RESUMEN
Zika virus (ZIKV) infection during pregnancy is associated with microcephaly, a congenital malformation resulting from neuroinflammation and direct effects of virus replication on the developing central nervous system (CNS). However, the exact changes in the affected CNS remain unknown. Here, we show by transcriptome analysis (at 48 h post-infection) and multiplex immune profiling that human induced-neuroprogenitor stem cells (hiNPCs) respond to ZIKV infection with a strong induction of type-I interferons (IFNs) and several type-I IFNs stimulated genes (ISGs), notably cytokines and the pro-apoptotic chemokines CXCL9 and CXCL10. By comparing the inflammatory profile induced by a ZIKV Brazilian strain with an ancestral strain isolated from Cambodia in 2010, we observed that the response magnitude differs among them. Compared to ZIKV/Cambodia, the experimental infection of hiNPCs with ZIKV/Brazil resulted in a diminished induction of ISGs and lower induction of several cytokines (IFN-α, IL-1α/ß, IL-6, IL-8, and IL-15), consequently favoring virus replication. From ZIKV-confirmed infant microcephaly cases, we detected a similar profile characterized by the presence of IFN-α, CXCL10, and CXCL9 in cerebrospinal fluid (CSF) samples collected after birth, evidencing a sustained CNS inflammation. Altogether, our data suggest that the CNS may be directly affected due to an unbalanced and chronic local inflammatory response, elicited by ZIKV infection, which contributes to damage to the fetal brain.
Asunto(s)
Sistema Nervioso Central/inmunología , Células Madre Pluripotentes Inducidas/citología , Microcefalia/inmunología , Células-Madre Neurales/citología , Virus Zika/inmunología , Brasil , Cambodia , Células Cultivadas , Sistema Nervioso Central/patología , Sistema Nervioso Central/virología , Quimiocina CXCL10/líquido cefalorraquídeo , Quimiocina CXCL10/inmunología , Quimiocina CXCL9/líquido cefalorraquídeo , Quimiocina CXCL9/inmunología , Citocinas/análisis , Femenino , Perfilación de la Expresión Génica , Humanos , Lactante , Inflamación/inmunología , Inflamación/patología , Interferón-alfa/líquido cefalorraquídeo , Interferón-alfa/inmunología , Interferón beta/inmunología , Masculino , Microcefalia/patología , Embarazo , Complicaciones Infecciosas del Embarazo/virología , Replicación Viral/inmunología , Infección por el Virus Zika/inmunologíaRESUMEN
Anti-Flavivirus antibodies are highly cross-reactive and may facilitate Zika virus (ZIKV) infection through the antibody-dependent enhancement (ADE) mechanism. We demonstrate that dengue-specific antibodies enhance the infection of a primary Brazilian ZIKV isolate in a FcγRII-expressing K562 cell line. In addition, we demonstrate that serum samples from dengue-immune pregnant women enhanced ZIKV infection. These findings highlight the need for epidemiological studies and animal models to further confirm the role of ADE in the development of congenital and neurological complications associated with ZIKV infections.