Since its introduction to Brazil in 2015, Zika virus (ZIKV), has caused an epidemic of fetal congenital malformations within the Americas. remains a controversial topic. In this review, Zimmerman et al. discuss the epidemiologic and experimental data highlighting the potential Rabbit Polyclonal to Catenin-alpha1 role of cross-reactive flavivirus antibodies on enhancement of systemic Dengue and Zika virus infection as well as Zika virus infection of the placenta. Introduction The family of positive-sense RNA viruses comprises a diverse group of mosquito-borne viruses (Dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV)) and tick-borne viruses (tick-borne encephalitis virus (TBEV)) responsible for a wide variety of clinical diseases in humans. DENV is usually a self-limiting, acute viral contamination responsible for approximately 50-100 million apparent and 300 million inapparent Pexidartinib (PLX3397) infections per year. DENV exists Pexidartinib (PLX3397) as four genetically distinct serotypes (DENV1-4) that co-circulate within endemic regions, including the tropics of Central and South America, sub-Saharan Africa, India, and Southeast Asia (Bhatt et al., 2013). Recent reports have detailed the increasing geographic distribution of DENV with the emergence of established autochthonous cases in the Mediterranean countries of Europe as well as the southern United States, including Florida and Texas (Fredericks and Fernandez-Sesma, 2014; Gossner et al., 2018). The major vectors for transmission of DENV are and chorionic villous explant studies. ZIKV was also found in Leydig cells and Sertoli cells of the male gonads as well as spermatogonia and semen in male subjects. ZIKV has been detected within the urine and saliva of non-human primates and humans. ZIKV also infects the retinal (bipolar neurons, ganglion cells, optic nerve) structures of the eye in mice and was found in the aqueous humor and tears in humans. ZIKV contamination has also been identified within the spleen. In this review, we will examine the virus-specific and cross-reactive antibody responses elicited during primary and secondary DENV and ZIKV contamination. We also highlight studies which provide evidence for and against the role of cross-reactive antibody-mediated enhancement of flavivirus contamination observed through human epidemiologic studies and animal model systems. We also expand upon a non-canonical mechanism of cross-reactive antibodies that appear to facilitate vertical transmission of ZIKV contamination across the placental barrier. Finally, we explore recent advances in vaccines and biologic therapeutics designed to protect against ZIKV contamination. Human antibody responses to DENV and ZIKV Upon contamination, the flavivirus positive-sense RNA genome is usually directly translated into a single polyprotein and post-translationally cleaved to generate three structural proteins, capsid (C), pre-membrane (prM), and envelope (E) and seven nonstructural Pexidartinib (PLX3397) proteins, NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5. The non-structural proteins function as the replication complicated to synthesize viral RNA aswell as comprise auxiliary features to antagonize sponsor innate immune system signaling pathways. The structural genes comprise the viral particle, which E and prM protein allow for connection to mobile receptors, facilitating viral entry and fusion in to the cell. Due to the outward orientation of E on adult viral particles, contaminated hosts generate an antibody (Ab) response Pexidartinib (PLX3397) to the proteins to neutralize the disease (Rodenhuis-Zybert et al., 2015). Major disease with DENV produces a powerful Ab response focusing on the E site I (EDI), EDII, and EDIII of the initial DENV serotype with reduced cross-reactivity to heterologous serotypes. EDI/EDII-specific Abs, including types focusing on the EDII fusion loop, comprise most the response but screen poor neutralizing activity as the EDIII-specific Abs, although reduced quantity, show excellent neutralization activity (Beltramello et al., 2010; Smit and Flipse, 2015). These cross-reactive, badly neutralizing DENV Abs made by major DENV infection have already been implicated in antibody-dependent improvement (ADE) and Pexidartinib (PLX3397) serious dengue instances during supplementary DENV disease (Guzman and Harris, 2015). Highly neutralizing Abs had been found to focus on the complicated quaternary epitopes spanning multiple domains across adjacent E proteins dimers (Beltramello et al., 2010; de Alwis et al., 2011). In another scholarly study, depletion of E-protein particular antibodies from major DENV-3-defense and DENV-2 sera with entire DENV-2.