Cell Host & Microbe
Previews Restriction of Zika Virus by Host Innate Immunity Xuping Xie,1 Chao Shan,1 and Pei-Yong Shi1,* 1Departments of Biochemistry & Molecular Biology and Pharmacology & Toxicology, and Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA *Correspondence:
[email protected] http://dx.doi.org/10.1016/j.chom.2016.04.019
Recent epidemics of Zika virus (ZIKV) have brought increasing concerns of heightened disease severity and neurotropism. In this issue of Cell Host & Microbe, Lazear et al. (2016) and Bayer et al. (2016) show that innate immunity can restrict ZIKV infection and disease development. Many flaviviruses are significant human pathogens, including dengue (DENV), yellow fever (YFV), Japanese encephalitis (JEV), West Nile (WNV), and tick-borne encephalitis viruses (TBEV). This lifethreatening list has recently expanded to include Zika virus (ZIKV), a flavivirus known for 70 years. Remarkably, during the first 60 years after its discovery in 1947, there were only 13 naturally acquired ZIKV infections reported; the infections were associated with mild disease, such as fever, lethargy, rash, conjunctivitis, myalgia, and arthralgia (Petersen et al., 2016). Thus, it came as a great surprise that ZIKV has emerged explosively since 2007 to cause frequent epidemics, recently with millions of human infections in the Americas. Of great concern is the increase in disease severity associated with the recent ZIKV epidemics, including Guillain–Barre´ syndrome, congenital microcephaly, and ocular anomalies, among which microcephaly is the most striking and has never been observed in any other flavivirus infections. Like DENV, YFV, and chikungunya virus (an emerging alphavirus), ZIKV is mainly transmitted by Aedes spp. mosquitoes; it can also be transmitted through sex, blood transfusion, organ transplantation, and potentially urine or saliva. Immune compromised individuals are more susceptible to ZIKV infection and development of severe disease (Shan et al., 2016). It is currently not known what has triggered the surge of recent epidemics and severe disease. Several non-exclusive mechanisms could be envisioned. For example, the current epidemic ZIKV has accumulated mutations that may increase viral fitness for mosquito transmission in the known vector (e.g., A, aegypti) and possibly expand its transmission by previously unknown vectors. The current virus may have also evolved changes
that could enhance viral replication and/ or more efficiently antagonize host immune response, leading to higher virus production and severer disease. Additionally, the current epidemic is likely caused by ZIKV infection in an immune naive population. To test these hypotheses, we need to develop experimental systems for mosquito transmission and viral pathogenesis. This issue of Cell Host & Microbe presents two elegant studies: one on ZIKV mouse model (Lazear et al., 2016) and another on placental restriction of ZIKV infection (Bayer et al., 2016). Both studies underscore the importance of innate immunity in modulating ZIKV infection and disease outcome. For ZIKV animal models, Michael Diamond’s team reports that Ifnar1 / mice lacking interferon a/b receptor and Irf3 / Irf5 / Irf7 / triple knockout (TKO) mice lacking transcription factors involved in interferon induction develop neurological disease and succumb to ZIKV infection, whereas wild-type and single Irf3 / , Irf7 / , and Mavs / mice did not show overt illness (Figure 1A) (Lazear et al., 2016). Since both Ifnar1 / and Irf3 / Irf5 / Irf7 / TKO mice lack the ability to induce and respond to IFN-a/b, the results indicate that ZIKV is incompetent in antagonizing murine innate immune response efficiently. A similar animal model—AG129 mice (lacking Ifnar1 and Ifngr1)—was previously developed for DENV research (Shresta et al., 2004). Several features of the current ZIKV Ifnar1 / mouse model are worth highlighting. (i) The infected mice develop high levels of ZIKV infection in the brain, spinal cord, and testes, which is relevant to human Guillain–Barre´ syndrome, congenital infection/microcephaly, and sexual transmission. (ii) Persistent ZIKV infection was observed in the brain and testes at
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28 days post-infection in the Ifnar1 / mice, which warrants further investigations to define the infected cell types in these immune privileged sites and to study sexual transmission. (iii) Ifnar1 / mice up to 6 months old were susceptible to ZIKV infection and developed morbidity and mortality, indicating that the model would be useful for vaccine testing. The result of (iii) is slightly different from a recent report that only young, 3-week-old Ifnar1 / mice succumbed to illness, with older mice showing signs of illness without death (Rossi et al., 2016). The discrepancy is likely due to different virus strains and infection routes used in the two studies, emphasizing that standardized reagents and protocols should be used among different research groups so that results could be directly compared. Furthermore, the authors showed that treatment of wild-type mice with a monoclonal antibody against IFNAR1 conferred robust viremia upon ZIKV infection, despite the fact that the mice did not lose weight or succumb to infection. This protocol may be useful for vaccine testing in immunocompetent mice through immunizing wild-type animals with vaccine candidates, challenging with virulent ZIKV under antibody-mediated IFNAR1-blockage, and measuring viremia as an efficacy readout. Mounting evidence supports that ZIKV could evade immune protection of placenta and cause congenital microcephaly (Petersen et al., 2016). Placental trophoblasts form the interface between the maternal and fetal environment and protect developing embryos from pathogen infection. Carolyn Coyne and Yoel Sadovsky’s laboratories previously showed that primary human trophoblasts (PHTs) produce miRNAs (associated with the placenta-specific chromosome 19 miRNA cluster) that can attenuate viral
Cell Host & Microbe
Previews replication in recipient cells tion also contributes to microthrough induction of autocephaly? In addition, genetic phagy (Delorme-Axford et al., mutations in specific mole2013). In the current study cules synthesized by the early published in this issue, the placenta (i.e., CEP63, CASC5, same laboratories report a and MCPH1-12) have been second antiviral mechanism. casually linked to microEven in the absence of viral cephaly (Homem et al., 2015). infection, PHTs constitutively Does ZIKV infection affect the produce anti-viral type III expression of these genes durinterferon IFNl1 that reing pregnancy? Further clinical stricts ZIKV infection in an auand epidemiological studies, in tocrine and paracrine manner combination with studies using (Figure 1B). The release of animal models, are required to IFNl1 seems to be associated unravel the mechanism of ZIKV with the fusion event of PHTs pathogenesis and disease to form syncytiotrophoblasts. outcome. Cell lines derived from trophoREFERENCES blasts do not possess such antiviral properties. CompariBayer, A., Lennemann, N.J., son of the molecular activaOuyang, Y., Bramley, J.C., Morosky, tion between PHTs and its deS., Marques, E.T., Jr., Cherry, S., Sadovsky, Y., and Coyne, C.B. rivative cell lines may (2016). Cell Host Microbe 19, this illuminate the mechanism of issue, 705–712. IFNl1 production. InterestDelorme-Axford, E., Donker, R.B., ingly, no antiviral activity was Mouillet, J.F., Chu, T., Bayer, A., observed when cells containOuyang, Y., Wang, T., Stolz, D.B., Sarkar, S.N., Morelli, A.E., et al. ing established viral replica(2013). Proc. Natl. Acad. Sci. USA tion were treated with IFNl1, 110, 12048–12053. suggesting that ZIKV proHomem, C.C., Repic, M., and Knotein(s) may antagonize IFNl1 blich, J.A. (2015). Nat. Rev. Neurosignaling. This is not surprisFigure 1. Restriction of ZIKV Infection by Host Innate Immunity sci. 16, 647–659. / / / / (A) Ifnar1 mice and Irf3 Irf5 Irf7 TKO mice developed neurological ing because flaviviruses have Lazear, H.M., Govero, J., Smith, disease and succumbed to ZIKV infection. evolved distinct mechanisms A.M., Platt, D.J., Fernandez, E., (B) Human placental trophoblasts produce IFNl1 to protect trophoblast and to evade innate immune Miner, J.J., and Diamond, M.S. non-trophoblast cells from ZIKV infection. (2016). Cell Host Microbe 19, this response (Shi, 2014). For issue, 720–730. ZIKV, viral elements responPetersen, L.R., Jamieson, D.J., Powers, A.M., and sible for antagonizing IFN (including have occurred at 7–13 weeks of gestation, Honein, M.A. (2016). N. Engl. J. Med. 374, 1552– but in some cases the infection could occur IFNl1) signaling remain to be determined. 1563. Collectively, the results suggest that, to ac- as late as 18 weeks of gestation (Petersen cess the fetal compartment, ZIKV must et al., 2016). Since the current study used Rossi, S.L., Tesh, R.B., Azar, S.R., Muruato, A.E., Hanley, K.A., Auguste, A.J., Langsjoen, R.M., evade restriction by PHT-derived IFNl1 PHTs isolated from full-term placentas, Paessler, S., Vasilakis, N., and Weaver, S.C. or use an alternative strategy to cross the the temporal and spatial pattern of antiviral (2016). Am. J. Trop. Med. Hyg., 16-0111. placental barrier. In line with the latter hy- activity of PHTs remains to be investigated Shan, C., Xie, X., Barrett, A.D.T., Garcia-Blanco, pothesis, it is known that expression of at different stages of pregnancy. Besides M.A., Tesh, R.B., Vasconcelos, P.F.D.C., Vasilakis, the alpha subunit of the IFNl receptor is ZIKV, maternal infections with cytomegalo- N., Weaver, S.C., and Shi, P.Y. (2016). ACS Infectious Diseases 2, 170–172. restricted to epithelial-derived cells; there- virus or rubella virus could also lead to fore, PHT-released IFNl1 primarily acts on microcephaly. Cytomegalovirus infection Shi, P.Y. (2014). Cell Host Microbe 16, 269–271. the epithelial cells, leaving other cells (that causes placental chronic villitis or inflamShresta, S., Kyle, J.L., Snider, H.M., Basavapatna, lack IFNl receptor) venerable to ZIKV mation of the villi. The degree of placental M., Beatty, P.R., and Harris, E. (2004). J. Virol. 78, inflammation correlates with the severity 2701–2710. infection (Sommereyns et al., 2008). Most maternal ZIKV infections in of the fetal effects, including microcephaly. Sommereyns, C., Paul, S., Staeheli, P., and Michiwomen delivering microcephalic babies Does inflammation induced by ZIKV infec- els, T. (2008). PLoS Pathog. 4, e1000017.
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