazilian adults. JAMA Neurol74:1190–8.
17.
DangJTiwariSKLichinchiGQinYPatilVSEroshkinAM, and others. 2016. Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Cell Stem Cell19:258–65.
18.
de OliveiraWKde FrancaGVACarmoEHDuncanBBde Souza KuchenbeckerRSchmidtMI. 2017. Infection-related microcephaly after the 2015 and 2016 Zika virus outbreaks in Brazil: a surveillance-based analysis. Lancet390:861–70.
19.
DejnirattisaiWSupasaPWongwiwatWRouvinskiABarba-SpaethGDuangchindaT, and others. 2016. Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus. Nat Immunol17:1102–8.
20.
DickGW. 1952. Zika virus. II. Pathogenicity and physical properties. Trans R Soc Trop Med Hyg46:521–34.
21.
DickGWKitchenSFHaddowAJ.1952. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg46:509–20.
22.
DingQGaskaJMDouamFWeiLKimDBalevM, and others. 2018. Species-specific disruption of STING-dependent antiviral cellular defenses by the Zika virus NS2B3 protease. Proc Natl Acad Sci U S A115:E6310–8.
23.
DirlikovEMajorCGMedinaNALugo-RoblesRMatosDMunoz-JordanJL, and others. 2018. Clinical features of Guillain-Barre syndrome with vs without Zika virus infection, Puerto Rico, 2016. JAMA Neurol75:1089–97.
24.
DrexlerJFCormanVMDrostenC.2014. Ecology, evolution and classification of bat coronaviruses in the aftermath of SARS. Antiviral Res101:45–56.
25.
DuffyMRChenTHHancockWTPowersAMKoolJLLanciottiRS, and others. 2009. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med360:2536–43.
26.
FalgoutBPethelMZhangYMLaiCJ.1991. Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins. J Virol65:2467–75.
27.
FigueiredoCPBarros-AragaoFGQNerisRLSFrostPSSoaresCSouzaINO, and others. 2019. Zika virus replicates in adult human brain tissue and impairs synapses and memory in mice. Nat Commun10:3890.
28.
FowlerAMTangWWYoungMPMamidiAViramontesKMMcCauleyMD, and others. 2018. Maternally acquired Zika antibodies enhance dengue disease severity in mice. Cell Host Microbe24:743–50.e5.
29.
FoyBDKobylinskiKCChilson FoyJLBlitvichBJTravassos da RosaAHaddowAD, and others. 2011. Probable non-vector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis17:880–2.
30.
FurtadoJMEspositoDLKleinTMTeixeira-PintoTda FonsecaBA.2016. Uveitis associated with Zika virus infection. N Engl J Med375:394–6.
31.
GordonDEJangGMBouhaddouMXuJObernierKWhiteKM, and others. 2020. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature583:459–68.
32.
GrantAPoniaSSTripathiSBalasubramaniamVMiorinLSourisseauM, and others. 2016. Zika virus targets human STAT2 to inhibit type i interferon signaling. Cell Host Microbe19:882–90.
33.
GrifoniAWeiskopfDRamirezSIMateusJDanJMModerbacherCR, and others. 2020. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell181: 1489–501.e15.
34.
GuJGongEZhangBZhengJGaoZZhongY, and others. 2005. Multiple organ infection and the pathogenesis of SARS. J Exp Med202:415–24.
35.
GuilmotAMaldonado SlootjesSSellimiABronchainMHanseeuwBBelkhirL, and others. 2021. Immune-mediated neurological syndromes in SARS-CoV-2-infected patients. J Neurol268:751–7.
36.
GurumayumSBrahmaRNaoremLDMuthaiyanMGopalJVenkatesanA.2018. ZikaBase: an integrated ZIKV-Human Interactome Map database. Virology514:203–10.
37.
Gutierrez-OrtizCMendez-GuerreroARodrigo-ReySSan Pedro-MurilloEBermejo-GuerreroLGordo-ManasR, and others. 2020. Miller Fisher syndrome and polyneuritis cranialis in COVID-19. Neurology95:e601–5.
38.
GuyRKDiPaolaRSRomanelliFDutchRE.2020. Rapid repurposing of drugs for COVID-19. Science368:829–30.
39.
HadjadjJYatimNBarnabeiLCorneauABoussierJSmithN, and others. 2020. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science369:718–24.
40.
HaiderASiddiqaAAliNDhalluM.2020. COVID-19 and the brain: acute encephalitis as a clinical manifestation. Cureus12:e10784.
41.
HamelRDejarnacOWichitSEkchariyawatPNeyretALuplertlopN, and others. 2015. Biology of Zika virus infection in human skin cells. J Virol89:8880–96.
42.
HastingsAKYockeyLJJaggerBWHwangJUrakiRGaitschHF, and others. 2017. TAM receptors are not required for Zika virus infection in mice. Cell Rep19:558–68.
43.
HelmsJKremerSMerdjiHClere-JehlRSchenckMKummerlenC, and others. 2020. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med382: 2268–70.
44.
HennesseyMFischerMStaplesJE. 2016. Zika virus spreads to new areas—region of the Americas, May 2015–January 2016. MMWR Morb Mortal Wkly Rep65:55–8.
45.
HikmetFMearLEdvinssonAMickePUhlenMLindskogC.2020. The protein expression profile of ACE2 in human tissues. Mol Syst Biol16:e9610.
46.
HoenBSchaubBFunkALArdillonVBoullardMCabieA, and others. 2018. Pregnancy outcomes after ZIKV infection in French territories in the Americas. N Engl J Med378:985–94.
47.
HoffmannMKleine-WeberHSchroederSKrugerNHerrlerTErichsenS, and others. 2020. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell181:271–80.e8.
48.
HuangYHJiangDHuangJT. 2020. SARS-CoV-2 detected in cerebrospinal fluid by PCR in a case of COVID-19 encephalitis. Brain Behav Immun87:149.
49.
HuberRGLimXNNgWCSimAYLPohHXShenY, and others. 2019. Structure mapping of dengue and Zika viruses reveals functional long-range interactions. Nat Commun10:1408.
50.
Hygino da CruzLCJrNascimentoOJMLopesFda SilvaIRF. 2018. Neuroimaging findings of Zika virus–associated neurologic complications in adults. AJNR Am J Neuroradiol39:1967–74.
51.
InciardiRMLupiLZacconeGItaliaLRaffoMTomasoniD, and others. 2020. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol5:819–24.
52.
IoannidisJPA. 2021. Infection fatality rate of COVID-19 inferred from seroprevalence data. In Bull World Health Organ99:19–33F.
53.
JacobFPatherSRHuangWKZhangFWongSZHZhouH, and others. 2020. Human pluripotent stem cell–derived neural cells and brain organoids reveal SARS-CoV-2 neurotropism predominates in choroid plexus epithelium. Cell Stem Cell27:937–50.e9.
54.
JiangXDongXLiSHZhouYPRaynerSXiaHM, and others. 2018. Proteomic analysis of Zika virus infected primary human fetal neural progenitors suggests a role for doublecortin in the pathological consequences of infection in the cortex. Front Microbiol9:1067.
55.
KanzawaNNishigakiKHayashiTIshiiYFurukawaSNiiroA, and others. 2006. Augmentation of chemokine production by severe acute respiratory syndrome coronavirus 3a/X1 and 7a/X4 proteins through NF-κB activation. FEBS Lett580:6807–12.
56.
KhailanyRASafdarMOzaslanM.2020. Genomic characterization of a novel SARS-CoV-2. Gene Rep19:100682.
57.
KoyamaTWeeraratneDSnowdonJLParidaL.2020. Emergence of drift variants that may affect COVID-19 vaccine development and antibody treatment. Pathogens9:324.
58.
LamersMMBeumerJvan der VaartJKnoopsKPuschhofJBreugemTI, and others. 2020. SARS-CoV-2 productively infects human gut enterocytes. Science369:50–4.
59.
LeeMJBingSJChoiJJangMLeeGLeeH, and others. 2016. IKKβ-mediated inflammatory myeloid cell activation exacerbates experimental autoimmune encephalomyelitis by potentiating Th1/Th17 cell activation and compromising blood brain barrier. Mol Neurodegener11:54.
60.
LiAWangWWangYChenKXiaoFHuD, and others. 2020. NS5 conservative site is required for Zika virus to restrict the RIG-I signaling. Front Immunol11:51.
61.
LiCWangQJiangYYeQXuDGaoF, and others. 2018. Disruption of glial cell development by Zika virus contributes to severe microcephalic newborn mice. Cell Discov4:43.
62.
LiCXuDYeQHongSJiangYLiuX, and others. 2016. Zika virus disrupts neural progenitor development and leads to microcephaly in mice. Cell Stem Cell19:120–6.
63.
LiHSaucedo-CuevasLYuanLRossDJohansenASandsD, and others. 2019. Zika virus protease cleavage of host protein septin-2 mediates mitotic defects in neural progenitors. Neuron101:1089–98.e4.
64.
LiWMooreMJVasilievaNSuiJWongSKBerneMA, and others. 2003. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature426:450–4.
65.
LiangQLuoZZengJChenWFooSSLeeSA, and others. 2016. Zika virus NS4A and NS4B proteins deregulate Akt-mTOR signaling in human fetal neural stem cells to inhibit neurogenesis and induce autophagy. Cell Stem Cell19:663–71.
66.
LiottaEMBatraAClarkJRShlobinNAHoffmanSCOrbanZS, and others. 2020. Frequent neurologic manifestations and encephalopathy-associated morbidity in Covid-19 patients. Ann Clin Transl Neurol7:2221–30.
67.
LundbergRMelenKWesteniusVJiangMOsterlundPKhanH, and others. 2019. Zika virus non-structural protein NS5 inhibits the RIG-I pathway and interferon lambda 1 promoter activation by targeting IKK epsilon. Viruses11:1024.
68.
MaJKetkarHGengTLoEWangLXiJ, and others. 2018. Zika virus non-structural protein 4A blocks the RLR-MAVS signaling. Front Microbiol9:1350.
69.
MackenzieJMWestawayEG. 2001. Assembly and maturation of the flavivirus Kunjin virus appear to occur in the rough endoplasmic reticulum and along the secretory pathway, respectively. J Virol75:10787–99.
70.
MarceauCDPuschnikASMajzoubKOoiYSBrewerSMFuchsG, and others. 2016. Genetic dissection of Flaviviridae host factors through genome-scale CRISPR screens. Nature535:159–63.
71.
MarinhoFAraujoVEPortoDLFerreiraHLCoelhoMRLeccaRC, and others. 2016. Microcephaly in Brazil: prevalence and characterization of cases from the Information System on Live Births (Sinasc), 2000-2015. Epidemiol Serv Saude25:701–12.
72.
MeadPSDuggalNKHookSADeloreyMFischerMOlzenak McGuireD, and others. 2018. Zika virus shedding in semen of symptomatic infected men. N Engl J Med378:1377–85.
73.
MecharlesSHerrmannCPoullainPTranTHDeschampsNMathonG, and others. 2016. Acute myelitis due to Zika virus infection. Lancet387:1481.
MerklerAEParikhNSMirSGuptaAKamelHLinE, and others. 2020. Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza. JAMA Neurol77:1–7.
76.
MierYT-RLDeloreyMJSejvarJJJohanssonMA. 2018. Guillain-Barre syndrome risk among individuals infected with Zika virus: a multi-country assessment. BMC Med16:67.
77.
MlakarJKorvaMTulNPopovicMPoljsak-PrijateljMMrazJ, and others. 2016. Zika virus associated with microcephaly. N Engl J Med374:951–8.
78.
NaqviAATFatimaKMohammadTFatimaUSinghIKSinghA, and others. 2020. Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: structural genomics approach. Biochim Biophys Acta Mol Basis Dis1866:165878.
Nielsen-SainesKBrasilPKerinTVasconcelosZGabagliaCRDamascenoL, and others. 2019. Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children. Nat Med25:1213–7.
81.
NowakowskiTJPollenAADi LulloESandoval-EspinosaCBershteynMKriegsteinAR. 2016. Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell18:591–6.
82.
NtaiosGMichelPGeorgiopoulosGGuoYLiWXiongJ, and others. 2020. Characteristics and outcomes in patients with COVID-19 and acute ischemic stroke: the Global COVID-19 Stroke Registry.Stroke51:e254–8.
83.
PedrosoCFischerCFeldmannMSarnoMLuzEMoreira-SotoA, and others. 2019. Cross-protection of dengue virus infection against congenital Zika syndrome, northeastern Brazil. Emerg Infect Dis25:1485–93.
84.
PolitiLSSalsanoEGrimaldiM.2020. Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (COVID-19) and anosmia. JAMA Neurol77:1028–9.
PuellesVGLutgehetmannMLindenmeyerMTSperhakeJPWongMNAllweissL, and others. 2020. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med383:590–2.
87.
QianXNguyenHNSongMMHadionoCOgdenSCHammackC, and others. 2016. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell165:1238–54.
88.
RadosevichCAWeitzmanSA. 1989. Hydrogen peroxide induces squamous metaplasia in a hamster tracheal organ explant culture model. Carcinogenesis10:1943–6.
89.
RamaniAMullerLOstermannPNGabrielEAbida-IslamPMuller-SchiffmannA, and others. 2020. SARS-CoV-2 targets neurons of 3D human brain organoids. EMBO J39:e106230.
90.
RiceMEGalangRRRothNMEllingtonSRMooreCAValencia-PradoM, and others. 2018. Vital signs: Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection—U.S. Territories and Freely Associated States, 2018. MMWR Morb Mortal Wkly Rep67:858–67.
91.
Rivera-CorreaJde SiqueiraICMotaSdo RosarioMSPereira de JesusPAAlcantaraLCJ, and others. 2019. Anti-ganglioside antibodies in patients with Zika virus infection-associated Guillain-Barre syndrome in Brazil. PLoS Negl Trop Dis13:e0007695.
92.
Rodenhuis-ZybertIAWilschutJSmitJM. 2010. Dengue virus life cycle: viral and host factors modulating infectivity. Cell Mol Life Sci67:2773–86.
93.
Sa RiberoMJouvenetNDreuxMNisoleS. 2020. Interplay between SARS-CoV-2 and the type I interferon response. PLoS Pathog16:e1008737.
94.
SavidisGMcDougallWMMeranerPPerreiraJMPortmannJMTrincucciG, and others. 2016. Identification of Zika virus and dengue virus dependency factors using functional genomics. Cell Rep16:232–46.
95.
ShangJYeGShiKWanYLuoCAiharaH, and others. 2020. Structural basis of receptor recognition by SARS-CoV-2. Nature581:221–4.
96.
SongZXuYBaoLZhangLYuPQuY, and others. 2019. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses11:59.
97.
StandlFJöckelKHBruneBSchmidtBStangA.2020. Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics [comment]. Lancet Infect Dis21:e77.
98.
TangHHammackCOgdenSCWenZQianXLiY, and others. 2016. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell18:587–90.
99.
TappeDPerez-GironJVZammarchiLRisslandJFerreiraDFJaenischT, and others. 2016. Cytokine kinetics of Zika virus–infected patients from acute to reconvalescent phase. Med Microbiol Immunol205:269–73.
100.
ToscanoGPalmeriniFRavagliaSRuizLInvernizziPCuzzoniMG, and others. 2020. Guillain-Barre syndrome associated with SARS-CoV-2. N Engl J Med382:2574–6.
101.
TsengCTTsengJPerroneLWorthyMPopovVPetersCJ. 2005. Apical entry and release of severe acute respiratory syndrome-associated coronavirus in polarized Calu-3 lung epithelial cells. J Virol79:9470–9.
102.
UhlenMFagerbergLHallstromBMLindskogCOksvoldPMardinogluA, and others. 2015. Proteomics. Tissue-based map of the human proteome. Science347:1260419.
103.
ViannaPGomesJDABoquettJAFragaLRSchuchJBViannaFSL, and others. 2018. Zika virus as a possible risk factor for autism spectrum disorder: neuroimmunological aspects. Neuroimmunomodulation25:320–7.
104.
WangSZhangQTiwariSKLichinchiGYauEHHuiH, and others. 2020. Integrin αvβ5 internalizes Zika virus during neural stem cells infection and provides a promising target for antiviral therapy. Cell Rep30:969–83.e4.
105.
WellsCRSahPMoghadasSMPandeyAShoukatAWangY, and others. 2020. Impact of international travel and border control measures on the global spread of the novel 2019 coronavirus outbreak. Proc Natl Acad Sci U S A117:7504–9.
106.
WelschSMillerSRomero-BreyIMerzABleckCKWaltherP, and others. 2009. Composition and three-dimensional architecture of the dengue virus replication and assembly sites. Cell Host Microbe5:365–75.
WuYLiuQZhouJXieWChenCWangZ, and others. 2017. Zika virus evades interferon-mediated antiviral response through the co-operation of multiple nonstructural proteins in vitro. Cell Discov3:17006.
109.
XiaHLuoHShanCMuruatoAENunesBTDMedeirosDBA, and others. 2018. An evolutionary NS1 mutation enhances Zika virus evasion of host interferon induction. Nat Commun9:414.
110.
XuJZhongSLiuJLiLLiYWuX, and others. 2005. Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis. Clin Infect Dis41:1089–96.
111.
YoonKJSongGQianXPanJXuDRhoHS, and others. 2017. Zika-virus-encoded NS2A disrupts mammalian cortical neurogenesis by degrading adherens junction proteins. Cell Stem Cell21:349–58.e6.
112.
YuYDengYQZouPWangQDaiYYuF, and others. 2017. A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses. Nat Commun8:15672.
113.
ZhangFHammackCOgdenSCChengYLeeEMWenZ, and others. 2016a. Molecular signatures associated with ZIKV exposure in human cortical neural progenitors. Nucleic Acids Res44:8610–20.
114.
ZhangQBastardPLiuZLe PenJMoncada-VelezMChenJ, and others. 2020. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science370:eabd4570.
115.
ZhangRMinerJJGormanMJRauschKRamageHWhiteJP, and others. 2016b. A CRISPR screen defines a signal peptide processing pathway required by flaviviruses. Nature535:164–8.
116.
ZhouFYuTDuRFanGLiuYLiuZ, and others. 2020. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet395:1054–62.
117.
ZhuZMesciPBernatchezJAGimpleRCWangXSchaferST, and others. 2020. Zika virus targets glioblastoma stem cells through a SOX2-integrin αvβ5 axis. Cell Stem Cell26:187–204.e10.
