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• W2327959547 abstract "•Development of a mouse model of ZIKV pathogenesis including multiple viral strains•Ifnar1−/− mice sustain high viral burden in brain, spinal cord, and testes•ZIKV can establish viremia in the absence of clinical signs in mice•ZIKV mouse model may be useful for vaccine and antiviral testing The ongoing Zika virus (ZIKV) epidemic and unexpected clinical outcomes, including Guillain-Barré syndrome and birth defects, has brought an urgent need for animal models. We evaluated infection and pathogenesis with contemporary and historical ZIKV strains in immunocompetent mice and mice lacking components of the antiviral response. Four- to six-week-old Irf3−/− Irf5−/− Irf7−/− triple knockout mice, which produce little interferon α/β, and mice lacking the interferon receptor (Ifnar1−/−) developed neurological disease and succumbed to ZIKV infection, whereas single Irf3−/−, Irf5−/−, and Mavs−/− knockout mice exhibited no overt illness. Ifnar1−/− mice sustained high viral loads in the brain and spinal cord, consistent with evidence that ZIKV causes neurodevelopmental defects in human fetuses. The testes of Ifnar1−/− mice had the highest viral loads, which is relevant to sexual transmission of ZIKV. This model of ZIKV pathogenesis will be valuable for evaluating vaccines and therapeutics as well as understanding disease pathogenesis. The ongoing Zika virus (ZIKV) epidemic and unexpected clinical outcomes, including Guillain-Barré syndrome and birth defects, has brought an urgent need for animal models. We evaluated infection and pathogenesis with contemporary and historical ZIKV strains in immunocompetent mice and mice lacking components of the antiviral response. Four- to six-week-old Irf3−/− Irf5−/− Irf7−/− triple knockout mice, which produce little interferon α/β, and mice lacking the interferon receptor (Ifnar1−/−) developed neurological disease and succumbed to ZIKV infection, whereas single Irf3−/−, Irf5−/−, and Mavs−/− knockout mice exhibited no overt illness. Ifnar1−/− mice sustained high viral loads in the brain and spinal cord, consistent with evidence that ZIKV causes neurodevelopmental defects in human fetuses. The testes of Ifnar1−/− mice had the highest viral loads, which is relevant to sexual transmission of ZIKV. This model of ZIKV pathogenesis will be valuable for evaluating vaccines and therapeutics as well as understanding disease pathogenesis. Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family, which includes globally relevant arthropod-transmitted human pathogens such as dengue (DENV), yellow fever (YFV), West Nile (WNV), Japanese encephalitis (JEV), and tick-borne encephalitis viruses (Lazear and Diamond, 2016Lazear H.M. Diamond M.S. Zika Virus: New Clinical Syndromes and its Emergence in the Western Hemisphere.J. Virol. 2016; (Published online March 9, 2016)https://doi.org/10.1128/JVI.00252-16Crossref PubMed Scopus (303) Google Scholar, Pierson and Diamond, 2013Pierson T.C. Diamond M.S. Flaviviruses.in: Knipe D.M. Howley P.M. Fields Virology. Wolter Kluwer, 2013: 747-794Google Scholar). Within the mosquito-borne clade of flaviviruses, ZIKV is a member of the Spondweni group; both genetically and serologically, ZIKV is related closely to the four serotypes of DENV with approximately 43% amino acid identity and extensive antibody cross-reactivity (Alkan et al., 2015Alkan C. Zapata S. Bichaud L. Moureau G. Lemey P. Firth A.E. Gritsun T.S. Gould E.A. de Lamballerie X. Depaquit J. Charrel R.N. Ecuador Paraiso Escondido Virus, a New Flavivirus Isolated from New World Sand Flies in Ecuador, Is the First Representative of a Novel Clade in the Genus Flavivirus.J. Virol. 2015; 89: 11773-11785Crossref PubMed Scopus (23) Google Scholar, Lanciotti et al., 2008Lanciotti R.S. Kosoy O.L. Laven J.J. Velez J.O. Lambert A.J. Johnson A.J. Stanfield S.M. Duffy M.R. Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007.Emerg. Infect. Dis. 2008; 14: 1232-1239Crossref PubMed Scopus (1416) Google Scholar). The first strain of ZIKV (MR 766) was isolated in 1947 from a febrile sentinel rhesus monkey in the Zika forest near Entebbe, Uganda after intracerebral passage in Swiss albino mice (Dick, 1952Dick G.W. Zika virus. II. Pathogenicity and physical properties.Trans. R. Soc. Trop. Med. Hyg. 1952; 46: 521-534Abstract Full Text PDF PubMed Scopus (434) Google Scholar, Dick et al., 1952Dick G.W. Kitchen S.F. Haddow A.J. Zika virus. I. Isolations and serological specificity.Trans. R. Soc. Trop. Med. Hyg. 1952; 46: 509-520Abstract Full Text PDF PubMed Scopus (1627) Google Scholar). In the decades following its discovery, ZIKV was isolated from human patients sporadically during outbreaks in Africa and Southeast Asia (Haddow et al., 2012Haddow A.D. Schuh A.J. Yasuda C.Y. Kasper M.R. Heang V. Huy R. Guzman H. Tesh R.B. Weaver S.C. Genetic characterization of Zika virus strains: geographic expansion of the Asian lineage.PLoS Negl. Trop. Dis. 2012; 6: e1477Crossref PubMed Scopus (505) Google Scholar, Hayes, 2009Hayes E.B. Zika virus outside Africa.Emerg. Infect. Dis. 2009; 15: 1347-1350Crossref PubMed Scopus (570) Google Scholar), but remained obscure due to the fairly benign nature of the infection (Lazear and Diamond, 2016Lazear H.M. Diamond M.S. Zika Virus: New Clinical Syndromes and its Emergence in the Western Hemisphere.J. Virol. 2016; (Published online March 9, 2016)https://doi.org/10.1128/JVI.00252-16Crossref PubMed Scopus (303) Google Scholar). Typically, ZIKV infection has been associated with a self-limiting febrile illness often including rash, arthralgia, and conjunctivitis, though most infections are asymptomatic (Brasil et al., 2016Brasil P. Pereira Jr., J.P. Raja Gabaglia C. Damasceno L. Wakimoto M. Ribeiro Nogueira R.M. Carvalho de Sequeira P. Machado Siqueira A. Abreu de Carvalho L.M. Cotrim da Cunha D. et al.Zika Virus Infection in Pregnant Women in Rio de Janeiro - Preliminary Report.N. Engl. J. Med. 2016; (Published online March 4, 2016)https://doi.org/10.1056/NEJMoa1602412Crossref PubMed Scopus (1119) Google Scholar, Duffy et al., 2009Duffy M.R. Chen T.H. Hancock W.T. Powers A.M. Kool J.L. Lanciotti R.S. Pretrick M. Marfel M. Holzbauer S. Dubray C. et al.Zika virus outbreak on Yap Island, Federated States of Micronesia.N. Engl. J. Med. 2009; 360: 2536-2543Crossref PubMed Scopus (1941) Google Scholar, Hayes, 2009Hayes E.B. Zika virus outside Africa.Emerg. Infect. Dis. 2009; 15: 1347-1350Crossref PubMed Scopus (570) Google Scholar). Despite the mild disease historically associated with ZIKV infection, more severe complications have been noted during recent outbreaks in the South Pacific and Latin America. The first association between ZIKV infection and neurological disorders occurred during the 2013–2014 ZIKV outbreak in French Polynesia (Cao-Lormeau et al., 2014Cao-Lormeau V.M. Roche C. Teissier A. Robin E. Berry A.L. Mallet H.P. Sall A.A. Musso D. Zika virus, French polynesia, South pacific, 2013.Emerg. Infect. Dis. 2014; 20: 1085-1086PubMed Google Scholar), which was associated with a 20-fold increase in cases of Guillain-Barré syndrome (GBS) (Cao-Lormeau et al., 2016Cao-Lormeau V.M. Blake A. Mons S. Lastère S. Roche C. Vanhomwegen J. Dub T. Baudouin L. Teissier A. Larre P. et al.Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study.Lancet. 2016; (Published online February 29, 2016)https://doi.org/10.1016/S0140-6736(16)00562-6Abstract Full Text Full Text PDF PubMed Scopus (1442) Google Scholar, Oehler et al., 2014Oehler E. Watrin L. Larre P. Leparc-Goffart I. Lastere S. Valour F. Baudouin L. Mallet H. Musso D. Ghawche F. Zika virus infection complicated by Guillain-Barre syndrome--case report, French Polynesia, December 2013.Euro Surveill. 2014; 19: 20720Crossref PubMed Google Scholar). GBS is a post-infection autoimmune peripheral neuropathy that can produce pain, weakness, and paralysis; although GBS usually is temporary, GBS-induced respiratory paralysis can be fatal (Willison et al., 2016Willison H.J. Jacobs B.C. van Doorn P.A. Guillain-Barré syndrome.Lancet. 2016; (Published online February 29, 2016)https://doi.org/10.1016/S0140-6736(16)00339-1Abstract Full Text Full Text PDF Scopus (529) Google Scholar). In support of a causal link between ZIKV and GBS, the emergence of ZIKV in the western hemisphere in 2015–2016 has been associated temporally with increased numbers of GBS cases in Brazil, El Salvador, and Colombia (European Centre for Disease Prevention and Control, 2016European Centre for Disease Prevention and ControlZika virus disease epidemic: potential association with microcephaly and Guillain-Barré syndrome (first update). ECDC, Stockholm2016Google Scholar). During the current epidemic in Latin America, ZIKV infection has been linked to the development of severe fetal abnormalities that include spontaneous abortion, stillbirth, hydranencephaly, microcephaly, and placental insufficiency that may cause intrauterine growth restriction (Brasil et al., 2016Brasil P. Pereira Jr., J.P. Raja Gabaglia C. Damasceno L. Wakimoto M. Ribeiro Nogueira R.M. Carvalho de Sequeira P. Machado Siqueira A. Abreu de Carvalho L.M. Cotrim da Cunha D. et al.Zika Virus Infection in Pregnant Women in Rio de Janeiro - Preliminary Report.N. Engl. J. Med. 2016; (Published online March 4, 2016)https://doi.org/10.1056/NEJMoa1602412Crossref PubMed Scopus (1119) Google Scholar, Sarno et al., 2016Sarno M. Sacramento G.A. Khouri R. do Rosário M.S. Costa F. Archanjo G. Santos L.A. Nery Jr., N. Vasilakis N. Ko A.I. de Almeida A.R. Zika Virus Infection and Stillbirths: A Case of Hydrops Fetalis, Hydranencephaly and Fetal Demise.PLoS Negl. Trop. Dis. 2016; 10: e0004517Crossref Scopus (237) Google Scholar, Ventura et al., 2016Ventura C.V. Maia M. Bravo-Filho V. Góis A.L. Belfort Jr., R. Zika virus in Brazil and macular atrophy in a child with microcephaly.Lancet. 2016; 387: 228Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar). Furthermore, a retrospective analysis identified an increase in microcephaly cases during the 2013–2014 ZIKV outbreak in French Polynesia (Cauchemez et al., 2016Cauchemez S. Besnard M. Bompard P. Dub T. Guillemette-Artur P. Eyrolle-Guignot D. Salje H. Van Kerkhove M.D. Abadie V. Garel C. et al.Association between Zika virus and microcephaly in French Polynesia, 2013-15: a retrospective study.Lancet. 2016; (Published online March 15, 2016)https://doi.org/10.1016/S0140-6736(16)00651-6Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar). Several cases of presumed intrauterine ZIKV infection resulted in coarse cerebral calcifications in different brain regions of newborn infants or fetuses in utero (Oliveira Melo et al., 2016Oliveira Melo A.S. Malinger G. Ximenes R. Szejnfeld P.O. Alves Sampaio S. Bispo de Filippis A.M. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?.Ultrasound Obstet. Gynecol. 2016; 47: 6-7https://doi.org/10.1002/uog.15831Crossref PubMed Scopus (572) Google Scholar). The reported congenital malformation cases may represent only the most severe end of the spectrum, with less severe infection producing long-term cognitive or functional sequelae. Indeed, ocular findings in infants with presumed ZIKV-associated microcephaly were reported recently (de Paula Freitas et al., 2016de Paula Freitas B. de Oliveira Dias J.R. Prazeres J. Sacramento G.A. Ko A.I. Maia M. Belfort Jr., R. Ocular Findings in Infants With Microcephaly Associated With Presumed Zika Virus Congenital Infection in Salvador, Brazil.JAMA Ophthalmol. 2016; https://doi.org/10.1001/jamaophthalmol.2016.0267Crossref PubMed Scopus (379) Google Scholar). While much remains to be determined about the mechanisms by which ZIKV mediates microcephaly and other birth defects, mounting molecular and immunologic evidence supports the conclusion that ZIKV can cross the placenta and damage a developing fetus. This evidence includes detection of ZIKV RNA, full-length viral genome, or viral particles in the amniotic fluid or brains of fetuses diagnosed with microcephaly, as well as ZIKV IgM in amniotic fluid, consistent with fetal infection (Calvet et al., 2016Calvet G. Aguiar R.S. Melo A.S. Sampaio S.A. de Filippis I. Fabri A. Araujo E.S. de Sequeira P.C. de Mendonça M.C. de Oliveira L. et al.Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study.Lancet Infect. Dis. 2016; (Published online February 17, 2016)https://doi.org/10.1016/S1473-3099(16)00095-5Abstract Full Text Full Text PDF PubMed Scopus (723) Google Scholar, Martines et al., 2016Martines R.B. Bhatnagar J. Keating M.K. Silva-Flannery L. Muehlenbachs A. Gary J. Goldsmith C. Hale G. Ritter J. Rollin D. et al.Notes from the Field: Evidence of Zika Virus Infection in Brain and Placental Tissues from Two Congenitally Infected Newborns and Two Fetal Losses - Brazil, 2015.MMWR Morb. Mortal. Wkly. Rep. 2016; 65: 159-160Crossref PubMed Scopus (341) Google Scholar, Mlakar et al., 2016Mlakar J. Korva M. Tul N. Popović M. Poljšak-Prijatelj M. Mraz J. Kolenc M. Resman Rus K. Vesnaver Vipotnik T. Fabjan Vodušek V. et al.Zika Virus Associated with Microcephaly.N. Engl. J. Med. 2016; 374: 951-958Crossref PubMed Scopus (1638) Google Scholar, Oliveira Melo et al., 2016Oliveira Melo A.S. Malinger G. Ximenes R. Szejnfeld P.O. Alves Sampaio S. Bispo de Filippis A.M. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?.Ultrasound Obstet. Gynecol. 2016; 47: 6-7https://doi.org/10.1002/uog.15831Crossref PubMed Scopus (572) Google Scholar, Petersen et al., 2016Petersen E.E. Staples J.E. Meaney-Delman D. Fischer M. Ellington S.R. Callaghan W.M. Jamieson D.J. Interim Guidelines for Pregnant Women During a Zika Virus Outbreak - United States, 2016.MMWR Morb. Mortal. Wkly. Rep. 2016; 65: 30-33Crossref PubMed Scopus (208) Google Scholar). Little is known about the cellular and tissue tropism of ZIKV, but keratinocytes and dendritic cells in the skin likely represent early targets of infection, similar to other flaviviruses (Hamel et al., 2015Hamel R. Dejarnac O. Wichit S. Ekchariyawat P. Neyret A. Luplertlop N. Perera-Lecoin M. Surasombatpattana P. Talignani L. Thomas F. et al.Biology of Zika Virus Infection in Human Skin Cells.J. Virol. 2015; 89: 8880-8896Crossref PubMed Scopus (707) Google Scholar, Lim et al., 2011Lim P.Y. Behr M.J. Chadwick C.M. Shi P.Y. Bernard K.A. Keratinocytes are cell targets of West Nile virus in vivo.J. Virol. 2011; 85: 5197-5201Crossref PubMed Scopus (79) Google Scholar, Limon-Flores et al., 2005Limon-Flores A.Y. Perez-Tapia M. Estrada-Garcia I. Vaughan G. Escobar-Gutierrez A. Calderon-Amador J. Herrera-Rodriguez S.E. Brizuela-Garcia A. Heras-Chavarria M. Flores-Langarica A. et al.Dengue virus inoculation to human skin explants: an effective approach to assess in situ the early infection and the effects on cutaneous dendritic cells.Int. J. Exp. Pathol. 2005; 86: 323-334Crossref PubMed Scopus (74) Google Scholar, Surasombatpattana et al., 2011Surasombatpattana P. Hamel R. Patramool S. Luplertlop N. Thomas F. Desprès P. Briant L. Yssel H. Missé D. Dengue virus replication in infected human keratinocytes leads to activation of antiviral innate immune responses.Infect. Genet. Evol. 2011; 11: 1664-1673Crossref PubMed Scopus (71) Google Scholar), and ZIKV can infect human skin explants and peripheral blood mononuclear cells in culture (Hamel et al., 2015Hamel R. Dejarnac O. Wichit S. Ekchariyawat P. Neyret A. Luplertlop N. Perera-Lecoin M. Surasombatpattana P. Talignani L. Thomas F. et al.Biology of Zika Virus Infection in Human Skin Cells.J. Virol. 2015; 89: 8880-8896Crossref PubMed Scopus (707) Google Scholar). Evidence from infants and fetuses infected in utero suggests ZIKV may be neurotropic (Mlakar et al., 2016Mlakar J. Korva M. Tul N. Popović M. Poljšak-Prijatelj M. Mraz J. Kolenc M. Resman Rus K. Vesnaver Vipotnik T. Fabjan Vodušek V. et al.Zika Virus Associated with Microcephaly.N. Engl. J. Med. 2016; 374: 951-958Crossref PubMed Scopus (1638) Google Scholar, Sarno et al., 2016Sarno M. Sacramento G.A. Khouri R. do Rosário M.S. Costa F. Archanjo G. Santos L.A. Nery Jr., N. Vasilakis N. Ko A.I. de Almeida A.R. Zika Virus Infection and Stillbirths: A Case of Hydrops Fetalis, Hydranencephaly and Fetal Demise.PLoS Negl. Trop. Dis. 2016; 10: e0004517Crossref Scopus (237) Google Scholar), and a recent report demonstrated ZIKV infection in human neuroprogenitor cells in culture (Tang et al., 2016Tang H. Hammack C. Ogden S.C. Wen Z. Qian X. Li Y. Yao B. Shin J. Zhang F. Lee E.M. et al.Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth.Cell Stem Cell. 2016; (Published online March 3, 2016)https://doi.org/10.1016/j.stem.2016.02.016Abstract Full Text Full Text PDF Scopus (793) Google Scholar). Vaccines and therapeutics are needed urgently to combat ZIKV, and testing would be expedited by animal models of the different manifestations of disease. Multiple monkey species in the Zika forest were found to be seropositive for ZIKV (McCrae and Kirya, 1982McCrae A.W. Kirya B.G. Yellow fever and Zika virus epizootics and enzootics in Uganda.Trans. R. Soc. Trop. Med. Hyg. 1982; 76: 552-562Abstract Full Text PDF PubMed Scopus (135) Google Scholar), suggesting they can become infected and support viral replication. Other mammals in the Zika forest (including squirrels, tree rats, giant pouched rats, and civets) did not show serological evidence of ZIKV infection (Haddow et al., 1964Haddow A.J. Williams M.C. Woodall J.P. Simpson D.I. Goma L.K. Twelve Isolations of Zika Virus from Aedes (Stegomyia) Africanus (Theobald) Taken in and above a Uganda Forest.Bull. World Health Organ. 1964; 31: 57-69PubMed Google Scholar), though a subsequent study in Kenya detected ZIKV antibodies in small mammals including rats and shrews (Johnson et al., 1977Johnson B.K. Chanas A.C. Shockley P. Squires E.J. Gardner P. Wallace C. Simpson D.I. Bowen E.T. Platt G.S. Way H. et al.Arbovirus isolations from, and serological studies on, wild and domestic vertebrates from Kano Plain, Kenya.Trans. R. Soc. Trop. Med. Hyg. 1977; 71: 512-517Abstract Full Text PDF PubMed Scopus (22) Google Scholar). In response to the ongoing epidemic, new ZIKV studies have been initiated in animals including rhesus macaques (https://zika.labkey.com/project/OConnor/ZIKV-001/begin.view). Until very recently, few studies had been performed in mice (Bell et al., 1971Bell T.M. Field E.J. Narang H.K. Zika virus infection of the central nervous system of mice.Arch. Gesamte Virusforsch. 1971; 35: 183-193Crossref PubMed Scopus (162) Google Scholar, Dick, 1952Dick G.W. Zika virus. II. Pathogenicity and physical properties.Trans. R. Soc. Trop. Med. Hyg. 1952; 46: 521-534Abstract Full Text PDF PubMed Scopus (434) Google Scholar, Way et al., 1976Way J.H. Bowen E.T. Platt G.S. Comparative studies of some African arboviruses in cell culture and in mice.J. Gen. Virol. 1976; 30: 123-130Crossref PubMed Scopus (49) Google Scholar). Although these early studies suggested that ZIKV can replicate and cause injury in cells of the central nervous system (CNS), it is uncertain whether this pathogenesis is related to ZIKV-induced neurodevelopmental defects or GBS in humans. Moreover, these studies used the prototype MR 766 strain of ZIKV, which had undergone extensive passage in suckling mouse brains, and to date no experiments have been reported in mice with more contemporary ZIKV isolates of greater clinical relevance. To address this fundamental gap in knowledge, we evaluated ZIKV infection and disease in wild-type (WT) C57BL/6 mice, as well as a large panel of immune-deficient transgenic mice, using several strains of ZIKV including a contemporary clinical isolate. Whereas 4- to 6-week-old WT mice did not develop clinically apparent disease, mice lacking interferon α/β (IFN-α/β) signaling (i.e., Ifnar1−/− or Irf3−/− Irf5−/− Irf7−/− triple knockout [TKO] mice) succumbed to infection with different ZIKV strains. Viral burden analysis revealed that Ifnar1−/− but not WT mice sustained high levels of ZIKV in all tissues tested, including serum, spleen, brain, spinal cord, and testes. Our studies establish a mouse model of ZIKV pathogenesis with contemporary and historical virus strains that will be valuable for evaluating candidate vaccines and therapeutics as well as understanding the basic biology of ZIKV infection and disease. Small animal models of ZIKV pathogenesis are a key research priority in response to the ZIKV epidemic in Latin America and the Caribbean. Historical studies indicated that mice could be infected with ZIKV via intracerebral inoculation, but determining mechanisms of pathogenesis and evaluating candidate antivirals and vaccines requires more clinically relevant inoculation routes and validation with contemporary ZIKV strains. We tested 5- to 6-week-old WT C57BL/6 mice as well as congenic transgenic mice lacking key components of innate antiviral immunity (Ifnar1−/−, Mavs−/−, Irf3−/−, Irf3−/− Irf5−/− Irf7−/− TKO) for susceptibility to disease induced by a contemporary human isolate of ZIKV (H/PF/2013) from French Polynesia, as well as the original ZIKV strain, MR 766 (Figures 1A–1D). Ifnar1−/− mice (which cannot respond to IFN-α/β) and Irf3−/− Irf5−/− Irf7−/− TKO mice (which produce almost no IFN-α/β) (Lazear et al., 2013Lazear H.M. Lancaster A. Wilkins C. Suthar M.S. Huang A. Vick S.C. Clepper L. Thackray L. Brassil M.M. Virgin H.W. et al.IRF-3, IRF-5, and IRF-7 coordinately regulate the type I IFN response in myeloid dendritic cells downstream of MAVS signaling.PLoS Pathog. 2013; 9: e1003118Crossref PubMed Scopus (205) Google Scholar) were highly vulnerable to ZIKV infection. Both strains of mice began to lose weight by 5 days after infection, and by day 7, when they began to succumb to infection, they had lost between 15% and 25% of their starting body weight. Ifnar1−/− and Irf3−/− Irf5−/− Irf7−/− TKO mice both exhibited 100% lethality by 10 days after infection with ZIKV (H/PF/2013). Ifnar1−/− and Irf3−/− Irf5−/− Irf7−/− TKO mice all developed neurological disease signs including hindlimb weakness and paralysis before succumbing to the infection (Figures 2A and 2B ). In comparison, WT mice or those lacking the signaling adaptor MAVS or the transcription factor IRF-3 (both of which play key roles in IFN-α/β induction) exhibited no weight loss, morbidity, or mortality. We saw a similar pattern of ZIKV susceptibility when WT, Ifnar1−/−, and Irf3−/− Irf5−/− Irf7−/− TKO mice were infected via an intravenous route, rather than a subcutaneous one (Figures 1E and 1F and Figure 2C).Figure 2ZIKV Infection Produces Neurologic Disease in Ifnar1−/− and Irf3−/− Irf5−/− Irf7−/− TKO MiceShow full caption(A–C) Mice of the indicated genotypes were infected with ZIKV strain H/PF/2013 (A) or MR 766 (B) by a subcutaneous (s.c.) (A and B) or intravenous (C) route, and disease signs were assessed daily for 10 days. The percentage of each group of mice displaying the indicated signs is shown. These are the same mice evaluated for weight loss and lethality in Figure 1.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A–C) Mice of the indicated genotypes were infected with ZIKV strain H/PF/2013 (A) or MR 766 (B) by a subcutaneous (s.c.) (A and B) or intravenous (C) route, and disease signs were assessed daily for 10 days. The percentage of each group of mice displaying the indicated signs is shown. These are the same mice evaluated for weight loss and lethality in Figure 1. Irf3−/− Irf5−/− Irf7−/− TKO mice were more susceptible to ZIKV infection than Ifnar1−/− mice following intravenous inoculation (p < 0.05 for H/PF/2013, p < 0.001 for MR 766), which suggests a possible role for IRF-3-dependent, IFN-α/β-independent restriction mechanisms (Lazear et al., 2013Lazear H.M. Lancaster A. Wilkins C. Suthar M.S. Huang A. Vick S.C. Clepper L. Thackray L. Brassil M.M. Virgin H.W. et al.IRF-3, IRF-5, and IRF-7 coordinately regulate the type I IFN response in myeloid dendritic cells downstream of MAVS signaling.PLoS Pathog. 2013; 9: e1003118Crossref PubMed Scopus (205) Google Scholar). ZIKV H/PF/2013 was more pathogenic than the original Ugandan strain, as 20% or 60% of Ifnar1−/− mice survived infection with MR 766 (by subcutaneous or intravenous inoculation, respectively) compared to 100% lethality after H/PF/2013 infection (p < 0.001 for subcutaneous, p < 0.0001 for intravenous). Although Ifnar1−/− and Irf3−/− Irf5−/− Irf7−/− TKO mice can be used as models to evaluate, for example, activity of candidate antivirals against ZIKV in vivo, there are limitations to pathogenesis studies in mice lacking a critical component of innate antiviral immunity. We selected three additional ZIKV strains for further characterization and corroboration: Dakar 41671, 41667, and 41519. These viruses were isolated in the 1980s from mosquitoes in the same area of Senegal. We evaluated different infection conditions (i.e., viral strain, inoculation route, mouse age, or mouse genotype) with the goal of identifying a more immunocompetent mouse system that was susceptible to ZIKV disease (Table 1). None of these conditions resulted in lethal ZIKV disease in an adult mouse, though larger group sizes would be necessary to detect infrequent disease presentations. In addition to WT and Ifnar1−/− mice, we evaluated infection in CD-1 mice (an outbred mouse line) and Irf5−/− mice, infecting 4-week-old mice with 103 focus-forming units (FFU) of each of the ZIKV strains from Senegal. Whereas Ifnar1−/− mice lost weight rapidly and succumbed to the infection within 1 week, we observed no weight loss or mortality in WT, CD-1, or Irf5−/− mice (Figures 3A–3C). However, when we infected suckling WT mice (1 week old), we observed susceptibility to infection, with 5 of 15 mice succumbing within 24 days (Figure 3D). Taken together, these data suggest that although ZIKV can cause disease in WT mice, it does so in an age-dependent manner and likely is inefficient in the context of a robust innate immune response.Table 1ZIKV Infection in Different Strains of MiceMouseAge (weeks)ZIKV Strain (Dakar)Dose (FFU)RouteNumber infectedSurvival (%)WT4415191 × 103s.c.5100WT4416671 × 103s.c.5100WT4416711 × 103s.c.5100WT1415191 × 104i.p.1567CD-14415191 × 103s.c.5100CD-14416671 × 103s.c.5100CD-14416711 × 103s.c.5100AG1294415191 × 104s.c.50Ifnar1−/−4415191 × 103s.c.30Ifnar1−/−4416671 × 103s.c.20Ifnar1−/−4416711 × 103s.c.20Mavs−/−7415191 × 104s.c.8100Ifnlr1−/−4415191 × 104s.c.5100Irf3−/−8415191 × 104i.p.4100Irf3−/−8415191 × 104s.c.4100Irf5−/−4415191 × 104i.p.5100Irf5−/−4415195 × 104i.p.2100Irf5−/−4415191 × 104s.c.8100Irf5−/−4415191 × 103s.c.5100Irf5−/−4416671 × 103s.c.5100Irf5−/−4416711 × 103s.c.5100Ifit1−/−4415191 × 104s.c.5100Ifit2−/−4415191 × 104s.c.5100Ifitm3−/−4415191 × 104s.c.3100Isg15−/−4415191 × 104s.c.4100Isg15−/−6415191 × 104s.c.10100Ube1l−/−4415191 × 104s.c.5100Mb21d1−/− (cGas)4415191 × 104s.c.5100Mb21d1−/− x Tmem173−/− DKO4415191 × 104s.c.3100Tmem173−/− (STING)4415191 × 104s.c.5100s.c., subcutaneous route of inoculation; i.p., intraperitoneal route of inoculation. Open table in a new tab s.c., subcutaneous route of inoculation; i.p., intraperitoneal route of inoculation. We performed additional experiments to characterize ZIKV infection in older Ifnar1−/− mice to determine the possible utility of the model for vaccine studies. Whereas 4- to 6-week-old Ifnar1−/− mice succumb to infection by several strains of ZIKV, vaccine studies will require mice to be older at the time of viral challenge due to the timing of prime-boost regimens. To test whether older Ifnar1−/− mice remain vulnerable to ZIKV infection, we infected 3-, 4-, and 6-month-old Ifnar1−/− mice with 103 FFU of ZIKV (H/PF/2013) and monitored weight loss and lethality (Figure 4). Mice of all ages lost weight after ZIKV infection, with ∼30% of starting weight lost by 9 days after infection. Despite the significant weight loss, 40%–80% of mice ultimately survived infection. Since IFN-α/β signaling appears to have a key role in restricting ZIKV infection in mice, we tested whether treatment with an IFNAR1-blocking monoclonal antibody (MAR1-5A3) (Sheehan et al., 2006Sheehan K.C. Lai K.S. Dunn G.P. Bruce A.T. Diamond M.S. Heutel J.D. Dungo-Arthur C. Carrero J.A. White J.M. Hertzog P.J. Schreiber R.D. Blocking monoclonal antibodies specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection.J. Interferon Cytokine Res. 2006; 26: 804-819Crossref PubMed Scopus (187) Google Scholar) could render WT mice susceptible to ZIKV disease. This strategy might be valuable for vaccine studies, as it would allow immune responses to be elicited in immunocompetent mice with the possibility of enhancing infection at the time of viral challenge. In prior studies with WNV, a related neurotropic flavivirus, we showed that blockade of IFN-α/β signaling with MAR1-5A3 could recapitulate the susceptible phenotype of Ifnar1−/− mice (Pinto et al., 2011Pinto A.K. Daffis S. Brien J.D. Gainey M.D. Yokoyama W.M. Sheehan K.C. Murphy K.M. Schreiber R.D. Diamond M.S. A temporal role of type I interferon signaling in CD8+ T cell maturation during acute West Nile virus infection.PLoS Pathog. 2011; 7: e1002407Crossref PubMed Scopus (77) Google Scholar, Sheehan et al., 2015Sheehan K.C. Lazear H.M. Diamond M.S. Schreiber R.D. Selective Blockade of Interferon-α and -β Reveals Their Non-Redundant Functions in a Mouse Model of West Nile Virus Infection.PLoS ONE. 2015; 10: e0128636Go" @default.
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• W2327959547 title "A Mouse Model of Zika Virus Pathogenesis" @default.
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